Clinical trial NCT04831281
Conditions: Parkinson Disease Dementia Dementia With Lewy Bodies
Keywords: Parkinson's Disease Dementia Dementia with Lewy Bodies Dementia HGF/MET Hepatocyte Growth Factor Neurotrophic ATH-1017 Event-Related Potential ERP P300
Sponsor: Athira Pharma
Start date: 2022-01-20; Completion date: 2023-04-19
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the safety and treatment effects of fosgonimeton (ATH-1017) in subjects with Parkinson's Disease Dementia or Dementia with Lewy Bodies, with a randomized treatment duration of 26 weeks.

Detailed description:
The study is designed to evaluate the safety and treatment effects of ATH-1017 in subjects with Parkinson's Disease Dementia or Dementia with Lewy Bodies, with a randomized, double-blind, placebo-controlled, parallel-arm treatment duration of 26 weeks.

Arms: arm 1: Daily subcutaneous injection of 40mg ATH-1017 arm 2: Daily subcutaneous injection of 70mg ATH-1017 arm 3: Daily subcutaneous injection of Placebo
Interventions: intervention 1: ATH-1017 intervention 2: Placebo
Intervention descriptions: intervention 1: Daily subcutaneous injection of ATH-1017 in a pre-filled syringe intervention 2: Daily subcutaneous injection of Placebo in a pre-filled syringe

Protocol documents:
Prot_000.pdf: 
Athira Pharma, Inc.  
Protocol ATH-1017-PD-0201  
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 3.00 
 Page 1 of 86 
05-NOV-2021 
 
CLINICAL STUDY PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017 Treatment in 
Subjects with Parkinson’s Disease Dementia or Dementia with Lewy Bodies 
 
Sponsor: 
Athira Pharma, Inc. 
18706 North Creek Parkway 
Suite 104 
Bothell, WA 98011 
USA 
Protocol No.: 
ATH-1017-PD-0201 
IND No.: 
141768 
Investigational Medicinal Product (IMP) 
Name: 
ATH-1017 
Development Phase: 
Phase 2 
Emergency Telephone Number: 
(Refer to the study contacts page) 
SAE Reporting FAX Number/Email: 
 
  
Date of Final Protocol: 
05-NOV-2021 
Version: 
3.00 
 
 
This clinical study will be conducted in accordance with the International Council for 
Harmonisation Tripartite Guideline for Good Clinical Practice (GCP) (E6), the protocol and with 
other applicable regulatory requirements. 
 
Confidentiality Statement 
This document contains confidential information of Athira Pharma, Inc. 
Do not copy or distribute without written permission from the Sponsor. 
 




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Protocol ATH-1017-PD-0201  
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SIGNATURE PAGE – INVESTIGATOR  
Declaration of the Principal Investigator 
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017 
Treatment in Subjects with Parkinson’s Disease Dementia or Dementia with Lewy Bodies 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal 
product (IMP), as well as with the moral, ethical, and scientific principles governing clinical 
research in accordance with the International Council for Harmonisation Tripartite Guideline for 
Good Clinical Practice (GCP) (E6 R2), the ethical principles outlined in the Declaration of 
Helsinki, the protocol and with other applicable regulatory requirements applicable to this 
clinical study. 
 
Principal Investigator 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with International Council for Harmonisation Tripartite Guideline for 
Good Clinical Practice (GCP) (E6 R2), the ethical principles outlined in the Declaration of 
Helsinki and with other regulatory requirements applicable to this clinical study. 
I agree that the Sponsor or its representatives shall have access to any source documents from 
which case report form information may have been generated. 
I further agree not to originate or use the name Athira Pharma Inc. and/or ATH-1017 in any 
publicity, news release, or other public announcement, written or oral, whether to the public, 
press, or otherwise, relating to this protocol, to any amendment hereto, or to the performance 
hereunder, without prior written consent of Athira Pharma Inc. 
 
 
Signature of Site Principal Investigator 
 
 
Date (dd mmm yyyy) 
Printed Name of Site Principal Investigator 
 
Institution 
Name:__________________________ 
 
 
 
 
 
 
 
 
 






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Protocol ATH-1017-PD-0201  
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Version 3.00 
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PROTOCOL SYNOPSIS 
Protocol Title: 
A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017 Treatment in 
Subjects with Parkinson’s Disease Dementia or Dementia with Lewy Bodies 
Study Number: 
ATH-1017-PD-0201 
Development Phase: 
Phase 2 
Sponsor: 
Athira Pharma, Inc. 
Type of Study 
Interventional 
Study Centers: 
The study will be conducted at a total of approximately 15 centers in the USA  
Study Objectives and 
Endpoints: 
 
Primary Objectives 
Primary Endpoints 
To evaluate the clinical effects of 
ATH-1017 in subjects with 
Parkinson’s disease dementia 
(PDD) or dementia with Lewy 
bodies (DLB) 
 
The Global Statistical Test (GST) (O’Brien, 
1984) that combines the scores from cognition 
(Alzheimer’s Disease Assessment Scale-
Cognitive Subscale 13-item version 
[ADASCog13]) and event-related potential 
(ERP) P300 latency, change from baseline at 
Week 26 compared to placebo  
To determine the safety and 
tolerability of ATH-1017 in 
subjects with PDD or DLB 
Analysis of adverse events (AEs), including 
injection site AEs; changes from baseline for 
the following variables: vital signs, 12-lead 
electrocardiogram (ECG), and laboratory tests 
(chemistry, hematology, urinalysis); 
concomitant medication assessments, physical 
and neurological exams, Columbia-Suicide 
Severity Rating Scale (C-SSRS), and Geriatric 
Depression Scale (GDS) 
Secondary Objectives 
Secondary Endpoints 
To evaluate the clinical effects of 
ATH-1017 separately on: 
(1) cognition and 
(2) ERP P300 latency 
• 
ADAS-Cog13 score: change from baseline 
at Weeks 2, 12, 20, and 26 compared to 
placebo 
• 
ERP P300 latency: change from baseline 
at Weeks 2, 12, and 26 compared to 
placebo 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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Study Design: 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, dose-ranging study comparing ATH-1017 40 mg/day and ATH-1017 
70 mg/day with placebo in subjects with a clinical diagnosis of PDD or DLB (Postuma, 
2015; Emre, 2007; McKeith, 2017) and with a Montreal Cognitive Assessment 
(MOCA) score of 11 to 23 at Screening (see Figure 1 for a diagram of the study 
schema). The study will be conducted at a total of approximately 15 centers in the 
USA. Subjects and their caregivers will be required to sign an informed consent form 
(ICF) and will be evaluated against the inclusion/exclusion criteria during a screening 
period; all eligible subjects will have the option to be tested for glucocerebrosidase 
(GBA) genotype. Subjects who meet all inclusion/exclusion criteria will undergo 
baseline ERP P300 assessments at 2 separate baseline visits. At the first baseline 
assessment (Visit 2a, Pre-baseline, Day -10 to Day -3), ERP P300 data shall be 
uploaded for quality check immediately after completion of the visit. At the second 


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baseline visit (Visit 2b, Baseline, Day 1), no more than 10 days after the Pre-baseline 
visit, eligible subjects will be randomized in a ratio of 1:1:1 to receive ATH-1017 
40 mg/day, ATH-1017 70 mg/day, or placebo. At this Baseline visit (Visit 2b), subjects 
will undergo pre-dose baseline and post-dose ERP P300. 
Study drug will be administered by subcutaneous (SC) injection once-daily (OD) 
preferably during daytime; subjects must not take another dose within 8 hours of the 
preceding dose. The first SC injection of study drug will be performed on site under 
supervision. The subject should withhold study drug administration on the day of 
subsequent clinic visits; study drug administration will be done on site under 
supervision of site staff at these visits. Each subject is required to have a primary 
caregiver willing to accept responsibility for supervising or, if required, administering 
study drug, and assessing the condition of the subject throughout the study in 
accordance with all protocol requirements. During the double-blind treatment period, 
clinic visits will take place on Day 1 and thereafter at Weeks 2, 6, 12, 16, 20, and 26, 
with a safety follow-up visit scheduled 4 weeks after completion of the double-blind 
period at Week 30 (see Table 1 for Schedule of Assessments). On Day 1, after 
completion of the first dose, subjects will remain on-site for 2 hours for post-treatment 
clinical observation. 
 ADAS-Cog13, 
 
 assessments shall occur at 
clinic visits in the morning at approximately the same time they were performed during 
the initial baseline assessment (Visit 2b). Subjects will undergo post-baseline ERP 
P300 at clinic visits (pre- and/or post-dose timepoints) as specified in Table 1. 
Subjects may live at home, in a senior residential setting, or an institutional setting 
without the need for continuous nursing care, and should not be likely to experience a 
change in living conditions (e.g., institutionalization, moving to a different city, etc.), 
or change in primary caregiver, during participation in the trial period. The end of the 
study is defined as the date of the safety follow-up visit, Visit 9/Week 30. Subjects 
who terminate prior to Visit 8 are to complete the same assessments as Visit 8/early 
termination (ET). 
Blood draws will take place at scheduled clinic visits for analysis of plasma 
concentrations of ATH-1017 (pro-drug) and ATH-1001 (DFWLYH PHWDEROLWH). 
Treatments 
Administered: 
Subjects will be randomized to one of 3 treatment groups: 
•
ATH-1017, 40 mg, OD, SC
•
ATH-1017, 70 mg, OD, SC
•
Placebo, OD, SC
An interim analysis of pharmacodynamics (ERP P300 latency) and safety is planned 
for when at least 30 subjects have completed their Week 2 assessment. Subjects 
subsequently recruited may be randomized to only 1 of the 2 doses of ATH-1017 
(either 40 mg or 70 mg, OD, SC) in a 2:1 ratio (ATH-1017:placebo); subjects already 
enrolled in the study will continue on their treatment as originally assigned. All 
personnel involved in the management and conduct of the study will remain blinded to 
dose assignments. 
Investigational 
Medicinal Products: 
Active Treatment: ATH-1017 will be presented in identical prefilled 1 mL syringes of 
40 mg/mL and 70 mg/mL 
Placebo: Placebo prefilled 1 mL syringes matching active treatment 
Number of Subjects: 
The study will randomize approximately 75 subjects in a 1:1:1 ratio to either 
ATH-1017 40 mg, ATH-1017 70 mg, or placebo  


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Duration of 
Treatment: 
The study will consist of up to 28 days of screening (Day -32 through Day -4) and a 
Pre-baseline period of up to 8 days (Day -10 to Day -3), 26 weeks of double-blind 
treatment, and a 4-week safety follow-up. Note: if 28 days is not sufficient to complete 
the screening period, an extension can be discussed with the Medical Monitor. 
Study Population: 
Inclusion 
1. 
Age 40 to 85 years, inclusive at the time of signing the informed consent. 
2. 
Subjects with a confirmed diagnosis of PDD (Emre, 2007), or DLB (McKeith, 
2017), preferably documented by subject medical records; caregiver reports with 
examples are acceptable. 
3. 
MOCA score 11 to 23 inclusive at the Screening visit. 
4. 
Body mass index of EHWZHHQ   DQG  5 kg/m2 for females and between  18 
DQG  35 kg/m2 for males at Screening. 
5. 
Female subjects of child-bearing potential must not be pregnant (i.e., a negative 
urine pregnancy result is required prior to randomization) and must not be 
breastfeeding. 
6. 
Male and female subjects of child-bearing potential and their partners must agree 
to use a double-barrier method of contraception during the study, including the 
follow-up period, unless the partner is not of childbearing potential. Female 
subjects of non-childbearing potential (i.e., permanently sterilized, 
postmenopausal) are eligible for participation. 
7. 
Reliable and capable support person/caregiver, who is willing to accept 
responsibility for supervising the treatment or, if required, administering study 
drug, and assessing the condition of the subject throughout the study in 
accordance with all protocol requirements. The support person/caregiver must 
see the subject at least once-daily for dose administration and/or observation.  
8. 
Subject capable of giving signed informed consent, which includes compliance 
with the requirements and restrictions listed in the ICF and in this protocol. If the 
subject is incapable of giving informed consent in the judgment of the 
investigator then consent may be provided by a legally acceptable representative. 
9. 
Written informed consent from a) the subject or legally acceptable representative 
and b) caregiver/support person has been obtained prior to any study-related 
procedures, including prior to initiating screening procedures to evaluate 
eligibility for the study. 
10. Written documentation has been obtained in accordance with the relevant country 
and local privacy requirements, where applicable (e.g., Written Authorization for 
Use and Release of Health and Research Study Information). 
11. Subjects and caregivers/support persons are able, as assessed by the investigator, 
and willing to follow study instructions and likely to complete all required study 
visits. 
12. Subjects must be in generally good health as assessed by the investigator from 
medical history and physical/neurological examination, vital signs, ECG, and 
standard laboratory tests. 


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Exclusion 
1. 
Subjects at modified Hoehn-Yahr stage 5. 
2. 
History of significant neurological disease other than PDD or DLB that may 
affect cognition, or concurrent neurological disease diagnosed at the time of 
onset of dementia. 
3. 
Subject has had neurosurgical procedure for treatment of PD (such as deep brain 
stimulation implant), or if such procedure is anticipated or planned during the 
study period. 
4. 
History of brain MRI scan indicative of any other significant abnormality, which 
would explain a dementing process other than PDD or DLB. Note: a new MRI 
scan is required if not done at or since the initial diagnosis of PD; a repeat MRI 
scan is required if there have been intervening changes to the subject’s clinical 
presentation in the past 12 months. CT scan is acceptable for subjects fitted with 
a non-MRI-safe cardiac pacemaker, or other relevant medical reason, with 
Medical Monitor approval. 
5. 
History of unexplained loss of consciousness, or epileptic fits (unless febrile). 
6. 
Inability to hear or differentiate the 2 different tones necessary for auditory ERP 
P300 assessment, using the centrally provided ERP equipment; subjects who 
wear a hearing aid must remove their hearing aid during the screening auditory 
test and during ERP P300 recordings. 
7. 
Diagnosis with current symptoms of severe major depressive disorder (GDS 
score [15-item scale] > 7 at Screening). In discussion with the Medical Monitor, 
subjects with a GDS score between 8 and 10 inclusive can be considered for 
study participation if the increased score is driven by specific domains related to 
the pandemic and its restrictions, rather than by major depression. 
8. 
Significant suicide risk as defined by suicidal ideation based on the C-SSRS 
within the last 12 months, at Screening and on Day 1 (i.e., a ‘yes’ response to 
Question 4 or 5, or any specific behaviors). 
9. 
Significant psychosis (according to the Diagnostic and Statistical Manual of 
Mental Disorders [5th ed.; DSM-5; American Psychiatric Association, 2013]) 
interfering with the ability of the subject to complete study procedures in the 
judgment of the investigator, for reasons such as requirement to reduce 
previously stable dopaminergic therapy.  
10. Moderate or severe substance abuse disorder (according to DSM-5, American 
Psychiatric Association, 2013). 
11. Untreated conditions, including hypothyroidism, diabetes mellitus, hypo- or 
hypertension, if clinically relevant in the judgment of the investigator. If treated, 
must be stably treated and symptom-free for at least 2 months before Screening. 
12. Abnormal serum electrolytes (potassium, sodium, magnesium) of clinical 
significance. If treated, must be stably treated for at least 30 days before 
Screening. 
13. Active, acute, or chronic infectious disease of any type. 


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14. Myocardial infarction or unstable angina within the last 6 months or history of 
more than one myocardial infarction within 5 years before Screening. 
15. Clinically significant (in the judgment of the investigator) cardiac arrhythmia 
(including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: 
pacemaker is acceptable). 
16. Subject has either hypertension not controlled by anti-hypertensives (supine 
mean diastolic blood pressure > 95 mmHg from 3 sequential measurements), or 
symptomatic hypotension in the judgment of the investigator. 
17. Clinically significant ECG abnormality at Screening as judged by the 
investigator, including but not limited to a confirmed corrected QT interval using 
)ULGHULFLD¶V IRUPXOD 47F) YDOXH   PVHF IRU PDOHV DQG  470 msec for 
females. For QTcF readings that are borderline, and in those where the T and U 
waves are superimposed or connected, a manual reading should be considered to 
determine eligibility, in discussion with the Medical Monitor. In subjects with a 
QRS value > 120 msec, those with a QTcF value < 500 msec may be eligible 
following discussion with the Medical Monitor. 
18. Positive results of serology screening for hepatitis B (hepatitis B surface antigen 
[HBsAg]), hepatitis C (anti-hepatitis C virus [HCV] antibodies) or human 
immunodeficiency virus (HIV) (antibodies type 1 and 2); past history of positive 
results with hepatitis B or hepatitis C may be eligible if fully recovered and 
asymptomatic, following discussion with the Medical Monitor and prior approval 
is required. 
19. Chronic kidney disease with estimated glomerular filtration rate (eGFR) 
< 45 mL/min using the Cockcroft and Gault formula, with age, sex and weight 
considered; subjects with moderate to severe impairment (eGFR between 44 and 
30 mL/min, inclusive) may be eligible following discussion with the Medical 
Monitor and prior approval is required. 
20. Hepatic impairment with alanine aminotransferase or aspartate aminotransferase 
> 2 times the upper limit of normal, or Child-Pugh class B and C. 
21. Malignant tumor within 3 years before Screening, except for the following 
conditions that are stable in the judgment of the investigator: 
a) 
Adequately treated squamous and basal cell carcinoma, or squamous and 
basal cell carcinoma in situ 
b) 
Prostate carcinoma in situ 
c) 
Fully-excised (biopsy-proven) melanoma in-situ; Medical Monitor prior 
approval is required. 
22. Clinically significant (in the judgment of the investigator) unintentional weight 
loss within 12 months of Screening. 
23. The consumption of grapefruit or grapefruit-containing products is prohibited 
beginning 7 days prior to the first dose of study medication (Day 1) and during 
the study. 


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24. Food supplements and nutraceuticals with potential effects on cognition, such as 
Axona and medium-chain triglyceride, are prohibited beginning 7 days prior to 
the first dose of study medication (Day 1) and for the duration of the study. 
25. Tetrahydrocannabinol (THC) is prohibited beginning 4 weeks prior to the first 
dose of study medication (Day 1) and for the duration of the study. Cannabidiol 
(CBD) without THC is allowed but not on the clinical visit days, except for 
topical applications. 
26. Prohibited prior and concomitant medications are excluded within 4 weeks prior 
to Screening. All allowed medications should remain stable in terms of dose and 
regimen throughout the study; for medications affecting cognition, the doses 
should be stable for at least 4 weeks before Screening and throughout the study, 
unless otherwise noted. If the permissibility of a specific medication is in 
question, please contact the Medical Monitor prior to randomization (refer to 
Appendix 1: List of Prohibited Medications; note: this is not an exhaustive list): 
a) 
Selegiline and trihexyphenidyl in any form or dosage. 
b) 
Memantine in any form, combination, or dosage. 
c) 
Donepezil at 23 mg. 
d) 
Antipsychotics: low doses (in the judgment of the investigator) are allowed 
if the subject has received a stable dose before Screening. If these 
medications are taken on a PRN basis they should not be taken the morning 
before any cognitive testing. 
e) 
Tryptophan supplements. 
f) 
Tricyclic antidepressants, irreversible monoamine oxidase B inhibitors, and 
S-ketamine; all other antidepressants are allowed only if the subject has 
received a stable dose for at least 3 months before Screening. 
g) 
Anxiolytics at high doses; low doses of benzodiazepines are allowed in the 
judgment of the investigator, but not the night before any cognitive 
assessments. 
h) 
Sedative hypnotics; Zolpidem is allowed. 
i) 
Barbiturates (unless given in low doses for benign tremor) 
j) 
Nicotine therapy (including patches), varenicline (Chantix), or similar 
therapeutic agent. 
k) 
Peripherally acting drugs with effects on cholinergic neurotransmission, 
e.g., oxybutinin. Solifenacin is allowed if the subject has received a stable 
dose for at least 3 months before Screening. 
l) 
Systemic immunosuppressants if taken in clinically immunosuppressive 
doses in the judgment of the investigator; inhaled steroids, otics, 
opthalmologics, topical applications, and intra-articular injections are 
allowed. 
m) 
Antiepileptic medication. 
n) 
Chronic intake of opioid-containing analgesics; PRN use is allowed (but not 
within 72 hours before any cognitive assessment). 


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o) 
Sedating H1 antihistamines; non-sedating H1 antihistamines are allowed and 
preferred. 
p) 
Systemic moderate to strong cytochrome P450 3A4 inhibitors or inducers; 
topical applications are allowed. 
27. Current enrollment in an investigational drug or device study, or have 
participated in another clinical trial with an investigational drug within 4 weeks 
of Screening, or 5 half-lives, whichever is longer, or within 6 months of 
Screening if an investigational drug for PD or cognition impairment. 
28. Subject has known allergy to any component of the investigational medicinal 
product or an allergy to latex. 
29. The subject has a condition or is in a situation which, in the investigator’s 
opinion, may put the subject at significant risk, may confound the study results, 
or may interfere significantly with the subject’s compliance or participation in the 
study. 
Statistical Methods: 
General Statistical Methods and Types of Analysis:  
Clinical effect analyses will be based on the modified intent-to-treat (MITT) 
Population, consisting of all randomized subjects who took at least one dose of the 
study medication and who completed both an ADAS-Cog13 score and ERP P300 
latency assessment during Baseline and at least one post-baseline visit. 
The primary clinical effect endpoint is the GST (combining the ADAS-Cog13 score and 
the ERP P300 latency) change from baseline at Week 26 relative to the placebo group. 
The primary analysis will use a mixed model for repeated measures (MMRM) with 
change from baseline as the outcome variable, and terms for baseline, baseline by time 
interaction, and baseline by time by treatment interaction in the model. Additional 
terms will be included for GBA genotype, and site (with smaller sites grouped). Least 
squares means and treatment differences will be estimated from the MMRM model. 
An interim analysis of the ERP-P300 and safety data is planned when at least 
30 subjects have completed the Week 2 visit. 
Safety analyses will be based on the Safety Population consisting of all randomized 
subjects who received at least one dose of the study medication. All safety parameters 
will be summarized descriptively. 
Sample Size Considerations: 
A total sample size of 75 evaluable subjects (25 per treatment arm) was chosen 
empirically; no formal sample size calculation was applied. 


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Figure 1
Study Schema








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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL .............................................................................................. 1 
SIGNATURE PAGE – SPONSOR .............................................................................................. 2 
SIGNATURE PAGE – INVESTIGATOR.................................................................................. 3 
 
PROTOCOL SYNOPSIS ............................................................................................................. 6 
TABLE OF CONTENTS ........................................................................................................... 18 
LIST OF TABLES ...................................................................................................................... 21 
LIST OF FIGURES .................................................................................................................... 21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 22 
1 
INTRODUCTION ................................................................................................. 25 
1.1 
Background ......................................................................................................... 25 
1.2 
Rationale for the Clinical Study ......................................................................... 28 
1.3 
Risk-Benefit Assessment .................................................................................... 28 
2 
STUDY OBJECTIVES AND ENDPOINTS ....................................................... 30 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ......................................... 32 
3.1 
Justification for Study Design ............................................................................ 33 
3.2 
Justification for Dose .......................................................................................... 33 
4 
STUDY POPULATION ........................................................................................ 36 
4.1 
Number of Subjects ............................................................................................ 36 
4.2 
Inclusion Criteria ................................................................................................ 36 
4.3 
Exclusion Criteria ............................................................................................... 37 
4.4 
Caregiver / Support Person Eligibility and Responsibility ................................. 40 
4.5 
Screen Failures ................................................................................................... 41 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................. 43 
5.1 
Identity of the Medicinal Products ..................................................................... 43 
5.2 
Supply, Packaging, Labeling, and Storage ......................................................... 43 
5.3 
Drug Accountability, Dispensing, and Destruction ............................................ 43 
5.4 
Subject Identification and Randomization ......................................................... 44 
5.4.1 
Screening Numbers ..................................................................................... 44 
5.4.2 
Randomization Numbers ............................................................................. 44 
5.5 
Administration of Investigational Medicinal Products ....................................... 44 
5.6 
Compliance with Investigational Medicinal Products ........................................ 44 


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5.7 
Blinding and Breaking the Blind ........................................................................ 45 
5.8 
Stopping Criteria ................................................................................................ 45 
5.9 
Treatment of Overdose ....................................................................................... 46 
5.10 
Treatment after the End of the Study ................................................................. 46 
6 
VARIABLES AND METHODS OF ASSESSMENT ........................................ 47 
6.1 
Screening Assessments ....................................................................................... 47 
6.1.1 
Montreal Cognitive Assessment (MOCA) ................................................... 47 
6.2 
Clinical Effect Variables .................................................................................... 47 
6.2.1 
Cognitive Variables ..................................................................................... 47 
6.2.2 
Disease Condition ....................................................................................... 48 
6.3 
Pharmacodynamic Variables .............................................................................. 51 
6.4 
Safety Variables .................................................................................................. 52 
6.4.1 
Adverse Events ............................................................................................ 52 
6.4.2 
Pregnancy .................................................................................................... 59 
6.4.3 
Clinical Laboratory Assessments ................................................................ 59 
6.4.4 
Vital Signs ................................................................................................... 61 
6.4.5 
Weight .......................................................................................................... 61 
6.4.6 
12-Lead Electrocardiogram ........................................................................ 61 
6.4.7 
Physical and Neurological Examination ..................................................... 62 
6.4.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................... 62 
6.4.9 
Geriatric Depression Scale (GDS) .............................................................. 62 
 
 
6.6 
Genotyping ......................................................................................................... 63 
 
 
7 
STUDY CONDUCT .............................................................................................. 64 
7.1 
Schedule and Order of Assessments ................................................................... 64 
7.1.1 
Unscheduled Visit(s) ................................................................................... 65 
7.2 
Pandemic Response ............................................................................................ 65 
7.3 
Concomitant Medications and Treatments ......................................................... 66 
7.3.1 
Prohibited Treatments During the Study .................................................... 66 
7.3.2 
Permitted Treatments .................................................................................. 67 
7.3.3 
Other Restrictions ....................................................................................... 68 
7.4 
Subject Withdrawal ............................................................................................ 69 


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7.4.1 
Discontinuation of Study Treatment ............................................................ 69 
7.4.2 
Withdrawal from the Study .......................................................................... 69 
7.5 
Lost to Follow-up ............................................................................................... 70 
7.6 
Termination of the Clinical Study ...................................................................... 71 
8 
STATISTICAL METHODS ................................................................................. 72 
8.1 
Populations for Analysis ..................................................................................... 72 
8.1.1 
MITT population ......................................................................................... 72 
8.1.2 
Per protocol population .............................................................................. 72 
8.1.3 
Safety population ......................................................................................... 72 
8.2 
General Considerations ...................................................................................... 72 
8.3 
Clinical Effect Analyses ..................................................................................... 73 
8.3.1 
Primary Clinical Effect Analysis - GST ...................................................... 73 
8.3.2 
Secondary Analysis – ADAS-Cog13 and ERP P300 .................................... 73 
 
 
 
 
8.4 
Safety Summaries ............................................................................................... 73 
8.4.1 
Adverse Events ............................................................................................ 74 
8.4.2 
Laboratory parameters ............................................................................... 74 
8.4.3 
12-Lead Electrocardiogram ........................................................................ 74 
8.4.4 
Columbia-Suicide Severity Rating Scale ..................................................... 74 
8.4.5 
Geriatric Depression Scale ......................................................................... 74 
 
 
8.6 
Determination of Sample Size ............................................................................ 75 
8.7 
Interim Analysis ................................................................................................. 75 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ............................ 76 
9.1 
Data Quality Assurance ...................................................................................... 76 
9.2 
Access to Source Data/Documents ..................................................................... 77 
9.3 
Archiving Study Documents .............................................................................. 77 
9.4 
Good Clinical Practice ........................................................................................ 77 
9.5 
Financial Disclosure ........................................................................................... 78 
9.6 
Informed Consent ............................................................................................... 78 
9.7 
Protocol Approval and Amendment(s) ............................................................... 79 
9.8 
Confidentiality Data Protection .......................................................................... 79 


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9.9 
Publication Policy ............................................................................................... 79 
10 
REFERENCE LIST .............................................................................................. 81 
11 
APPENDICES ....................................................................................................... 84 
11.1 
Appendix 1: List of Prohibited Medications (Non-exhaustive Examples) ........ 84 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ............................................................................................ 15 
Table 2 
Identity of Investigational Products ............................................................................ 43 
Table 3 
Assessment of Relationship of Adverse Events to IMP/Study Procedure .................. 55 
Table 4 
Clinical Laboratory Assessments ................................................................................ 59 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema.............................................................................................................. 14 
Figure 2 
Mechanism of ATH-1017 ........................................................................................... 27 
Figure 3 
Dose selection based on PK-PD modeling ................................................................. 34 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
ADAS-Cog13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale, 13-item 
version 
 
 
 
AE 
Adverse event 
AKT 
Protein kinase B 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APP/PS1 
Amyloid precursor protein/presenilin 1 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CBC 
Complete blood count 
CBD 
Cannabidiol 
 
 
 
 
 
 
COVID-19 
Coronavirus disease – 2019 
 
 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CYP3A4 
Cytochrome P450 3A4 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
C-SSRS 
Columbia-suicide severity rating scale 
CT 
Computerized tomography 
DLB 
Dementia with Lewy bodies 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
eGFR 
Estimated glomerular filtration rate 
ERP 
Event-related potentials 


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ET 
Early termination 
FSH 
Follicle-stimulating hormone 
fT3 
Free tri-iodothyronine 
fT4 
Free thyroxine 
FWER 
Family-wise error rate 
GBA 
Glucocerebrosidase 
GCP 
Good Clinical Practice 
GDS 
Geriatric depression scale 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GST 
Global Statistical Test 
Hb1Ac 
Glycated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HGF 
Hepatic growth factor 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
LAR 
Legally authorized representative 
LBD 
Lewy body dementia 
LTP 
Long-term potentiation 
MAO-B 
Monoamine oxidase B 
MAPK 
Mitogen-activated protein kinase 
MCT 
Medium-chain triglyceride 
MDS-UPDRS 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale 
MET 
MET receptor tyrosine kinase 
mITT 
Modified intent-to-treat 
MMRM 
Mixed model for repeated measures 
 
 
MOCA 
Montreal Cognitive Assessment 
MRI 
Magnetic resonance imaging 


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NMDA 
N-methyl D-aspartate 
 
 
OD 
Once-daily 
OLEX 
Open-label extension 
P 
Phosphorylated 
PD 
Parkinson’s disease 
PDD 
Parkinson’s disease dementia 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic(s) 
PK-PD 
Pharmacokinetic-pharmacodynamic 
PKC 
Protein kinase C 
3/&Ȗ 
Phospholipase C-gamma 
PRN 
As needed 
PT 
Prothrombin time 
qEEG 
Quantitative electroencephalogram 
QTcF 
Corrected QT interval using Fridericia’s formula 
RAC1 
Ras-related C3 botulinum toxin substrate 1 
RAF 
Rapidly accelerated fibrosarcoma (protein) 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SOP 
Standard operating procedure 
STAT3 
Signal transducer and activator of transcription 3 
SUSAR 
Suspected unexpected serious adverse reaction 
THC 
Tetrahydrocannabinol 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US(A) 
United States (of America) 
VAS 
Visual analog scale 
WBC 
White blood cells 
 


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1 
INTRODUCTION 
ATH-1017 is an experimental treatment for dementia, including Alzheimer’s disease (AD) 
dementia, Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB). 
ATH-1017 is formulated as a sterile solution for subcutaneous (SC) injection. ATH-1017 is a 
prodrug, which is rapidly converted to the DFWLYH PHWDEROLWH ATH-1001 in the plasma after SC 
injection. ATH-1017 was developed as a water-soluble prodrug of ATH-1001 to allow SC 
dosing in aqueous vehicles. The DFWLYH PHWDEROLWH ATH-1001 acts as an agonist of the hepatic 
growth factor (HGF) receptor and its tyrosine kinase, MET in the brain. The HGF/MET system 
presents a new therapeutic target to treat neurodegeneration and restore cognitive function in 
AD, PDD, and DLB. 
1.1 
Background 
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by a movement 
disorder consisting of bradykinesia, rest tremor, and rigidity, along with postural instability, a 
range of other more-subtle motor features, and many non-motor features (Kalia, 2015). The 
clinical diagnosis of PD follows validated criteria (Postuma, 2015). Globally, PD prevalence 
ranges from 1 to 2 per 1000, and is increasing with age; 1% of the population over 60 years 
suffers from PD (Tysnes, 2017); the prevalence of PD has more than doubled between 1990 and 
2016 (Rocca, 2018). There is a significant correlation between quality of life scores and 
non-motor symptoms (Duncan, 2014). At least 75% of PD patients who survive for more than 
10 years will develop dementia. In addition, mild cognitive impairment (MCI) is common even 
at disease onset, and is associated with a shorter time to dementia (Aarsland, 2010a; Hely, 2008). 
At presentation, 25% of individuals with PD exhibit mild cognitive impairment (Aarsland, 
2010b) 
PD, PDD, and DLB have been grouped under an umbrella term referred to as Lewy body 
disorders (Lippa, 2007), characterized by Lewy body pathology at autopsy; however, there are 
no definite pathological criteria that separate PD, DLB, and PDD from each other (McKeith, 
2004). The earliest signs of DLB and PDD differ but reflect the same biological changes in the 
brain and over time they may develop similar symptoms, collectively known as Lewy body 
dementia (LBD) (McKeith, 2004; McKeith, 2017). In general, DLB and PDD are clinically 
distinguished by the sequence of their symptoms. If dementia occurs before, concurrently, or 
within 1 year of motor parkinsonism, DLB is diagnosed; if dementia occurs more than 1 year 
after an established PD diagnosis, then PDD is diagnosed (Emre, 2007).  
PDD and DLB are progressive disorders, following roughly the same stages as AD dementia, 
with considerable variability from patient to patient. Virtually every individual with PD 
experiences some degree of cognitive deficit, ranging from mild cognitive impairment to 
dementia. Patients diagnosed with PDD have a substantially reduced life expectancy compared 
to persons in the general population (Buter, 2008). 


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Current treatments for PDD are mostly derived from those utilized in AD, with cholinesterase 
inhibitors and Memantine being 2 of the main approaches, and in some cases in combination 
with antipsychotic drugs (Szeto, 2016). There are no treatments to slow or stop neuro-
degeneration, the main underlying condition contributing to progressive deterioration in 
dementia symptoms. 
Growing evidence suggests that complex central nervous system (CNS) disorders, like AD, 
PDD, and DLB are unlikely to be caused by a single route of pathology; they are likely the result 
of a multifactorial interplay related to genetics, age, and environment. Pharmacological 
stimulation of a critical neurotrophic factor system (HGF/MET) may stop neurodegeneration and 
promote neuro-regeneration. Neurotrophic factors represent a promising therapeutic target for 
the treatment of dementia caused by neurodegeneration, including AD, PDD, and DLB by 
protecting existing neurons, promoting synaptogenesis, stimulating neuronal growth, and 
inducing regenerative mechanisms. Pharmacological stimulation of neurotrophic systems has the 
potential to treat all stages of AD, PDD, and DLB by directly targeting neurodegeneration, 
improving cognition, and addressing multiple aspects of the disease, by decreasing inflammation 
and improving cerebral blood flow (Funakoshi, 2011). The therapeutic promise of neurotrophic 
factors in neurodegenerative disorders is hampered by the lack of efficient and non-invasive 
delivery to the brain. Gene therapy strategies, primarily using adeno-associated viral vectors, 
have been developed and clinically evaluated for therapeutic potential in AD and PDD patients. 
These strategies are largely hindered by challenges related to gene delivery and transduction with 
limited brain exposure, uncontrollable dose over long-term treatment, and potential immune 
complications (Piguet, 2017). Therefore, a small molecule approach capable of passing the blood 
brain barrier and entering all regions of the brain, presents a superior therapeutic strategy for 
targeting neurotrophic factors to treat neurodegenerative disorders.  
ATH-1017 represents a new approach to treat AD, PDD, and DLB in a systemic approach. The 
mechanism of action of ATH-1017 is augmentation of HGF function and facilitation of signal 
transduction through MET phosphorylation (Figure 2). 




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1.2 
Rationale for the Clinical Study 
The Sponsor has completed a Phase 1a/b study of ATH-1017 in which preliminary safety and 
tolerability, pharmacokinetics (PK), and pharmacodynamics based on quantitative 
electroencephalogram (qEEG) and event-related potentials (ERP P300) was established in young 
healthy and elderly healthy subjects, and elderly subjects with mild to moderate AD/MCI 
(Study NDX-1017-0101; see Sections 6.3.1.1 and 6.3.1.2 also). Quantitative EEG was employed 
in both preclinical and clinical studies providing a translatable biomarker of neuronal network 
activity, as a function of pharmacological intervention. The qEEG analysis, combined with 
pharmacokinetic-pharmacodynamic (PK-PD) modeling, and preclinical behavioral study results, 
have supported the identification of an active clinical dose range in humans (see Section 3.2). 
Additionally, in an ERP auditory oddball paradigm, ATH-1017 treatment in AD subjects 
significantly reduced ERP P300 latency after 8 days of treatment when compared to placebo 
(refer to the Investigator’s Brochure). This finding suggests ATH-1017 treatment has potential 
effects on cognitive processing and working memory access in AD. 
A Phase 2 study, ATH-1017-AD-0201, was subsequently initiated as a randomized, 
placebo-controlled, 26-week, multi-center trial, powered to provide primary evidence on the 
safety and efficacy of ATH-1017 at 2 dose levels (40 and 70 mg, SC, once daily [OD]) in the 
treatment of mild to moderate AD, followed by an optional open-label extension (OLEX) 
protocol. 
A second Phase 2 study, ATH-1017-AD-0202, was designed to provide evidence for the 
functional translational biomarker ERP P300 latency as being predictive of pro-cognitive effects 
induced by ATH-1017 therapy. In addition, the study will determine time to onset and degree of 
maintenance of P300 latency reduction over 26 weeks. Eligible subjects receive OD SC 
injections of ATH-1017 at 1 of 2 dose levels (40 mg or 70 mg) or placebo, over a 26-week 
double-blind period, followed by an optional OLEX protocol. 
This study (ATH-1017-PD-0201) is designed to demonstrate the effect of ATH-1017 on ERP 
P300 latency, as well as cognitive and functional effects in subjects with PDD or DLB, and to 
establish long-term safety information. Eligible participants will receive OD SC injections of 
ATH-1017 (40 mg or 70 mg) or placebo, over a 26-week double-blind period, followed by a 
4-week safety follow-up. 
1.3 
Risk-Benefit Assessment 
Whilst qEEG and ERP P300 results in humans are indicative of CNS penetration and target 
engagement, efficacy in subjects with PDD or DLB (in terms of cognitive, functional, or 
behavioral improvement) has not been established. Therefore, the benefits to study subjects of 
participating in this clinical trial are not yet known. 


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In clinical studies of ATH-1017, single SC administration of 2, 6, 20, 40, 60, and 90 mg in 
healthy young subjects, and multiple administration of 20, 40, 60, and 80 mg (SC, OD, over 
9 consecutive days) in healthy elderly subjects, and 40 mg (SC, OD, over 9 consecutive days) in 
AD subjects were safe and well tolerated. Injection site reactions included pain, pruritus, and/or 
erythema, were mild in nature, and resolved without specific therapy. A potential risk for 
hepatotoxicity identified in nonclinical studies has not been observed in human studies but will 
be closely monitored in this study. To date, no CNS-specific adverse events have been observed 
in humans. 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objectives 
Primary Endpoints 
To evaluate the clinical effects of 
ATH-1017 in subjects with PDD or 
DLB  
The Global Statistical Test (GST) (O’Brien, 1984) that 
combines the scores from cognition (Alzheimer’s 
Disease Assessment Scale-Cognitive Subscale 13-item 
version [ADASCog13]) and ERP P300 latency, change 
from baseline at Week 26 compared to placebo 
To determine the safety and 
tolerability of ATH-1017 in 
subjects with PDD or DLB 
Analysis of adverse events (AEs), including injection 
site AEs; changes from baseline for the following 
variables: vital signs, 12-lead electrocardiogram (ECG), 
and laboratory tests (chemistry, hematology, urinalysis); 
concomitant medication assessments, physical and 
neurological exams, Columbia-Suicide Severity Rating 
Scale (C-SSRS), and Geriatric Depression Scale (GDS) 
Secondary Objectives 
Secondary Endpoints 
To evaluate the clinical effects of 
ATH-1017 separately on: 
(1) cognition and 
(2) ERP P300 latency 
• 
ADAS-Cog13 score: change from baseline at 
Weeks 2, 12, 20, and 26 compared to placebo 
• 
ERP P300 latency: change from baseline at 
Weeks 2, 12, and 26 compared to placebo 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-ranging study comparing ATH-1017 40 mg/day and ATH-1017 70 mg/day with placebo in 
subjects with a clinical diagnosis of PDD or DLB (Postuma, 2015; Emre, 2007; McKeith, 2017), 
and with a Montreal Cognitive Assessment (MOCA) score of 11 to 23 at Screening (see Figure 1 
for a diagram of the study schema). The study will be conducted at a total of approximately 
15 centers in the USA. Subjects and their caregivers will be required to sign an informed consent 
form (ICF) and will be evaluated against the inclusion/exclusion criteria during a screening 
period; all eligible subjects will have the option to be tested for glucocerebrosidase (GBA) 
genotype. Subjects who meet all inclusion/exclusion criteria will undergo baseline ERP P300 
assessments at 2 separate baseline visits. At the first baseline assessment (Visit 2a, Pre-baseline, 
Day -10 to Day -3), ERP P300 data shall be uploaded for quality check immediately after 
completion of the visit. At the second baseline visit (Visit 2b, Baseline, Day 1), no more than 
10 days after the Pre-baseline visit, eligible subjects will be randomized in a ratio of 1:1:1 to 
receive ATH-1017 40 mg/day, ATH-1017 70 mg/day, or placebo. At this Baseline visit 
(Visit 2b), subjects will undergo pre-dose baseline and post-dose ERP P300. 
Study drug will be administered by SC injection OD preferably during daytime; subjects must 
not take another dose within 8 hours of the preceding dose. The first SC injection of study drug 
will be performed on site under supervision. The subject should withhold study drug 
administration on the day of subsequent clinic visits; study drug administration will be done on 
site under supervision of site staff at these visits. Each subject is required to have a primary 
caregiver willing to accept responsibility for supervising or, if required, administering study 
drug, and assessing the condition of the subject throughout the study in accordance with all 
protocol requirements. During the double-blind treatment period, clinic visits will take place on 
Day 1 and thereafter at Weeks 2, 6, 12, 16, 20, and 26, with a safety follow-up visit scheduled 
4 weeks after completion of the double-blind period at Week 30 (see Table 1 for Schedule of 
Assessments). On Day 1, after completion of the first dose, subjects will remain on-site for 
2 hours for post-treatment clinical observation. 
 ADAS-Cog13, and 
 assessments 
shall occur at clinic visits in the morning at approximately the same time they were performed 
during the initial baseline assessment (Visit 2b). Subjects will undergo post-baseline ERP P300 
assessments at clinic visits (pre- and/or post-dose timepoints) as specified in Table 1. 
Subjects may live at home, in a senior residential setting, or an institutional setting without the 
need for continuous nursing care, and should not be likely to experience a change in living 
conditions (e.g., institutionalization, moving to a different city, etc.), or change in primary 
caregiver, during participation in the trial period. The end of the study is defined as the date of 
the safety follow-up visit, Visit 9/Week 30. Subjects who terminate prior to Visit 8 are to 
complete the same assessments as Visit 8/early termination (ET). 


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Blood draws will take place at scheduled clinic visits for analysis of plasma concentrations of 
ATH-1017 (pro-drug) and ATH-1001 (DFWLYH PHWDEROLWH) (see Table 1 for Schedule of 
Assessments). 
3.1 
Justification for Study Design 
The study is designed as a safety and proof of concept study of ATH-1017 in PDD and DLB 
subjects using a double-blind, placebo-controlled, parallel-arm treatment duration of 26 weeks. 
The target population is based on clinical diagnostic criteria of PDD (Emre, 2007) or DLB 
(McKeith, 2017) in combination with severity assessments and the inclusion/exclusion criteria. 
Any rational assessment of cognitive change can only be performed using a double-blind, 
placebo-controlled, randomized study design. A study duration of 26 weeks is in keeping with 
the rivastigmine trial (Emre, 2004) that led to US FDA approval for the use of rivastigmine in 
PDD subjects. 
Clinical effects in the target patient population are assessed by improvement in cognition and 
global as well as functional variables comparing treatment to placebo. The GST combines the 
endpoints ADAS-Cog13 (i.e., cognition) and change in ERP P300 latency into a single primary 
endpoint, allowing an unbiased assessment of the overall treatment effects of ATH-1017 in this 
complex disorder. The inclusion of an additional assessment of ERP P300 at a pre-Baseline visit 
in addition to corresponding baseline assessments pre-dose at the Baseline/ Day 1 visit of the 
study is intended to reduce possible variability of the baseline measure for this functional 
variable. 
As well as providing pharmacodynamic data on the effect of ATH-1017 on ERP P300 latency in 
this patient population, this study will provide data on clinical effects using validated outcome 
scales for cognitive function, executive memory function, activities of daily living, motor 
function, and behavioral changes. 
The safety assessments for the study are generally accepted measures for ensuring safety of 
subjects during a double-blind clinical trial. In addition, subject safety will be closely monitored 
and stopping criteria implemented (see Section 5.8). 
The PK sampling schedule is considered appropriate given the information available. The 
rationale for dose selection is discussed in Section 3.2. 
3.2 
Justification for Dose 
The dose selection for this clinical study is based on safety, PK, and PK-PD modeling of 
ATH-1017’s treatment effect in nonclinical studies in animal models, a qEEG study in amyloid 
precursor protein/presenilin 1 (APP/PS1) mice, and the qEEG and ERP P300 results of a 
completed Phase 1a/b study. 
In the randomized placebo-controlled Phase 1a/b study (Study NDX-1017-0101), ATH-1017 
was evaluated for safety, PK, and pharmacodynamics in a total of 88 subjects (of whom 65 were 


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exposed to active study drug), including healthy young, healthy elderly, and AD subjects. 
ATH-1017 was evaluated over a wide dose range (2 to 90 mg) to understand the safety profile 
and pharmacodynamic effects based on qEEG and ERP assessment. The observed qEEG effects 
(i.e., gamma power induction) are thought to be linked to the mechanism of action of ATH-1017, 
indicative of CNS penetration and target engagement. PK-PD modeling has been employed to 
guide dose selection, considering data from a nonclinical qEEG study in APP/PS1 mice, 
nonclinical efficacy studies in animal models (i.e., scopolamine-induced amnesia in rat and aged 
dementia rat), and the Phase 1a/b human clinical study. The results were compared based on 
equivalent PK exposures to inform dose selection for further clinical studies.
As summarized in Figure 3, the active pharmacodynamic dose range in humans (20 to 90 mg) 
overlaps with exposures that lead to qEEG gamma induction as well as improved behavioral 
measures and regenerative effects in nonclinical studies. Higher doses in humans and animal 
efficacy studies have not been tested, therefore the upper limit of the pharmacodynamic dose 
range is not defined. The PK profile is highly consistent across multiple species including rat, 
mouse, dog, and human, further supporting the utility of PK-PD modeling in guiding dose 
selection. The use of qEEG as a translational biomarker to guide dose optimization in clinical
trials of ATH-1017 allowed for efficient selection of doses that fall within the cross-species 
pharmacodynamic dose range.
Figure 3
Dose selection based on PK-PD modeling
The doses selected for the proposed study are 40 mg (SC, OD) and 70 mg (SC, OD). Both the 
40 mg and 70 mg doses are covered by the current pharmacodynamic active dose range (20 mg 
to 90 mg) defined by human qEEG studies, while the upper boundary is not yet determined. 
Equivalent dose exposure levels (Cmax-based) have been tested in nonclinical studies and showed 


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positive qEEG effects and functional improvement. The safety and tolerability of both doses are 
supported by the Phase 1a/b results. The 40 mg dose has been evaluated in 8 healthy young 
subjects (SC, single dose; 6 active versus 2 placebo), 8 healthy elderly subjects (SC, OD, over 
9 days; 6 active versus 2 placebo), and 11 AD subjects (SC, OD, over 9 days; 7 active versus 
4 placebo), with consistent and dose-linear PK, and good safety across all 3 cohorts. The 
normalization of ERP P300 in AD subjects treated with 40 mg ATH-1017 suggests a 
treatment-dependent promotion of synaptic activity, and further suggests a therapeutic potential 
of ATH-1017 at the 40 mg dose level.  
In reference to the 40 mg dose, a high dose range is defined based on pharmacodynamics and 
safety, including dose levels between 60 mg and 90 mg. In the healthy subject single-dose 
studies, there was a dose-dependent increase in the qEEG signal (i.e., gamma power induction) 
across 20 mg and 90 mg. The most notable effects in gamma power induction were observed in 
the high dose groups including 60 mg (SC; 6 treated versus 2 placebo) and 90 mg (SC; 6 treated 
versus 2 placebo). The 90 mg dose demonstrated a statistically significant effect in the frontal 
area of the brain when compared to placebo (p< 0.05; n=6 treated versus n=6 placebo). In 
healthy elderly subject studies, the 80 mg dose was evaluated over 9 days (SC, OD; 4 active 
versus 1 placebo), with PK results in keeping with dose-linearity, and supportive safety data. The 
70 mg dose is therefore selected in reference to the high dose range defined as 60 mg to 90 mg. 
The selection of the 40 mg and 70 mg doses is supported by the 26-week Good Laboratory 
Practice (GLP) toxicology studies in rats and dogs.  
In summary, the selected doses of 40 mg and 70 mg cover the nonclinical effects and the clinical 
pharmacodynamic range, were well-tolerated in humans based on safety data from the 
Phase 1a/b study, and are covered by the 26-week GLP nonclinical toxicology studies in animals 
at equivalent doses (please refer to the ATH-1017 Investigator’s Brochure for further details). 
The doses of ATH-1017 used for evaluation of clinical effects and safety in this study will 
support selection of an appropriate dose for registration of ATH-1017 as a potential treatment for 
subjects with PDD or DLB). 


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4 
STUDY POPULATION 
All subjects must meet all the inclusion criteria and none of the exclusion criteria. 
Protocol exemptions related to enrollment criteria are only allowed with prior investigator, 
Medical Monitor, and Sponsor approval, supported by documented agreement from the IRB/IEC. 
4.1 
Number of Subjects 
The study will randomize approximately 75 subjects in a 1:1:1 ratio to ATH-1017 40 mg, 
ATH-1017 70 mg, and placebo groups. 
4.2 
Inclusion Criteria 
1. Age 40 to 85 years, inclusive at the time of signing the informed consent. 
2. Subjects with a confirmed diagnosis of PDD (Emre, 2007), or DLB (McKeith, 2017), 
preferably documented by subject medical records; caregiver reports with examples are 
acceptable. 
3. MOCA score 11 to 23 inclusive at the Screening visit. 
4. Body mass index (BMI) of EHWZHHQ   DQG   NJP2 for females and between   DQG
 35 kg/m2 for males at Screening. 
5. Female subjects of child-bearing potential must not be pregnant (i.e., a negative urine 
pregnancy result is required prior to randomization) and must not be breastfeeding. 
6. Male and female subjects of child-bearing potential and their partners must agree to use a 
double-barrier method of contraception during the study, including the follow-up period, 
unless the partner is not of childbearing potential. Female subjects of non-childbearing 
potential (i.e., permanently sterilized, postmenopausal) are eligible for participation. 
7. Reliable and capable support person/caregiver, who is willing to accept responsibility for 
supervising the treatment or, if required, administering study drug, and assessing the 
condition of the subject throughout the study in accordance with all protocol requirements. 
The support person/caregiver must see the subject at least once-daily for dose administration 
and/or observation. 
8. Subject capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. If the subject is incapable 
of giving informed consent in the judgment of the investigator then consent may be provided 
by a legally acceptable representative. 
9. Written informed consent from a) subject or legally acceptable representative and 
b) caregiver/support person has been obtained prior to any study-related procedures, 
including prior to initiating screening procedures to evaluate eligibility for the study. 


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10. Written documentation has been obtained in accordance with the relevant country and local 
privacy requirements, where applicable (e.g., Written Authorization for Use and Release of 
Health and Research Study Information). 
11. Subjects and caregivers/support persons are able, as assessed by the investigator, and willing 
to follow study instructions and likely to complete all required study visits. 
12. Subjects must be in generally good health as assessed by the investigator from medical 
history and physical/neurological examination, vital signs, ECG, and standard laboratory 
tests. 
4.3 
Exclusion Criteria 
1. Subjects at modified Hoehn-Yahr stage 5. 
2. History of significant neurologic disease, other than PDD or DLB that may affect cognition, 
or concurrent neurological disease diagnosed at the time of onset of dementia. 
3. Subject has had neurosurgical procedure for treatment of PD (such as deep brain stimulation 
implant), or if such procedure is anticipated or planned during the study period. 
4. History of brain magnetic resonance imaging (MRI) scan indicative of any other significant 
abnormality, which would explain a dementing process other than PDD or DLB. Note: a 
new MRI scan is required if not done at or since the initial diagnosis of PD; a repeat MRI 
scan is required if there have been intervening changes to the subject’s clinical presentation 
in the past 12 months. CT scan is acceptable for subjects fitted with a non-MRI-safe cardiac 
pacemaker, or other relevant medical reason, with Medical Monitor approval. 
5. History of unexplained loss of consciousness, or epileptic fits (unless febrile). 
6. Inability to hear or differentiate the 2 different tones necessary for auditory ERP P300 
assessment, using the centrally provided ERP equipment; subjects who wear a hearing aid 
must remove their hearing aid during the screening auditory test and during ERP P300 
recordings. 
7. Diagnosis with current symptoms of severe major depressive disorder (GDS score [15-item 
scale] > 7 at Screening). In discussion with the Medical Monitor, subjects with a GDS score 
between 8 and 10 inclusive can be considered for study participation if the increased score is 
driven by specific domains related to the pandemic and its restrictions, rather than by major 
depression. 
8. Significant suicide risk as defined by suicidal ideation based on the C-SSRS within the last 
12 months, at Screening and on Day 1 (i.e., a ‘yes’ response to Question 4 or 5, or any 
specific behaviors). 
9. Significant psychosis (according to the Diagnostic and Statistical Manual of Mental 
Disorders, [5th edition; DSM-5; American Psychiatric Association, 2013]) interfering with 


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the ability of the subject to complete study procedures in the judgment of the investigator, 
for reasons such as requirement to reduce previously stable dopaminergic therapy.  
10. Moderate or severe substance abuse disorder (according to DSM-5; American Psychiatric 
Association, 2013). 
11. Untreated conditions, including hypothyroidism, diabetes mellitus, hypo- or hypertension, if 
clinically relevant in the judgment of the investigator. If treated, must be stably treated and 
symptom-free for at least 2 months before Screening. 
12. Abnormal serum electrolytes (potassium, sodium, magnesium) of clinical significance. If 
treated, must be stably treated for at least 30 days before Screening. 
13. Active, acute, or chronic infectious disease of any type. 
14. Myocardial infarction or unstable angina within the last 6 months or history of more than 
one myocardial infarction within 5 years before Screening. 
15. Clinically significant (in the judgment of the investigator) cardiac arrhythmia (including 
atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: pacemaker is 
acceptable). 
16. Subject has either hypertension not controlled by anti-hypertensives (supine mean diastolic 
blood pressure > 95 mmHg from 3 sequential measurements), or symptomatic hypotension 
in the judgment of the investigator. 
17. Clinically significant ECG abnormality at Screening as judged by the investigator, including 
but not limited to a confirmed corrected QT interval using Fridericia’s formula (QTcF) value 
  PVHF IRU PDOHV DQG  470 msec for females. For QTcF readings that are borderline, 
and in those where the T and U waves are superimposed or connected, a manual reading 
should be considered to determine eligibility, in discussion with the Medical Monitor. In 
subjects with a QRS value > 120 msec, those with a QTcF value < 500 msec may be eligible 
following discussion with the Medical Monitor. 
18. Positive results of serology screening for hepatitis B (hepatitis B surface antigen [HBsAg]), 
hepatitis C (anti-hepatitis C virus [HCV] antibodies) or human immunodeficiency virus 
(HIV) (antibodies type 1 and 2); past history of positive results with hepatitis B or 
hepatitis C may be eligible if fully recovered and asymptomatic, following discussion with 
the Medical Monitor and prior approval is required. 
19. Chronic kidney disease with estimated glomerular filtration rate (eGFR) < 45 mL/min using 
the Cockcroft and Gault formula, with age, sex and weight considered; subjects with 
moderate to severe impairment (eGFR between 44 and 30 mL/min, inclusive) may be 
eligible following discussion with the Medical Monitor and prior approval is required. 
20. Hepatic impairment with alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 2 times the upper limit of normal, or Child-Pugh class B and C. 


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21. Malignant tumor within 3 years before Screening, except for the following conditions that 
are stable in the judgment of the investigator: 
a) Adequately treated squamous and basal cell carcinoma, or squamous and basal cell 
 
carcinoma in situ 
b) Prostate carcinoma in situ 
c) Fully-excised (biopsy-proven) melanoma in-situ; Medical Monitor prior approval is 
 
required. 
22. Clinically significant (in the judgment of the investigator) unintentional weight loss within 
12 months of Screening. 
23. The consumption of grapefruit or grapefruit-containing products is prohibited beginning 
7 days prior to the first dose of study medication (Day 1) and during the study. 
24. Food supplements and nutraceuticals with potential effects on cognition, such as Axona and 
medium chain triglyceride (MCT), are prohibited beginning 7 days prior to the first dose of 
study medication (Day 1) and for the duration of the study. 
25. Tetrahydrocannabinol (THC) is prohibited beginning 4 weeks prior to the first dose of study 
medication (Day 1) and for the duration of the study. Cannabidiol (CBD) without THC is 
allowed but not on the clinical visit days, except for topical applications. 
26. Prohibited prior and concomitant medications are excluded within 4 weeks prior to 
Screening. All allowed medications should remain stable in terms of dose and regimen 
throughout the study; for medications affecting cognition, the doses should be stable for at 
least 4 weeks before Screening and throughout the study, unless otherwise noted. If the 
permissibility of a specific medication is in question, please contact the Medical Monitor 
prior to randomization (refer to Appendix 1: List of Prohibited Medications; note: this is not 
an exhaustive list): 
a) Selegiline and trihexyphenidyl in any form or dosage. 
b) Memantine in any form, combination, or dosage. 
c) Donepezil at 23 mg. 
d) Antipsychotics: low doses (in the judgment of the investigator) are allowed if the subject 
has received a stable dose before Screening. If these medications are taken on a PRN 
basis they should not be taken the morning before any cognitive testing. 
e) Tryptophan supplements. 
f) Tricyclic antidepressants, irreversible monoamine oxidase B (MAO-B) inhibitors, and 
S-ketamine; all other antidepressants are allowed only if the subject has received a stable 
dose for at least 3 months before Screening. 


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g) Anxiolytics at high doses; low doses of benzodiazepines are allowed in the judgment of 
the investigator, but not the night before any cognitive assessments. 
h) Sedative hypnotics; Zolpidem is allowed. 
i) Barbiturates (unless given in low doses for benign tremor). 
j) Nicotine therapy (including patches), varenicline (Chantix), or similar therapeutic agent. 
k) Peripherally acting drugs with effects on cholinergic neurotransmission, e.g., oxybutinin. 
Solifenacin is allowed if the subject has received a stable dose for at least 3 months 
before Screening. 
l) Systemic immunosuppressants if taken in clinically immunosuppressive doses in the 
judgment of the investigator; inhaled steroids, otics, opthalmologics, skin creams, and 
intra-articular injections are allowed. 
m) Antiepileptic medication. 
n) Chronic intake of opioid-containing analgesics; PRN use is allowed (but not within 
72 hours before any cognitive assessment). 
o) Sedating H1 antihistamines; non-sedating H1 antihistamines are allowed and preferred. 
p) Systemic moderate to strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers; 
topical applications are allowed. 
27. Current enrollment in an investigational drug or device study, or have participated in another 
clinical trial with an investigational drug within 4 weeks of Screening, or 5 half-lives, 
whichever is longer, or within 6 months of Screening if an investigational drug for PD or 
cognition impairment. 
28. Subject has known allergy to any component of the investigational medicinal product (IMP) 
or an allergy to latex. 
29. The subject has a condition or is in a situation which, in the investigator’s opinion, may put 
the subject at significant risk, may confound the study results, or may interfere significantly 
with the subject’s compliance or participation in the study. 
4.4 
Caregiver / Support Person Eligibility and Responsibility 
For the purpose of this study, all subjects must have a suitable designated caregiver/support 
person who must meet the following eligibility criteria: 
1. Understand and agree with the potential risks and benefits to subjects as well as the nature of 
all procedures and restrictions associated with this study 
2. Understand, agree to, and sign a separate caregiver/support person’s ICF 
3. Willing to receive caregiver training related to the conduct of this study 


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4. Willing and able to administer and/or supervise the administration of all study drugs 
5. Willing and able to evaluate the subject’s tolerability to study drugs and any associated AEs 
6. Able to communicate by phone/email/text message or in person between clinic visits 
7. Able to accompany the subject to all clinic visits 
8. Available for scheduled weekly phone calls from site personnel 
9. Has frequent and sufficient contact with the subject to be able to provide accurate 
information regarding the subject’s cognitive, behavioral and functional abilities at study 
visits (which require caregiver/support person input for scale completion) 
Site personnel will instruct the caregiver / support person about: 
x Study drug administration and disposal of empty syringes 
x Study drug storage requirements 
x The nature of expected AEs 
x How to report AEs 
x Scheduled weekly phone calls from site personnel 
A consistent caregiver/support person is necessary for the conduct of the study. If an unforeseen 
change in caregiver/support person occurs during the course of study, please inform your 
assigned Study Monitor immediately. The replacement caregiver/support person must meet all 
requirements as outlined in the protocol and discussed with the Contract Research Organization 
(CRO) and/or Sponsor. 
4.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to treatment/entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened unless the investigator feels that rescreening would be appropriate, the reason for 
rescreening has been discussed with the Medical Monitor, and Sponsor approval has been 
obtained. Individuals who are rescreened will receive a new screening number. (Note: clinical 


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laboratory test results, ECGs, and vital signs may be repeated during Screening if outside the 
normal range and not considered clinically significant). 


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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 
Identity of the Medicinal Products 
The products that will be used in this study are outlined in Table 2. 
Table 2 
Identity of Investigational Products 
Study Drug Name 
Formulation 
Strength 
Route 
Manufacturer 
ATH-1017 40 mg 
Injection 
40 mg/mL 
SC 
Patheon 
ATH-1017 70 mg 
Injection 
70 mg/mL 
SC 
Patheon 
Placebo  
Injection 
NA 
SC 
Patheon 
NA = not applicable; SC = subcutaneous 
 
Pre-filled syringes of active IMP at 40 mg will contain 1.0 mL of 40 mg/mL ATH-1017 in a 
solution of 10 mM sodium phosphate and 0.5% sodium chloride. Pre-filled syringes of active 
IMP at 70 mg will contain 1.0 mL of 70 mg/mL ATH-1017 in a solution of 10 mM sodium 
phosphate. Each pre-filled syringe of placebo will contain 1.0 mL of a solution of 10 mM sodium 
phosphate and 1.1% sodium chloride. All IMPs are adjusted to pH of approximately 7.6. 
5.2 
Supply, Packaging, Labeling, and Storage 
IMP (ATH-1017 and placebo) will be provided as blinded subject kits and will be labeled 
according to applicable local and regulatory requirements. 
IMP will be stored under refrigerated conditions (between 2°C and 8°C) at study sites in a 
securely locked area, accessible to authorized persons only. Once dispensed, study subjects may 
store the product under refrigerated conditions (between 2°C and 8°C) or ambient conditions 
(between 15°C and 25°C, as supported by stability data). 
5.3 
Drug Accountability, Dispensing, and Destruction 
Randomization and dispensation will be controlled by an interactive response technology (IRT) 
system. Dispensation will occur every 2 weeks, or as needed, at the study site or by direct-to-
patient shipment. Larger provision of study drug will be permitted to accommodate personal 
need, e.g., vacation. Study subjects will be provided with sharps containers for proper disposal of 
used IMP.  
The caregiver/support person will supervise or record daily administration of IMP. Each site will 
ship any product materials (kits and sharps containers) to a central location for destruction or will 
destruct on-site. Reconciliation of IMP will be managed at each study site. 


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5.4 
Subject Identification and Randomization 
5.4.1 
Screening Numbers 
All screened subjects are assigned a unique Screening Number. The Screening Numbers identify 
subjects from time of Screening until time of randomization. Enrolled subjects who drop out of 
the clinical study before randomization will retain their Screening Number. 
5.4.2 
Randomization Numbers 
Prior to dosing on Day 1, subjects will be assigned a randomization number generated by an IRT 
system; the randomization numbers will subsequently be incorporated into the Electronic Data 
Capture (EDC) system.  
Once a randomization number has been allocated to 1 subject, it may not be assigned to another 
subject. 
5.5 
Administration of Investigational Medicinal Products 
Training on safe and effective use of prefilled syringes will be provided to study subjects and 
caregivers by site staff. Practice syringes (filled with placebo) in kits and injection pads will be 
provided to each site. Capable subjects will be allowed to self- administer upon judgment of site 
staff; those not capable will require caregiver-assisted administration after deemed capable by 
site staff. If stored at refrigerated conditions, pre-filled syringes should be kept at room 
temperature for at least 30 minutes after taking out of the refrigerator before administering the 
injection. The first dose will be administered on Day 1 (Visit 2b) at the clinic site; site staff will 
be expected to observe dose administration on day of study visit to ensure safe and effective use. 
Subjects will remain at the clinic site for 2-hour clinical observation (± 15 minutes). The subject 
may be discharged from the clinic following the 2-hour observation period provided they have 
no systemic AEs. Should there be AEs of a systemic nature, they should be observed an 
additional 2 hours. They should in all cases be discharged only after approval of the investigator. 
Subsequent visits do not have a specified period of observation but in all cases subjects must be 
discharged by the investigator.  
Should self-administration or caregiver-assisted administration not be judged adequate a suitable 
caregiver must be identified, otherwise subject discontinuation will be required.  
5.6 
Compliance with Investigational Medicinal Products 
IMP compliance will be determined from daily records of IMP administration recorded by the 
caregiver/support person. If a subject demonstrates consistent poor compliance during the study 
(< 80%), the investigator should evaluate whether the subject should be discontinued from the 
study, in discussion with the Medical Monitor. Subjects who are off drug for  14 consecutive 
days may be prematurely discontinued from the study, in discussion with the Medical Monitor. 


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The study centers will keep an accurate drug disposition record that specifies the subject kit ID 
number, number of kits dispensed to each subject, and the date of dispensation. 
5.7 
Blinding and Breaking the Blind 
The clinical study will be performed in a double-blind manner. 
The study blind should not be broken except in a medical emergency (where knowledge of the 
IMP administered would affect the treatment of the emergency). The decision to break the blind 
will be made on a case-by-case basis, at the discretion of the Principal Investigator in 
collaboration with the Sponsor and Medical Monitor. The applicable CRO standard operating 
procedure (SOP) will be followed for blind breaking procedures. 
An interim analysis is planned when at least 30 subjects have completed the Week 2 visit (see 
Section 8.7). Adequate measures will be defined in the final statistical analysis plan (SAP) and 
implemented with the aim to maintain the blind for all involved in actual study conduct at the 
Sponsor, the CRO, or any vendor. 
After database lock, the overall randomization code will be broken only for reporting purposes. 
5.8 
Stopping Criteria 
For all subjects, at any time during the study, study treatment should be discontinued and the 
subject will be withdrawn immediately if any of the following criteria/AEs are recorded: 
x 
ALT or AST > 5 × ULN for more than 2 weeks  
x 
ALT or AST > 8 × upper limit of normal (ULN) 
x 
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN, or international normalized ratio 
[INR] > 1.5 
x 
ALT or AST > 3 × ULN with symptoms (the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia > 5%) 
x 
AEs: 
 Any SAE confirmed as probably or definitely related to the IMP 
 
 
 Any AE of severe intensity confirmed as probably or definitely related to the IMP and 
associated with clinically significant findings 
 
(Note: causality as determined by the Sponsor) 


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x ECG criterion: 
 QTcF > 500 msec (if prolonged QTcF interval is observed during the study, then a 
minimum of 2 repeat ECGs should be obtained over a brief period. The mean of the 
3 ECGs will be used to determine this stopping criterion). 
For QTcF readings that are borderline, or difficult to interpret due to e.g., presence of a branch 
bundle block, or in those where the T and U waves are superimposed or connected, a manual, 
local reading using the same ECG device should be considered to determine applicability of this 
ECG stopping criterion, in discussion with the Medical Monitor. Baseline conditions should be 
taken into account when considering the ECG stopping criterion (see Section 4.3, exclusion 
criterion #17). 
In addition, if any of the above criteria are met, the event must be reported and discussed with 
the Medical Monitor. 
5.9 
Treatment of Overdose 
Overdose: Unintentional administration of a quantity of the study treatment given per 
administration or per day that is above the maximum recommended dose according to the 
protocol for the study treatment (see Section 6.4.1.1 for reporting of overdose). This also takes 
into account cumulative effects due to overdose. 
There is no prior knowledge of clinical symptoms occurring with ATH-1017 overdose. In case of 
suspected or reported overdose, treatment of any clinical signs will be symptomatic. 
5.10 
Treatment after the End of the Study 
Access to study treatment will be limited to the period of study participation. 
Upon discontinuation of double-blind treatment, subjects will return to their original medication; 
tapering off study medication is not required. 
The investigator will determine whether additional care is needed after the subject completes or 
discontinues from the study. 


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6 
VARIABLES AND METHODS OF ASSESSMENT 
6.1 
Screening Assessments 
6.1.1 
Montreal Cognitive Assessment (MOCA) 
The MOCA was designed as a rapid screening instrument for mild cognitive dysfunction. It 
assesses different cognitive domains: attention and concentration, executive functions, memory, 
language, visuoconstructional skills, conceptual thinking, calculations, and orientation. 
The total possible score is 30 points; a final total score of 26 and above is considered normal. 
The MOCA is administered at Screening only; a score of 11 to 23 inclusive is required to meet 
the subject eligibility criterion. 
6.2 
Clinical Effect Variables 
As specified by each assessment scale, a qualified, trained and certified rater will administer 
questionnaires to the study subject and/or dedicated support person/caregiver. Rater training and 
certification (as applicable) will occur, and if necessary be repeated, in a standardized manner. 
 ADAS-Cog13, 
 assessments should be done in the same time frame at all 
visits, in the morning. 
6.2.1 
Cognitive Variables 
 
 
 
 
 
 
6.2.1.2 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale, 13-Item Version 
(ADAS-Cog13) 
The ADAS-Cog13 is designed to measure cognitive symptom change in subjects with MCI as 
well as AD (Mohs, 1997). In addition to the standard 11 items present in the ADAS-Cog11 (word 
recall, commands, constructional praxis, naming objects and fingers, ideational praxis, 
orientation, word recognition, spoken language ability, comprehension of spoken language, 
word-finding difficulty, and remembering test instructions), the ADAS-Cog13 includes a test of 
delayed word recall and a number cancellation task. The test comprises 9 performance items and 
4 clinician-rated items, with a total score ranging from 0 (no impairment) to 85 (severe 
impairment). Therefore, higher scores indicate more severe cognitive impairment. 




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6.2.2.6 
 
 
 
 
 


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6.3 
Pharmacodynamic Variables 
Pharmacodynamic variables will consist of ERP P300 assessments. ERP P300 should be 
performed when the subject is not experiencing interfering motor disturbances that might affect 
the quality of ERP P300 data; if necessary, the time window for ERP P300 assessments can be 
extended. 
ERP P300 is a method of recording brain activity elicited by external stimuli, e.g., an oddball 
auditory stimulus, and is a well-established functional biomarker, particularly of working 
memory access (Ally, 2006). ERP P300 is characterized by a stereotyped series of voltage 
deflections occurring after the respective odd tone to be counted, with early features 
(< 100 msec) corresponding to unconscious sensory transmission (auditory cortex, N100), and 
later features produced by cognitive processing in the ventral attentional network, i.e., P300, 
referring to the large positive deflection at roughly 300 msec in healthy adults (young or elderly). 
The P300 latency is sensitive to detecting reduced synaptic transmission related to cognitive 
decline in AD patients and other dementias (Olichney, 2011). 
To assess the P300 wave (latency and amplitude), the subject is in a semi-sitting position, eyes 
closed, and has to perform a task related to auditory stimuli. The stimulus consists of an oddball 
paradigm with 2 sound stimuli. Stimuli are presented through headphones and auditory 
stimulation for P300 will be assessed in a recording lasting up to 10 minutes. 
ERP P300 will be performed at the Pre-baseline visit (Visit 2a, Day -10 to Day -3, no dosing). 
ERP P300 data should be uploaded for quality check immediately after the completion of the 
Pre-baseline visit (Visit 2a). 
At Baseline/Day 1 (Visit 2b), ERP P300 will be performed at pre-dose following the completion 
of baseline assessments of 
,ADAS-Cog13, and 
 up to 1.5 hour before dose in 
clinic. EEG will be assessed post-dose at approximately 2 (±1) hours after IMP dosing. 


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At Visits 3, 5, and 8, ERP P300 will be performed at pre-dose up to 1 hour before dose in clinic. 
ERP P300 will be assessed post-dose following the completion of 
 
ADAS-Cog13, 
 assessments, at approximately 2 (±1) hours after IMP dosing. 
ERP P300 will also be performed at the Safety follow-up visit (Visit 9, no dosing). 
6.4 
Safety Variables 
6.4.1 
Adverse Events 
AE reporting will begin at Screening (Visit 1) and will continue until the end of the study (28 
days from last dose of IMP, Visit 9 – Safety Follow-up). AEs will be reported by the subject (or, 
when appropriate, by a caregiver, support person, or the subject’s legally authorized 
representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AE 
(see Section 6.4.1.5). 
6.4.1.1 
Definitions 
An AE is any untoward medical occurrence in a study subject which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including a clinically significant abnormal laboratory finding), symptom, or disease (new 
or exacerbated), temporally associated with the use of the IMP, whether or not considered related 
to the IMP. 
Events meeting the definition of AE include: 
x Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease) 
x Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 


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Events not meeting the definition of AE include: 
x Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition 
x The disease/disorder being studied or expected progression, signs, or symptoms (clearly 
defined) of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition 
x Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen (note: pre-existing conditions will be 
recorded as part of the subject’s medical history). 
6.4.1.2 
Recording of Adverse Events 
AEs should be collected and recorded for each subject from signing informed consent until the 
end of their participation in the study, i.e., from Screening until the subject has discontinued or 
completed the study, including the post-treatment Safety Follow-up period at the timepoints 
specified in the Schedule of Assessments (Table 1). AEs identified after signing the ICF and 
before dosing will be recorded as pre-treatment AEs. If AEs occur, the first concern will be the 
safety of the study subjects. 
AEs may be volunteered spontaneously by the study subject, or discovered by the study staff 
during physical examinations or by asking an open, non-leading question such as ‘How have you 
been feeling since you were last asked?’ All AEs and any required remedial action will be 
recorded. The nature of AE, date (and time, if known) of AE onset, date (and time, if known) of 
AE outcome to date, severity, and action taken of the AE will be recorded together with the 
investigator’s assessment of the seriousness of the AE and causal relationship to IMP and/or 
study procedure on an AE electronic case report form (eCRF).  
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. It 
is not acceptable for the investigator to send photocopies of the subject’s medical records to the 
sponsor in lieu of completion of the AE/SAE eCRF page. 


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There may be instances when copies of medical records for certain cases are requested by the 
Sponsor and/or CRO. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission. 
All AEs should be recorded individually in the study subject’s own words (verbatim) unless, in 
the opinion of the investigator, the AEs constitute components of a recognized condition, disease 
or syndrome. In the latter case, the condition, disease or syndrome should be named rather than 
each individual symptom. 
6.4.1.3 
Assessment of Adverse Events 
Each AE will be assessed by the investigator with regard to the categories discussed in the 
sections below. 
Intensity 
The investigator will assess all AEs for severity in accordance with the following standard 
ratings: 
x Mild: Ordinarily transient symptoms, does not influence performance of subject’s daily 
activities. Treatment is not ordinarily indicated or may be minimal. 
x Moderate: Marked symptoms, sufficient to make the subject uncomfortable. Moderate 
influence on performance of subject’s daily activities. Treatment may be necessary to 
alleviate symptoms. 
x Severe: Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities, or significantly affects clinical status. The subject may be unable to 
continue in the study and intensive treatment may be necessary. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity recorded for the event should be noted. 
Note: an event is defined as serious when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE (see later), NOT when it is rated as severe. 
Causality 
The investigator will assess the causality/relationship between the AE and IMP/study procedure. 
One of the categories described in Table 3 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. In this study AEs will be 
considered related to IMP/study procedure if causality is ascribed as either related, probably 
related, or possibly related. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 


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There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Table 3 
Assessment of Relationship of Adverse Events to IMP/Study Procedure 
Related 
 
A clinical event, including laboratory test abnormality, which occurs in a 
plausible time relationship to treatment administration, and which concurrent 
disease or other drugs or chemicals cannot explain. The response to withdrawal 
of the treatment (dechallenge*) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory 
rechallenge† procedure if necessary. 
Probably related 
 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the treatment, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
Possibly related 
 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the treatment, but which could also be explained 
by concurrent disease or other drugs or chemicals. Information on treatment 
withdrawal may be lacking or unclear. 
Unlikely to be 
related 
 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
Unrelated 
 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration. May have negative dechallenge and 
rechallenge information. Typically explained by extraneous factors (e.g., 
concomitant disease, environmental factors or other drugs or chemicals). 
*Dechallenge is when a drug suspected of causing an AE is discontinued. If the symptoms of the AE disappear partially 
or completely, within a reasonable time from drug discontinuation, this is termed a positive dechallenge. If the 
symptoms continue despite withdrawal of the drug, this is termed a negative dechallenge. Note that there are 
exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
†Rechallenge is when a drug suspected of causing an AE in a specific subject in the past is re-administered to that 
subject. If the AE recurs upon exposure, this is termed a positive rechallenge. If the AE does not recur, this is termed 
a negative rechallenge. 
 


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Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose: 
x Results in death. 
x Is life-threatening; this means that the subject was at risk of death at the time of the event; 
it does not mean that the event hypothetically might have caused death if it were more 
severe. 
x Requires inpatient hospitalization or prolongation in existing hospitalization; in general, 
hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
x Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
x Is a congenital anomaly or birth defect, or 
x Is another important medical event (see below) 
Important medical events that do not result in death, are not life-threatening or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such medical events include invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
A distinction should be drawn between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. For example, a mild degree of 


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gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes would be 
considered an SAE, but is not necessarily severe. Similarly, an AE that is severe in intensity is 
not necessarily an SAE. For example, headache may be assessed as severe in intensity but would 
not be considered an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.4.1.4 
Reporting of Serious Adverse Events 
Prompt (within 24 hours) notification by the investigator to the Sponsor’s designated Drug 
Safety and Pharmacovigilance vendor, i.e., MMS, of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study treatment 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, institutional review boards (IRBs)/independent ethics committees 
(IECs), and investigators. 
The investigator will review each SAE and evaluate the intensity and the causal relationship of 
the event to IMP/study procedure. All SAEs will be recorded from signing of informed consent 
until completion of the Safety Follow-up. SAEs occurring after the Safety Follow-up Visit and 
coming to the attention of the investigator must be reported only if there is (in the opinion of the 
investigator) reasonable causal relationship with the IMP. 
The investigator is responsible for updating the EDC and providing notification to MMS Drug 
Safety and Pharmacovigilance of any SAE, whether deemed IMP-related or not, that a subject 
experiences during their participation in study within 24 hours of becoming aware of the event 
to: 
 
 
MMS Drug Safety and Pharmacovigilance is responsible for providing notification to the 
Sponsor of any SAE as soon as they become aware of the event. 
As a minimum requirement, the initial notification should provide the following information: 
x Identifiable subject 
x Identifiable event (including causality assessment) 
x Identifiable IMP 


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x Identifiable reporter 
MMS Drug Safety and Pharmacovigilance will request clarification of omitted or discrepant 
information from the initial notification. The Principal Investigator or an authorized designee is 
responsible for faxing or emailing the requested information to MMS Drug Safety and 
Pharmacovigilance within 24 hours of the request. 
It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
the Sponsor in lieu of appropriate completion of an SAE Report Form. Additional information 
(copies of laboratory reports, consultant reports, copies of discharge summaries, etc.) should be 
provided on request to MMS Drug Safety and Pharmacovigilance. If an SAE Report Form is 
faxed or emailed, then the Principal Investigator must sign and date the form.  
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE Report Form within the designated reporting time frames. Contacts for SAE 
reporting can be found on the protocol title page 
All SAE reports submitted by the investigator will be reviewed by the study Sponsor and 
assessed for meeting criteria of suspected unexpected serious adverse reactions (SUSARs). All 
SUSARs will be reported by the Sponsor to competent national authorities and investigators 
according to local regulatory requirements and Sponsor policy. 
An investigator who receives an individual case safety report describing a SUSAR or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will review and 
then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 
6.4.1.5 
Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality or seriousness, will be 
monitored until the event has resolved, until any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the investigator and Medical Monitor, until there is 
a satisfactory explanation for the changes observed or until the subject is lost to follow-up. If a 
subject is lost to follow-up and has not answered any phone calls from the site (at least 3 calls), a 
final proof of contact via certified letter is required (see Section 7.5). 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor and/or 
CRO to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
All AEs/SAEs that are still present after the last study drug administration (including AEs that 
have led to premature discontinuation), will be followed-up at the Safety follow-up visit. In case 


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the AE/SAE is still ongoing after that timepoint, this will be followed up until its resolution or 
until otherwise agreed between the Sponsor and the investigator. 
Additional safety data collected after the Safety follow-up visit to follow-up the ongoing AE will 
not be included into the clinical database, if this was already locked; therefore the clinical 
database lock will not be delayed due to this situation. Any SAE will be followed up, if needed, 
after clinical database lock, and the information will be only stored in the safety database. 
6.4.2 
Pregnancy 
Female subjects who become pregnant during the study will be withdrawn. 
The investigator will attempt to collect pregnancy information on (i) any female participant or 
(ii) male participant’s female partner (after obtaining the necessary signed informed consent) 
who becomes pregnant while participating in this study. 
The investigator will record pregnancy information on the appropriate form and submit it to 
MMS Drug Safety and Pharmacovigilance within 24 hours of learning of the pregnancy. The 
pregnant participant /female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
6.4.3 
Clinical Laboratory Assessments 
The following laboratory variables will be determined as outlined in Table 4 below: 
Table 4 
Clinical Laboratory Assessments 
Test 
Parameters 
Hematology 
CBC 
Hb1Ac 
Hemoglobin 
Hematocrit 
Erythrocytes (RBC) 
Leukocytes (WBC)  
Differential WBC 
Platelets 
Biochemistry 
Sodium 
Potassium 
Magnesium 
FSH (post-menopausal females only) a 
Calcium 
Chloride 
Glucose 
Creatinine 
ALP 
AST 
ALT 
GGT 
CPK 
Total bilirubin 
Total protein 
Albumin 
Total Cholesterol 
Low-density lipoprotein  
High-density lipoprotein 
Triglycerides 
TSH, fT3 and fT4 a 


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Coagulation 
INR 
PT 
aPTT 
Serology 
HBsAg  a 
HCV  a 
HIV type 1 or type 2  a 
Urinalysis  
pH 
glucose 
ketones 
specific gravity 
HCG 
(females 
of 
child-bearing 
potential only) 
nitrite 
protein 
bilirubin 
blood 
AST = aminotransferase; ALP = alkaline phosphatase; ALT = alanine transaminase; CBC = complete blood count; 
CPK = creatine phosphokinase; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; Hb1Ac = glycated 
hemoglobin; HBsAg = hepatitis B surface antigen; HCG = human chorionic gonadotropin; HIV = human immunodeficiency 
virus; INR = international normalized ratio; PT = prothrombin time; aPTT = activated partial thromboplastin time; RBC = red 
blood cells; fT3 =free tri-iodothyronine; fT4 =free  thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cells. 
a 
Measured only at Screening for eligibility; not included in subsequent safety labs. 
 
Any value outside the normal range will be flagged for clinical interpretation by the investigator 
or designee at the site. In this study, ALT or AST > 2 times the upper limit of normal, or 
Child-Pugh class B and C (i.e., including total bilirubin, albumin, and INR values), will be 
exclusionary. For transaminase liver enzymes, a repeat laboratory assessment may be performed 
if outside of the normal range. If the transaminases remain elevated the investigator should 
consider stopping study medication and withdrawing the subject as described in Section 5.8. 
A medical alert for potential Hy’s laws cases (possible drug-induced liver injury) will be issued 
based on laboratory values and supported by Medical Monitor interpretation. Investigators, the 
Sponsor, Medical Monitor, and MMS (the Sponsor’s designated vendor for Drug Safety and 
Pharmacovigilance) will immediately be notified when the above criteria have been met through 
a central laboratory alert. The AE eCRF should be completed within 3 business days. Every 
effort to determine the cause of the liver enzyme abnormalities must be made, and close 
monitoring should be initiated in conjunction with the Medical Monitor and in accordance with 
the FDA Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 
Criteria for potential Hy’s law cases are as follows:  
x 
$/7 RU $67   î 8/1 $1'  
x 
7RWDO ELOLUXELQ   î 8/1 $1'  
x 
Alkaline phosphatase < 2 × ULN 
Typically, all 3 analytes will be obtained from the same sample, but they may come from 
multiple samples taken within a 24-hour period. This requirement applies from the time the 
subject signs the ICF for the study until 4 weeks after the final protocol-defined study visit or the 
last known dose of study treatment (if the final visit does not occur). 


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Any clinically significant abnormalities from Screening labs must be discussed with the Medical 
Monitor to confirm eligibility of the subject. Additional testing during the study may be done if 
medically indicated. If a clinically significant abnormality is found in the samples taken after 
dosing, during the study, and/or at the safety follow-up visit, it should be recorded as an AE and 
the subject will be followed until the test(s) has (have) normalized or stabilized. 
6.4.4 
Vital Signs 
Vital signs will be assessed pre-dose at the timepoints detailed in the Schedule of Assessments 
(Table 1). The following vital signs will be measured:  
x Blood pressure (supine) (systolic and diastolic [mmHg]) 
x Orthostatic blood pressure (systolic and diastolic [mmHg])) 
x Heart rate (bpm) 
x Body temperature (°C) (oral, tympanic, temporal, or forehead infrared) 
x Respiratory rate (breaths per minute) 
Supine BP and HR recordings will be made after the subject has been supine for at least 
5 minutes. 
Orthostatic blood pressure will be recorded as specified in Table 1. The first blood pressure will 
be the average of 3 measurements recorded after the subject is supine for 5 minutes; the second 
blood pressure will be recorded after the subject has stood for up to 3 minutes. A drop in blood 
pressure of  20 mmHg, or in diastolic blood pressure of  10 mmHg will be considered 
abnormal. 
6.4.5 
Weight 
Weight will be measured at Screening (for calculation of BMI as part of the eligibility criteria), 
at Baseline/Day 1 (Visit 2b), Visit 5 (Week 12), Visit 8 (Week 26), and Visit 9 (Safety 
follow-up). 
6.4.6 
12-Lead Electrocardiogram 
Standard safety 12-lead ECGs will be performed at Screening, at pre-dose and 30 (± 15) minutes 
post-dose on Day 1 and 30 (± 15) minutes post-dose at all other visits. All ECGs will be 
performed in triplicate, as detailed in the Schedule of Assessments (Table 1). 
The 12-lead ECGs will be performed after the subject has been resting supine for  5 minutes. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing. The following ECG parameters will be collected: PR interval, QRS interval, RR interval, 
QT interval, and QTcF. 


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All ECGs must be evaluated by the investigator or qualified designee for the presence of 
abnormalities. Collection and analysis of ECG data will be performed by a central ECG vendor. 
6.4.7 
Physical and Neurological Examination 
Physical and neurological examination will be performed by the investigator or designee at the 
timepoints detailed in the Schedule of Assessments (Table 1). 
The physical examination includes an assessment of general appearance and a review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric 
systems). 
Body weight (kg) and height (meters) will be assessed at Screening. Body weight and height will 
be used to calculate BMI using the following formula: weight (kg)/[height (m)]2. 
Neurological components include, but are not limited to, the following assessments: mental 
status, cranial nerves, muscle strength, tone, and bulk, reflexes, coordination, sensory function, 
and gait. 
6.4.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be performed at Screening, Baseline/Day 1 (Visit 2b), Visit 3 (Week 2), Visit 4 
(Week 6), Visit 5 (Week 12), Visit 6 (Week 16), Visit 7 (Week 20), Visit 8/ET, and Visit 9 
(Safety follow-up) (Week 30) (Table 1). The C-SSRS supports suicide risk assessment through a 
series of simple, plain-language questions. The responses assist in identifying whether a subject 
is at risk for suicide, assesses the severity and immediacy of that risk, and gauge the level of 
support that the subject may require. If items 1 to 5 of the C-SSRS have a positive response and 
are of clinical concern, as judged by the investigator during the study, the Medical Monitor must 
be contacted. 
6.4.9 
Geriatric Depression Scale (GDS) 
The GDS is a self-report measure of depression in older adults with a “Yes/No” response format. 
The GDS was originally developed as a 30-item instrument. It has since been validated in a 
shortened form comprising 15 items (Sheikh, 1986). The total score range is 0 to 15, with a 
higher score indicating moUH VHYHULW\ $ *'6 VFRUH RI  7 is required at Screening. In discussion 
with the Medical Monitor, subjects with a GDS score between 8 and 10 inclusive can be 
considered for study participation if the increased score is driven by specific domains related to 
the pandemic and its restrictions, rather than by major depression. 
GDS assessments will be performed at Screening, Visit 2b (Baseline/Day 1), Visit 5 (Week 12), 
Visit 8/ET (Week 26), and Visit 9 (Safety follow-up). 


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6.6 
Genotyping 
Blood sample(s) will be collected at Screening for analysis of GBA genotype in subjects who 
consented to genotyping. 
 
 
 
 
 
 
 
 
 


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7 
STUDY CONDUCT 
x Study procedures and their timing are summarized in the Schedule of Assessments 
(Table 1). 
x Protocol exemptions related to enrollment criteria are only allowed with prior 
investigator, Medical Monitor, and Sponsor approval, supported by documented 
agreement from the IRB/IEC. 
x Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
treatment. 
x Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. Screening procedures may be conducted on up to 
2 separate dates if necessary to accommodate subject and study center schedule. 
However, every effort should be made to conduct all procedures as early as possible in 
the screening period. The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
x Due to the quantitative functional biomarker nature of this study, particular precautions 
will have to be implemented at each site for the electrophysical assessments, i.e. 
availability of a dedicated quiet EEG room with controlled lighting and temperature. 
7.1 
Schedule and Order of Assessments 
The study will consist of up to 28 days of Screening (Day -32 through Day -4), a Pre-baseline 
visit (Visit 2a, Day -10 to Day -3), Baseline (Visit 2b, Day 1, randomization), followed by 
26 weeks of double-blind treatment, and a 4-week safety follow-up. Note: if 28 days is not 
sufficient to complete the screening period, the possibility of an extension can be discussed with 
the Medical Monitor. 
All assessments to be performed during the study are detailed by visit/timepoint in Table 1. 
For clinical outcome assessments evaluating subject’s cognitive condition, the general order 
should be followed: 


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(1) 
 
(2) ADAS-Cog13 
(3) 
 
(4) ERP P300 assessments 
All cognitive assessments including MMSE, ADAS-Cog13, and 
 shall occur at clinic 
visits in the morning, in the specified order when applicable.  
 
ADAS-Cog13 assessments will be performed pre-dose at Baseline/Day 1 (Visit 2b), and 
post-dose at approximately 1 hour (± 30 minutes) at Week 2 (Visit 3), Week 12 (Visit 5), 
Week 20 (Visit 7), and Week 26 (Visit 8). 
 
 
 
 
 
 
 
 
The order of assessments and timing for all other endpoints
 
 are flexible. 
7.1.1 
Unscheduled Visit(s) 
An unscheduled visit may be performed at any time during the study as deemed necessary by the 
investigator. The date and reason for the unscheduled visit will be recorded. AE monitoring and 
concomitant medication recording should be performed by the investigator. Other procedures 
and evaluations will be completed as deemed necessary by the investigator and may include (but 
not limited to) laboratory tests, ECG, vital signs, and physical examination. Please ensure to 
discuss with the Medical Monitor prior to conducting any unscheduled visit. 
7.2 
Pandemic Response 
In the event of a pandemic that impacts study conduct, the following protocol changes will be 
implemented should the situation arise (implementation should be discussed on a case-by-case 
basis, with sponsor approval): 


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x Visit 1 (Screening), Visit 2 (Pre-baseline, Day -10 to Day -3; Baseline/Day 1), Visit 5 
(Week 12), Visit 8 (Week 26), and Visit 9 (Safety follow-up) are considered essential 
visits, and these visits need to be conducted on-site, with proper site arrangements to 
protect the safety of study participants and site staff, including personal protection 
equipment, proper spacing between subjects to avoid crowding and allow proper 
cleaning, transportation arrangements, etc. (full details will be agreed with the CRO and 
study sites) 
x Visit 3 (Week 2), Visit 4 (Week 6), Visit 6 (Week 16), and Visit 7 (Week 20) should be 
conducted on-site if conditions permit, but flexibility will be allowed upon agreement 
between sites, CRO, and sponsor. These visits are to be completed according to one of 
the following options: 
a. On-site visit with proper safety arrangements 
b. Site staff visit to the subject at home 
c. Travel nurse visits the subject at home 
d. Tele-health using phone, video call, or others 
e. Subject goes to local laboratory for biological samples to be taken 
Any coronavirus disease – 2019 (COVID-19) vaccinations received before screening and during 
the study through to the Safety follow-up visit will be recorded, and specific guidance in relation 
to visits will be provided. 
7.3 
Concomitant Medications and Treatments 
7.3.1 
Prohibited Treatments During the Study 
Concomitant use of the following drugs is excluded within 4 weeks prior to Screening and for 
the duration of the study. All allowed medications should remain stable throughout the study; for 
medications affecting cognition, the doses should be stable for at least 4 weeks before Screening 
and throughout the study, unless otherwise noted.: 
x Selegiline and trihexyphenidyl in any form or dosage. 
x Memantine in any form, combination, or dosage. 
x Donepezil at 23 mg. 
The following drugs are prohibited during the study: 
x Psychoactive medications (including antipsychotics, tricyclic antidepressants, anxiolytics 
or sedative hypnotics, including barbiturates) having significant anticholinergic effects 
and/or believed to affect cognitive function (for exceptions see Section 7.3.2). 


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x Nicotine therapy (including patches), varenicline (Chantix), or similar therapeutic agent. 
x Peripherally acting drugs with effects on cholinergic neurotransmission, e.g., oxybutinin 
(for exception see Section 7.3.2).  
x Systemic immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses in the judgment of the investigator (for exceptions see 
Section 7.3.2). 
x Antiepileptic medication. 
x Chronic intake of opioid containing analgesics; PRN use is allowed (but not within 
72 hours before any cognitive assessment). 
x Sedating H1 antihistamines; non-sedating H1 antihistamines are allowed and preferred. 
x Systemic moderate to strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
fluconazole, cimetidine, clarithromycin, erythromycin, troleandomycin) (see Appendix 1: 
List of Prohibited Medications for non-exhaustive list). 
x Systemic moderate to strong CYP3A4 inducers (e.g., carbamazepine, rifabutin, ritonavir, 
and St. John’s wort) (see Appendix 1: List of Prohibited Medications for non-exhaustive 
list). 
Subjects that use prohibited medications listed above during the double-blind treatment period of 
the study may be discontinued from study drug. 
Note: The discontinuation of a subject due to use of a prohibited medication shall be discussed 
between the investigator, Medical Monitor, and Sponsor. The investigator should contact the 
Medical Monitor prior to discontinuing a subject for disallowed medications. 
See Appendix 1: List of Prohibited Medications for a non-exhaustive list of prohibited 
medications. 
7.3.2 
Permitted Treatments 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
x Indication 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency 


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In this study, subjects may be taking a stable dose of acetylcholinesterase inhibitors (e.g., 
rivastigmine), as long the dose and dosage form have been stable for 3 months prior to Screening 
and no changes are planned during the study.  
Solifenacin is allowed if the subject has received a stable dose for at least 3 months before 
Screening. 
The dosage(s) of other allowed concomitant medications should have been stabilized for at least 
4 weeks prior to Screening and should remain constant during the course of the study. For 
concomitant medications that affect cognition, the dosage(s) must have been stabilized for at 
least 4 weeks prior to Screening and should remain constant during the course of the study. With 
the exception of medications listed in the Exclusion Criteria (Section 4.3), in Section 7.3.1, and 
below, concomitant medications will be allowed at the investigator’s discretion. When in doubt, 
the Medical Monitor should be contacted. 
In close communication with the Medical Monitor, low doses of antipsychotics (except 
clozapine) may be allowed if the subject has received a stable dose for at least 4 weeks before 
Screening. If these medications are taken on a PRN basis, they should not be taken the morning 
before any cognitive testing. Pimavanserine and aripiprazole (oral) are allowed. 
Low doses (in the judgment of the investigator) of anxiolytics may be given PRN but not the 
night before any cognitive assessments. Barbiturates are allowed only if given for benign tremor 
in low doses (in the judgment of the investigator). Zolpidem is allowed. 
With the exception of tricyclic antidepressants, irreversible MAO-B inhibitors, and S-ketamine, 
all other antidepressant medications are allowed. 
Immunosuppressants in the form of inhaled steroids, otics, opthalmologics, skin creams, and 
intra-articular injections are allowed. 
Topical application of moderate to strong cytochrome P450 3A4 inhibitors or inducers is 
allowed. 
If the permissibility of a specific medication/treatment is in question, please contact the Medical 
Monitor. 
7.3.3 
Other Restrictions 
7.3.3.1 
Food and Food Supplements 
The consumption of grapefruit or grapefruit-containing products is prohibited beginning 7 days 
prior to the first dose of study medication (Day 1) and during the study. 
Food supplements and nutraceuticals with potential effects on cognition, such as Axona, 
tryptophan supplements, and MCT, are excluded during the study, beginning 7 days prior to the 
first dose of study medication (Day 1). Tetrahydrocannabinol (THC) is prohibited beginning 
4 weeks prior to the first dose of study medication (Day 1) and for the duration of the study. 


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Cannabidiol (CBD) without THC is allowed but not on the clinical visit days, except for topical 
applications. CBD use should be recorded as concomitant medication. 
7.3.3.2 
Contraceptives 
Sexually active males and females and their partners must ensure that a double barrier method of 
contraception is used (i.e., condom plus diaphragm, condom or diaphragm plus spermicide gel or 
foam) for the duration of the study, including the 4-week safety follow-up period. 
7.4 
Subject Withdrawal 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
investigator and/or Sponsor, in accordance with his/her best professional judgment. However, it 
is encouraged that the investigator contacts the Sponsor, when possible, to discuss possible 
reasons for discontinuation prior to withdrawing a subject from the study. Notification of early 
subject discontinuation from the study and the reason for discontinuation will be made to the 
Sponsor and will be clearly documented on the appropriate eCRF. 
7.4.1 
Discontinuation of Study Treatment 
All subjects who permanently discontinue study treatment, for whatever reason, will be 
withdrawn from the study. Upon discontinuation of study drug, subjects will continue with their 
original treatment; tapering off study medication is not required. 
See the schedule of activities for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed (Table 1). 
7.4.2 
Withdrawal from the Study 
x A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons, including protocol deviations 
x Subjects must be discontinued from the study and/or receive no further study treatment, if 
any of the following criteria are met: 
o 
Any of the stopping criteria described in Section 5.8 
o 
Any AE or safety finding that may jeopardize the subject’s health in the 
investigator’s judgment, and which is considered to be at least possibly related to the 
study drug. 
o 
Withdrawal of informed consent by subject/legally authorized representative. In the 
event that a subject’s decision to withdraw from the study is motivated by adverse 


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event(s) or stated lack of efficacy, these reasons should be recorded as the reason for 
early termination. 
o 
Physician decision 
o 
Non-compliance with study drug 
o 
Site terminated by sponsor 
o 
Repeat incapacity of subject and/or caregiver (in the judgment of the investigator) to 
properly administer study drug despite training and testing 
o 
Prolonged or definitive loss of caregiver without adequate replacement 
o 
Nursing home placement 
x If the subject withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
x If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
x All subjects who prematurely discontinue from the study, i.e., prior to Visit 8 (Week 26), 
unless the cause is screen failure, should return for an early termination visit and 
complete all the assessments scheduled for the Week 26 visit (Visit 8); see the schedule 
of activities (Table 1) for data to be collected. 
x Unless the reasons of premature discontinuation prevent further meaningful testing, 
investigators should make every effort to motivate subjects who discontinue early (and 
caregiver) to return for a Visit 8 (Week 26) for final assessments 
Upon discontinuation of study drug, subjects will continue with their original treatment; tapering 
off study medication is not required. 
7.5 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
x The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 


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schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
x Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls/emails, 
and if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s study 
records. 
x Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
7.6 
Termination of the Clinical Study 
The Sponsor designee reserves the right to close the study site(s) or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
x Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or Good Clinical Practice (GCP) 
guidelines 
x Inadequate recruitment of participants by the investigator 
x Discontinuation of further study treatment development 


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8 
STATISTICAL METHODS 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below. Any deviations from the planned 
analyses will be described and justified in the clinical study report. 
8.1 
Populations for Analysis 
8.1.1 
MITT population 
The modified intent-to-treat (mITT) population will include all randomized subjects who took at 
least one dose of the study medication and who completed both an ADAS-Cog13 and ERP P300 
assessment at Baseline and during at least one post-baseline visit. Subjects will be analyzed 
according to the dose they were randomized to. 
8.1.2 
Per protocol population 
The per protocol population will include all mITT subjects who were medication compliant 
during the 26 weeks of double-blind treatment (as defined in Section 5.6) and completed both an 
ADAS-Cog13 and ERP P300 assessment during at least one post-baseline visit, and did not have 
any major protocol deviations. Subjects will be analyzed based on actual treatment received. 
8.1.3 
Safety population 
The Safety population will include all randomized subjects who received at least one dose of the 
study medication. Subjects will be analyzed based on actual treatment received. 
8.2 
General Considerations 
Descriptive statistics for continuous variables will include number of subjects (n), arithmetic 
mean, standard deviation, median, minimum, maximum and first and third quartile limits unless 
otherwise noted. Frequency and percentage will be calculated for categorical variables. 
Change from baseline is calculated by subtracting the baseline score from the observed value at 
any subsequent visit. For safety summaries, the last pre-randomization measurement is defined 
as the baseline value. For clinical effect measures baseline is defined as the last pre-
randomization measurement. 
Percentages are based on the number of subjects in each treatment group in the given population 
for AE summary tables, and additionally overall for medical history, prior and concomitant 
medications. For all other tables, percentages are based on the number of subjects with 
non-missing data in each treatment group and overall for the given population. 


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8.3 
Clinical Effect Analyses 
8.3.1 
Primary Clinical Effect Analysis - GST 
The primary hypothesis is that treatment with ATH-1017 will result in a statistically significant 
reduction in change from baseline in the GST score (O’Brien, 1984) (combining the 
ADAS-Cog13 score and the change from baseline in ERP P300 at Week 26) relative to the 
placebo group in the mITT population. The primary analysis will test the statistical hypothesis of 
no difference between placebo and 70 mg ATH-1017 first and then 40 mg ATH-1017 versus 
placebo. 
The primary analysis will use a mixed model with repeated measures (MMRM) to compare the 
estimated change from baseline between active treatment and placebo in the GST score. This 
analysis will assess whether or not there is a difference in estimated GST values between 
treatment groups and placebo at 26 weeks using least squares means estimates from the MMRM 
model, and will include terms for baseline, baseline by time interaction, and baseline by time by 
treatment interaction in the model. Additional terms will be included for GBA genotype, and site 
(with smaller sites grouped), and age. Least squares means and standard errors will be estimated 
from the MMRM model at Week 26. Further details relating to the primary analysis will be 
described in the SAP. 
8.3.2 
Secondary Analysis – ADAS-Cog13 and ERP P300 
The separate secondary variables of ADAS-Cog13 and ERP P300 will be analyzed using the 
same MMRM model that was used for analysis of the primary endpoint. 
 
.  
 
 
 
 
 
 
. 
8.4 
Safety Summaries 
The Safety population will be used for analyses of each of the safety endpoints. All concomitant 
medications will be tabulated according to drug class and preferred term using the World Health 
Organization Drug dictionary. Clinical laboratory tests, vital signs, physical and neurological 
examinations, and ECG results will be summarized by number of subjects, frequency rates and 
by treatment group. The timepoint of each event will also be summarized. 


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8.4.1 
Adverse Events 
AEs occurring after the start of study drug dosing on Day 1 will be summarized descriptively for 
the Safety population. All AEs will be coded according to system organ class and preferred term 
using a Medical Dictionary for Regulatory Activities dictionary. Summary tables showing the 
number of subjects and percentage within each category will be generated for each of the 
following types of AEs:  
x 
All events 
x 
Serious events 
x 
Deaths 
x 
Events leading to study discontinuation 
x 
Events related to study treatment (study drug and injection procedure separately) 
x 
Severe events 
8.4.2 
Laboratory parameters 
Laboratory parameters and vital signs will be summarized by visit. Frequencies of high and low 
values with respect to the normal range will be displayed, as will shift tables comparing results at 
each treatment visit. 
8.4.3 
12-Lead Electrocardiogram 
12-lead ECG data (observed and change from baseline) will be listed for each subject by visit. 
Observed values and change from baseline will be summarized descriptively.  
8.4.4 
Columbia-Suicide Severity Rating Scale 
Results from the C-SSRS questionnaire will be listed and summarized using descriptive statistics 
by treatment group and visit. 
8.4.5 
Geriatric Depression Scale 
Results from the GDS questionnaire will be listed and summarized using descriptive statistics by 
treatment group and visit. 
 
 
 


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8.6 
Determination of Sample Size 
A total sample size of 75 evaluable subjects (25 per treatment arm) was chosen empirically for 
this proof-of-concept study based on ERP P300 latency results obtained in the Phase 1a/b study, 
NDX-1017-0101; no formal sample size calculation was applied. 
 
 
 
 
 
 
 
 
 
 
 
 


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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The CRO/Sponsor will conduct a study initiation visit to verify the qualifications of the 
investigator, inspect the facilities, and inform the investigator of responsibilities and procedures 
for ensuring adequate and correct documentation. 
The investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study subject. 
Audio recording for certain clinical assessments, including 
 MOCA, 
 and 
ADAS-Cog13 will be done for quality control purposes. No personal identifying information will 
be included in the recording. 
The investigator is responsible for ensuring that data are properly recorded on each subject’s 
eCRF and related documents in a timely manner. An investigator who has signed the protocol 
signature page should electronically sign for the eCRFs (as indicated in the eCRFs) to ensure that 
the observations and findings are recorded on the eCRFs correctly and completely. The eCRFs 
are to be submitted in a timely manner, or as otherwise specified by the Sponsor, and will be 
maintained in a central data repository. 
Frequent communication between the study site and the CRO/Sponsor is essential to ensure that 
the safety of the study is monitored adequately. The investigator will make all appropriate safety 
assessments on an ongoing basis. The Medical Monitor may review safety information as it 
becomes available throughout the study. 
All aspects of the study will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Study Monitor will be an authorized 
individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study 
with the Principal Investigator. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator at least 2 years after the last approval of a marketing application in 
an International Council for Harmonisation (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period however if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. No records 
may be destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 


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9.2 
Access to Source Data/Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
The investigator will ensure the accuracy, completeness and timeliness of the data reported to the 
Sponsor. Data reported or entered in the eCRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records. Also, current medical records 
must be available. 
Data collection processes and procedures will be reviewed and validated to ensure completeness, 
accuracy, reliability, and consistency. A complete audit trail will be maintained of all data 
changes. The investigator or designee will cooperate with the Sponsor’s representative(s) for the 
periodic review of study documents to ensure the accuracy and completeness of the data capture 
system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE, and concomitant medication reporting, raw data collection forms, 
as well as the results of diagnostic tests such as MRI scans and laboratory tests) designed to 
record all observations and other pertinent data for each subject receiving IMP. 
The investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors and the IRB/IEC to have direct access to all documents pertaining to the 
study. 
9.3 
Archiving Study Documents 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IMP. However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
9.4 
Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the investigator abide by the ICH Tripartite Guideline for GCP (E6) and with other applicable 
regulatory requirements. The clinical study also will be carried out in keeping with national and 


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local legal requirements (in accordance with United States Investigational New Drug 
Regulations [21 CFR 56]). 
9.5 
Financial Disclosure 
Investigators and subinvestigators will provide the Sponsor or designee with sufficient, accurate 
financial information as requested to allow the Sponsor or designee to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
9.6 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
from the subject or his/her legally authorized representative (LAR) according to the applicable 
regulatory and legal requirements. As part of this procedure, the investigator or appropriately 
qualified designee must explain orally and in writing (when possible) the nature, duration, and 
purpose of the study and the action of the IMP in such a manner that the study subject is aware of 
the potential risks, inconveniences, or AEs that may occur, and answer all questions regarding 
the study. The study subject should be informed that their participation is voluntary and that 
he/she is free to withdraw from the study at any time. If a subject, LAR, and caregiver/support 
person is not able to review consent in person at the clinic due to travel restrictions, documented 
oral review by the investigator or appropriately qualified designee with the subject, LAR, and 
caregiver/support person must occur and be documented in the subject’s study records. 
Subjects or their LAR will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study center. The 
investigator or designee will provide the CRO with a copy of the IRB/IEC-approved ICF prior to 
the start of the study. 
The informed consent document must be signed and dated; the authorized person obtaining the 
informed consent must also sign the ICF. One copy will be provided to the subject/LAR and to 
the caregiver/support person, and the investigator will retain a copy as part of the clinical study 
records.  
If the caregiver/support person is different from the LAR, a specific ICF must be explained and 
this person be consented to the tasks and duties during the study; since many assessments rely 
only on the input from the caregiver/support person, it is important they understand fully their 
role in the trial. The investigator will not undertake any investigation specifically required for the 
clinical study until written consent has been obtained. The terms of the consent and when it was 
obtained must also be documented.  


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If a protocol amendment is required, then the informed consent document(s) may need to be 
revised to reflect the changes to the protocol. If the informed consent document(s) are revised, 
they must be reviewed and approved by the responsible IRB/IEC, and signed by all subjects/ 
LARs/caregiver/support persons subsequently enrolled in the clinical study as well as those 
currently enrolled in the clinical study. 
9.7 
Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents 
will be approved by the IRB/IEC, in accordance with local legal requirements. The Sponsor must 
ensure that all ethical and legal requirements have been met before the first subject is enrolled in 
the clinical study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
which must be released by the Sponsor and receive IRB/IEC approval prior to implementation 
(as appropriate). 
Administrative changes may be made without the need for a formal amendment, but will also be 
mentioned in the integrated clinical study report. All amendments will be distributed to all study 
protocol recipients, with appropriate instructions. 
9.8 
Confidentiality Data Protection 
All clinical study findings and documents will be regarded as confidential. Study documents 
(protocols, Investigator Brochures, and other material) will be stored appropriately to ensure 
their confidentiality. The investigator and members of his/her research team (including the 
IRB/IEC) must not disclose such information without prior written approval from the Sponsor, 
except to the extent necessary to obtain informed consent from subjects who wish to participate 
in the trial or to comply with regulatory requirements. 
The anonymity of participating subjects must be maintained. Subjects will be specified on study 
documents by their subject number, initial or birth date, not by name. Documents that identify 
the subject (e.g., the signed informed consent document) must be maintained in confidence by 
the investigator. The subject must be informed that his/her personal study-related data will be 
used by the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject/LAR. 
9.9 
Publication Policy 
By signing the clinical study protocol, the investigator agrees with the use of results of the 
clinical study for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals. If necessary, the competent 


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authorities will be notified of the investigator’s name, address, qualifications, and extent of 
involvement. 
The sponsor has proprietary interest in this study. Authorship and manuscript composition will 
reflect joint cooperation between multiple investigators and sites and Sponsor personnel. 
Authorship will be established prior to the writing of the manuscript. As this study involves 
multiple centers, no individual publications will be allowed prior to completion of the final 
report of the multicenter study except as agreed with the Sponsor. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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10 
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antidementia drugs: Additions to the Alzheimer’s Disease Assessment Scale that broaden its 
scope. Alzheimer’s Disease and Associated Disorders, 11, S13-S21. 
Molnarfi, N., et al. (2014). Hepatocyte growth factor: A regulator of inflammation and 
autoimmunity. Autoimmun Rev. 14, 293–303. 
O’Brien, P.C. (1984). Procedures for comparing samples with multiple endpoints. Biometrics 40, 
1079-1087. 
Olichney, J.M., et al. (2011). Cognitive event-related potentials: Biomarkers of synaptic 
dysfunction across the stages of Alzheimer’s disease. Journal of Alzheimer’s Disease 26, 215-
228. 


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Organ, S.L., and Tsao, M-S. (2011). An overview of the c-MET signaling pathway. Ther Adv 
Med Oncol. 3, S7-S19. 
Piguet, F., et al. (2017). Clinical gene therapy for neurodegenerative diseases: Past, Present, and 
Future. Human Gene Therapy 28, 988-1003. 
Postuma, R.B., et al. (2015). MDS clinical diagnostic criteria for Parkinson’s disease. Mov. 
Disord. 30, 1591-1599. 
Rocca, W.A. (2018). The burden of Parkinson’s Disease: a worldwide perspective. Lancet 
Neurology 17, 928-929. 
 
 
Shang, J., et al. (2011). Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of 
hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. J. 
Neurosci. Res. 89, 86–95. 
Sheikh, J.I., and Yesavage, J.A. (1986). Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontologist: The Journal of Aging and Mental 
Health, 5, 165–173. 
 
 
Szeto, J.Y.Y., and Lewis, S.J.G. (2016). Current treatment options for Alzheimer’s disease and 
Parkinsons’ disease dementia. Current Neuropharmacol. 14, 326-338.  
Tyndall, S.J., et al. (2007). Hepatocyte growth factor-induced enhancement of dendritic 
branching is blocked by inhibitors of N-methyl-D-aspartate receptors and calcium/calmodulin-
dependent kinases. J. Neurosci. Res. 85, 2343–2351. 
Tysnes, O.B., and Storstein, A. (2017). Epidemiology of Parkinson’s disease. J. Neural. Transm. 
124, 901-905. 


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11 
APPENDICES 
11.1 
Appendix 1: List of Prohibited Medications (Non-exhaustive Examples) 
This is not an exhaustive list; if the permissibility of a specific medication is in question, please 
contact the Medical Monitor. 
Category of Prohibited Medications 
Examples: General Name (Trade Name) 
NMDA receptor antagonists 
• Memantine (Namenda) in any form, combination 
or dosage 
• Dextromethorphan 
High-dose donepezil  
• Donepezil (Aricept) at 23 mg 
Dopamine receptor antagonists (not 
antipsychotics) 
• Metoclopramide (Reglan) 
Peripherally acting anticholinergics 
(exception: solifenacin [Vesicare] is 
allowed) 
• Fesoterodine (Taviaz) 
• Oxybutynin (Ditropan, Ditropan XL, Gelnique, 
Oxytrol) 
• Tolterodine (Detrol, Detrol LA) 
• Trospium (Sanctura, Sanctura XR) 
Nicotine therapy  
• Nicotine patches, gum, sprays, inhalers, 
lozenges, etc. 
• Varenicline (Chantix) or similar therapeutic 
agent 
Psychoactive medications having 
significant anticholinergic effects 
and/or believed to affect cognitive 
function including antipsychotics 
(Exclusion Criterion 26(d)), 
anti-depressants (tricyclics, 
irreversible MAO-B inhibitors 
(Exclusion Criterion 26(f)), 
anxiolytics (Exclusion Criterion 26(g)) 
or sedative hypnotics (Exclusion 
Criteria 26(h) and 26(i)) 
  
Antipsychotics (please refer to Exclusion Criterion 
26(d) [Section 4.3] for conditions under which 
antipsychotics may be allowable): 
• Haloperidol (Haldol, Serenace) 
• Pimozide (Orap) 
• Perazine (Peragal, Perazin, Pernazinum, Taxilan) 
• 
Perphenazine (Trilafon) 
• 
Prochlorperazine (Compazine) 
• 
Promethazine (Avomine, Phenergan) 
• 
Trifluoperazine (Stelazine) 
• 
Clopenthixol (Sordinol) 
• 
Tiotixene (Navane, Thixit) 
• 
Loxapine (Adasuve, Loxitane) 
• 
Amoxapine (Asendin) 
• 
Asenapine (Saphris, Sycrest)  
• 
Clozapine (Clozaril)  
• 
Iloperidone (Fanapt, Fanapta) 
• 
Lurasidone (Latuda) 
• 
Olanzapine (Zyprexa)  
• 
Paliperidone (Invega) 
• 
Quetiapine (Seroquel)  


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Category of Prohibited Medications 
Examples: General Name (Trade Name) 
• 
Risperidone (Risperdal)  
• 
Trimipramine (Surmontil) 
• 
Ziprasidone (Geodon, Zeldox)  
Antidepressants (tricyclics and irreversible MAO-B 
inhibitors): 
• Selegiline (Eldepryl, Emsam) 
• Clomipramine (anafranil) 
• Imipramine (tofranil, Janimine, Praminil) 
• Desipramine (Norpramin, Pertofrane) 
• Nortriptiline (Pamelor, Aventyl, Norpress) 
• Protriptyline (Vivactil) 
• Amitriptyline (Tryptomer, Elavil, Endep) 
• Amitripyilinoxide (Amioxid, Ambivalon, 
Equilibrin) 
• Amoxapin (Asendin) 
• Trimipramine (Surmontil) 
• Doxepin (Adapin, Sinequan) 
Other: 
• Trihexyphenidyl (Artane) 
• Sedating H1 antihistamines 
• Chronic opioids 
• S-ketamine 
• Anti-epileptics 
Moderate or strong CYP3A4 
inhibitors 
• Boceprevir (Victrelis) 
• Cimetidine 
• Clarithromycin (Biaxin, Prevpac) 
• Conivaptan (Vaprisol) 
• Diltiazem 
• Erythromycin 
• Fluconazole 
• Indinavir (Crixivan) 
• Itraconazole (Onmel, Sporanox) 
• Ketoconazole (Exina, Ketozole, Nizoral) 
• Lopinavir/ritonavir (Kaletra) 
• Mibefradil 
• Nefazodone (Serzone) 
• Nelfinavir (Viracept) 
• Posaconazole (Noxafil) 
• Ritonavir (Norvir) 
• Saquinavir (Fortovase, Invirase) 
• Telaprevir (Incivek) 
• Telithromycin (Ketek) 


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Category of Prohibited Medications 
Examples: General Name (Trade Name) 
• Troleandomycin 
• Verapamil 
• Voriconazole (Vfend) 
Moderate or strong CYP3A4 inducers 
• 
Avasimibe 
• 
Carbamazepine (Tegretol, Tegretol XR, 
Carbatrol, Epitol, Equetro, Teril) 
• 
Mitotane (Lysodren) 
• 
Modafinil (at doses 400 mg/day and above) 
• 
Nafcillin (Unipen, Nallpen) 
• 
Phenobarbital (Solfoton, Luminal) 
• 
Phenytoin (Dilantin, Cerebyx, Phenytek, 
Phenytex) 
• 
Primidone (Mysoline) 
• 
Rifampin (Rifater, Rimactane, Rifamate, 
Rifadin) 
• 
St. John’s wort 
• 
Rifabutin (Mycobutin) 
• 
Ritonavir (Norvir) 
Systemic immunosuppressants 
 
• Tacrolimus 
• Sirolimus 
• Cyclophosphamide 
• Methotrexate 
• Azathioprine 
• Prednisone 
• Prednisolone 
• Methylprednisolone 
 

SAP_001.pdf: 
Statistical Analysis Plan: ATH-1017-PD-0201
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Statistical Analysis Plan: ATH-1017-PD-0201 
Study Title:
A Randomized, Placebo-Controlled, Double-Blind Study of ATH-
1017 Treatment in Subjects with Parkinson’s Disease Dementia or 
Dementia with Lewy Bodies 
Study Number:
ATH-1017-PD-0201
Study Phase: 
Phase 2 
Sponsor: 
Athira Pharma, Inc.
18706 North Creek Parkway
Suite 104 
Bothell, WA 98011 
USA
NCT #: 
NCT04831281
Version: 
Final v1.0
Date: 
08 Aug 2023
Confidentiality Statement 
This document contains confidential and proprietary information, and is not to be distributed 
to any third party. 
 


Statistical Analysis Plan: ATH-1017-PD-0201
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS .........................................................................................................2
LIST OF TABLES...........................................................................................................................4
LIST OF FIGURES .........................................................................................................................4
LIST OF APPENDICES..................................................................................................................4
2
SIGNATURE PAGE ................................................................................................................5
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................6
4
INTRODUCTION....................................................................................................................9
5
STUDY OBJECTIVES AND ENDPOINTS..........................................................................10
5.1
Primary Objective..............................................................................................................10
5.2
Secondary Objectives.........................................................................................................10
6
STUDY DESIGN CONSIDERATIONS................................................................................14
6.1
Study Design ......................................................................................................................14
6.1.1
Safety Review Committee/Data Monitoring Committee .............................................15
6.1.2
Justification of Sample Size .........................................................................................15
6.2
Efficacy Measures ..............................................................................................................15
6.2.1
Cognitive Variables & Pharmacodynamic Variable ....................................................16
6.2.1.1 
Global Statistical Test (GST) score .......................................................................16
6.2.1.2 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-
Cog13)....................................................................................................................16
6.2.1.3 
Pharmacodynamic Variables .................................................................................16
 
 
 
 
  
  
 
 
  
6.4
Safety Measures .................................................................................................................20
6.4.1
Adverse Events ............................................................................................................20
6.4.1.1 
Definitions..............................................................................................................20
6.4.1.2 
Assessment of Adverse Events..............................................................................21
6.4.1.3 
Follow-up of Adverse Events ................................................................................24
6.4.2
Pregnancy .....................................................................................................................24


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6.4.3
Clinical Laboratory Assessments.................................................................................24
6.4.4
Vital Signs ....................................................................................................................26
6.4.5
Weight..........................................................................................................................26
6.4.6
12-Lead Electrocardiogram .........................................................................................26
6.4.7
Physical and Neurological Examination......................................................................27
6.4.8
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................................27
6.4.9
Geriatric Depression Scale (GDS)...............................................................................27
6.5
Pharmacokinetic Measures/Parameters .............................................................................27
6.6
Genotyping.........................................................................................................................27
6.7
Plasma Samples and Biobanking .......................................................................................27
7
STUDY POPULATIONS.......................................................................................................29
7.1
Analysis Populations ..........................................................................................................29
7.1.1
Intent-to-Treat (ITT) Population..................................................................................29
7.1.2
Modified Intent-to-Treat (mITT) Population ...............................................................29
7.1.3
Per Protocol (PP) Population  ......................................................................................29
7.1.4
Safety Population .........................................................................................................29
8
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL .........30
9
OVERALL STATISTICAL CONSIDERATIONS................................................................31
9.1
General Conventions ..........................................................................................................31
9.2
Baseline Definition ............................................................................................................31
9.3
Handling of Partial Dates ...................................................................................................31
9.4
Interim Analysis .................................................................................................................32
9.5
Pooling Strategy for Study Sites ........................................................................................32
9.6
Visit Windows / Unscheduled Visits.................................................................................32
10 STATISTICAL ANALYSIS METHODS..............................................................................34
10.1
Subject Disposition............................................................................................................34
10.2
Demographics and Baseline Characteristics......................................................................34
10.3
Prior and Concomitant Medications and Procedures .........................................................35
10.4
Treatment Compliance and Exposure ................................................................................35
10.5
Efficacy 
..........................................................................................................................35
10.5.1 
Primary Analysis ..........................................................................................................36
10.5.1.1 
Subgroup Analyses ................................................................................................36
10.5.2 
Secondary Analysis ......................................................................................................37
 
 
10.5.5 
Interim Analysis ...........................................................................................................38
10.5.6 
Final Analysis ..............................................................................................................38
10.6
Safety and Tolerability .......................................................................................................38
10.6.1 
Adverse Events ............................................................................................................38


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10.6.2 
Clinical Laboratory ......................................................................................................39
10.6.3 
Electrocardiograms ......................................................................................................40
10.6.4
Vital Signs....................................................................................................................40
10.6.5 
Physical and Neurological Examination ......................................................................40
10.6.6
Columbia-Suicide Severity Rating Scale.....................................................................40
10.6.7 
Geriatric Depression Scale  ..........................................................................................40
11
REFERENCES .......................................................................................................................42
12
APPENDICES ........................................................................................................................44
LIST OF TABLES
Table 1.
Study Objectives and Associated Endpoints..........................................................11
Table 2.
Assessment of Relationship of Adverse Events to IMP/Study Procedure .............22
Table 3.
Clinical Laboratory Assessments...........................................................................24
Table 4.
Imputation Rules for Partial Dates – Adverse Events ...........................................51
Table 5.
Imputation Rules for Partial Dates – Prior and Concomitant Medications ...........51
Table 6.
Analyses of Efficacy Parameters ...........................................................................52
LIST OF FIGURES 
Figure 1. 
Study Schema.........................................................................................................15
LIST OF APPENDICES 
APPENDIX 1. 
DERIVATION OF GST SCORES..................................................................45
APPENDIX 2. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES.............................47
APPENDIX 3.
IMPUTATION OF PARTIAL DATES...........................................................51
APPENDIX 4. 
SUMMARY OF EFFICACY ANALYSES.....................................................52
 




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3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Amyloid-
AD
Alzheimer’s disease 
ADAS-Cog13
Alzheimer’s Disease Assessment Scale-Cognitive Subscale, 13-item 
version  
  
 
  
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BILI
Bilirubin
CBC 
Complete blood count 
 
  
 
 
 
 
CI
Confidence interval
 
 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CPK 
Creatine phosphokinase 
C-SSRS 
Columbia-suicide severity rating scale  
DLB 
Dementia with Lewy bodies  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
ERP 
Event-related potentials 
ET
Early termination
FSH
Follicle-stimulating hormone


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fT3
Free tri-iodothyronine 
fT4
Free thyroxine
GBA
Glucocerebrosidase
GCP
Good Clinical Practice 
GDS
Geriatric depression scale
GFAP
Glial fibrillary acidic protein
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
GST
Global Statistical Test
Hb1Ac
Glycated hemoglobin
HBsAg
Hepatitis B surface antigen 
HCG
Human chorionic gonadotropin 
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate 
ICF
Informed consent form
IFN-
Interferon gamma
IMP
Investigational medicinal product
INR
International normalized ratio
IL
Interleukin
ITT
Intent-to-treat
LAR
Legally authorized representative
LBD
Lewy body dementia
MDS-UPDRS 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale 
mITT
Modified intent-to-treat
MMRM 
Mixed model for repeated measures
MOCA
Montreal Cognitive Assessment
MRI
Magnetic resonance imaging 
NfL
Neurofilament light chain
 
OD
Once-daily 


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PD
Parkinson’s disease 
PDD
Parkinson’s disease dementia
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetic(s)
PK-PD
Pharmacokinetic-pharmacodynamic
PKC
Protein kinase C
Phospholipase C-gamma
PP
Per-protocol
PRN
As needed 
PT
Prothrombin time
p-tau 
Phosphorylated tau
QTcB 
Corrected QT interval using Bazett’s formula
QTcF
Corrected QT interval using Fridericia’s formula
RBC
Red blood cells
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SC
Subcutaneous 
SD
Standard deviation
SE
Standard error 
SOP
Standard operating procedure
TNF-
Tumor necrosis factor alpha  
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal 
VAS
Visual analog scale
WBC
White blood cells 


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4
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to describe the framework for the reporting, 
summarization and statistical analysis methodology of the safety and efficacy parameters 
measured throughout the study. It is based on Protocol v3.0 dated 05 Nov 2021. 


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5
STUDY OBJECTIVES AND ENDPOINTS
5.1
Primary Objective
To evaluate the clinical effects of ATH-1017 in subjects with Parkinson’s disease 
dementia (PDD) or dementia with Lewy bodies (DLB)
To determine the safety and tolerability of ATH-1017 in subjects with PDD or DLB
5.2
Secondary Objectives
 To evaluate the clinical efficacy of ATH-1017 separately on:  
1) Cognition and  
2) ERP P300 latency  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 










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conditions (e.g. institutionalization, moving to a different city, etc.), or change in primary 
caregiver, during participation in the trial period. The end of the study is defined as the date of the 
safety follow-up visit, Visit 9/Week 30. Subjects who terminate prior to Visit 8 are to complete 
the same assessments as Visit 8/early termination (ET). 
Figure 1. Study Schema 
6.1.1 Safety Review Committee/Data Monitoring Committee 
All aspects of the study will be carefully monitored with respect to GCP and SOPs for compliance 
with applicable government regulations. The Study Monitor will be an authorized individual 
designated by the Sponsor. The Study Monitor will have access to all records necessary to ensure 
integrity of the data and will periodically review the progress of the study with the Principal 
Investigator. 
 
6.1.2 Justification of Sample Size 
A total sample size of 75 evaluable subjects (25 per treatment arm) was chosen empirically for this 
proof-of-concept study based on ERP P300 latency results obtained in the Phase 1a/b study, NDX-
1017-0101; no formal sample size calculation was applied. 
6.2 
Efficacy Measures 
A qualified, trained, and certified rater will administer questionnaires to the study subject and/or 
dedicated support person/caregiver. 


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6.2.1 Cognitive Variables & Pharmacodynamic Variable
6.2.1.1 
Global Statistical Test (GST) score
A composite approach will be used to facilitate the assessment of an overall change in disease 
status/trajectory in the trial. The GST score will be defined as a single outcome variable based on 
standardizing and then combining individual patient-level change from baseline cognition (ADAS-
Cog13) and change from baseline in ERP P300 latency. The GST score will be determined for each 
patient at each time point and the resulting scores will define the efficacy outcome variable to be 
used in the primary efficacy analysis. A formal definition of the GST score is given in Appendix
1. The assessment will be performed as per Appendix 2 Schedule of Assessment. 
6.2.1.2 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog13) 
The ADAS-Cog13 is designed to measure cognitive symptom change in subjects with MCI as well 
as AD (Mohs et al, 1997). In addition to the standard 11 items present in the ADAS-Cog11 (word 
recall, commands, constructional praxis, naming objects and fingers, ideational praxis, orientation, 
word recognition, spoken language ability, comprehension of spoken language, word-finding 
difficulty, and remembering test instructions), the ADAS-Cog13 includes a test of delayed word 
recall and a number cancellation task. The test comprises 9 performance items and 4 clinician-
rated items, with a total score ranging from 0 (no impairment) to 85 (severe impairment). 
Therefore, higher scores indicate more severe cognitive impairment. The assessment will be 
performed as per Appendix 2 Schedule of Assessment. 
 
6.2.1.3 
Pharmacodynamic Variables  
Pharmacodynamic variables will consist of ERP P300 assessments through electroencephalogram 
(EEG) assessments. ERP P300 should be performed when the subject is not experiencing 
interfering motor disturbances that might affect the quality of ERP P300 data; if necessary, the 
time window for ERP P300 assessments can be extended.  
ERP P300 is a method of recording brain activity elicited by external stimuli, e.g., an oddball 
auditory stimulus, and is a well-established functional biomarker, particularly of working memory 
access (Ally et al, 2006). ERP P300 is characterized by a stereotyped series of voltage deflections 
occurring after the respective odd tone to be counted, with early features (< 100 msec) 
corresponding to unconscious sensory transmission (auditory cortex, N100), and later features 
produced by cognitive processing in the ventral attentional network, i.e., P300, referring to the 
large positive deflection at roughly 300 msec in healthy adults (young or elderly). The P300 latency 
is sensitive to detecting reduced synaptic transmission related to cognitive decline in AD patients 
and other dementias (Olichney et al, 2011).  
The EEG assessment will be performed as per Appendix 2 Schedule of Assessment.   
 
 
 
 
 


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6.2.2 
Disease Condition 
 
  
 
 
 
  
 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
  
 
 
  
 
  


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6.4
Safety Measures 
6.4.1
Adverse Events  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AE (see 
Section 6.4.1.3).  
6.4.1.1 
Definitions  
An AE is any untoward medical occurrence in a study subject which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including a clinically significant abnormal laboratory finding), symptom, or disease (new or 
exacerbated), temporally associated with the use of the IMP, whether or not considered related to 
the IMP.  
Events meeting the definition of AE include:  
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease).  
 Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.  
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.  
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae.  
Events not meeting the definition of AE include:  
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.  
 The disease/disorder being studied or expected progression, signs, or symptoms (clearly 
defined) of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 


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 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.  
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).  
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen (note: preexisting conditions will be 
recorded as part of the subject’s medical history).  
6.4.1.2 
Assessment of Adverse Events  
Each AE will be assessed by the investigator with regard to the categories discussed in the sections 
below.  
Intensity  
The investigator will assess all AEs for severity in accordance with the following standard ratings: 
 Mild: Ordinarily transient symptoms, does not influence performance of subject’s daily 
activities. Treatment is not ordinarily indicated or may be minimal.  
 Moderate: Marked symptoms, sufficient to make the subject uncomfortable. Moderate 
influence on performance of subject’s daily activities. Treatment may be necessary to 
alleviate symptoms.  
 Severe: Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities, or significantly affects clinical status. May be unable to continue in the study 
and intensive treatment may be necessary. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity recorded for the event should be noted.  
Note: an event is defined as serious when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE (see later), NOT when it is rated as severe.  
Causality  
The investigator will assess the causality/relationship between the AE and IMP/study procedure. 
One of the categories described in Table 2 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. In this study AEs will be considered 
related to IMP/study procedure if causality is ascribed as either related, probably related, or 
possibly related. 


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Table 2.
Assessment of Relationship of Adverse Events to IMP/Study Procedure
Related 
  
A clinical event, including laboratory test abnormality, which occurs in a 
plausible time relationship to treatment administration, and which 
concurrent disease or other drugs or chemicals cannot explain. The 
response to withdrawal of the treatment (dechallenge*) should be 
clinically plausible. The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory rechallenge† procedure if 
necessary. 
Probably related 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment, unlikely to be attributed 
to concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfil this definition.
Possibly related  
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on treatment withdrawal may be lacking or unclear.  
Unlikely 
to 
be 
related   
A clinical event, including laboratory test abnormality, with a temporal 
relationship to treatment administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations.  
Unrelated  
  
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration. May have negative 
dechallenge and rechallenge information. Typically explained by 
extraneous factors (e.g., concomitant disease, environmental factors or 
other drugs or chemicals).  
*Dechallenge is when a drug suspected of causing an AE is discontinued. If the symptoms of the AE disappear partially 
or completely, within a reasonable time from drug discontinuation, this is termed a positive dechallenge. If the 
symptoms continue despite withdrawal of the drug, this is termed a negative dechallenge. Note that there are 
exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia).  
†Rechallenge is when a drug suspected of causing an AE in a specific subject in the past is readministered to that 
subject. If the AE recurs upon exposure, this is termed a positive rechallenge. If the AE does not recur, this is termed 
a negative rechallenge.  
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment.  
The causality assessment is one of the criteria used when determining regulatory reporting 
requirement.  


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Seriousness  
An SAE is defined as any untoward medical occurrence that at any dose: 
Results in death.  
Is life-threatening; this means that the subject was at risk of death at the time of the event; 
it does not mean that the event hypothetically might have caused death if it were more 
severe. 
Requires hospitalization or prolongation in existing hospitalization; in general, 
hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization 
for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.  
 Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., 
sprained ankle) which may interfere with or prevent everyday life functions but do not constitute 
a substantial disruption.  
 Is a congenital anomaly or birth defect, or  
 Is another important medical event (see below) 
Important medical events that do not result in death, are not life-threatening or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse.  
A distinction should be drawn between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. For example, a mild degree of gastrointestinal 
bleeding requiring an overnight hospitalization for monitoring purposes would be considered an 
SAE but is not necessarily severe. Similarly, an AE that is severe in intensity is not necessarily an 
SAE. For example, headache may be assessed as severe in intensity but would not be considered 
an SAE.  


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Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.4.1.3 
Follow-up of Adverse Events  
All AEs experienced by a subject, irrespective of the suspected causality or seriousness, will be 
monitored until the event has resolved, until any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the investigator and Medical Monitor, until there is a 
satisfactory explanation for the changes observed or until the subject is lost to follow-up. 
All AEs/SAEs that are still present after the last study drug administration (including AEs that 
have led to premature discontinuation), will be followed-up at the Safety follow-up visit. In case 
the AE/SAE is still ongoing after that timepoint, this will be followed up until its resolution or 
until otherwise agreed between the Sponsor and the investigator.  
Additional safety data collected after the Safety follow-up visit to follow-up the ongoing AE will 
not be included into the clinical database, if this was already locked; therefore, the clinical database 
lock will not be delayed due to this situation. Any SAE will be followed up, if needed, after clinical 
database lock, and the information will be only stored in the safety database. 
6.4.2 
Pregnancy 
Female subjects who become pregnant during the study will be withdrawn.  
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
6.4.3 
Clinical Laboratory Assessments  
The assessment will be performed as per Appendix 2 Schedule of Assessment. The following 
laboratory variables will be determined as outlined in Table 3 below:
Table 3.
Clinical Laboratory Assessments
Test 
Parameters 
 
Hematology 
CBC 
Hb1Ac  
Hemoglobin  
Hematocrit 
Erythrocytes (RBC) 
Leukocytes (WBC)  
Differential WBC 
Platelets 


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Biochemistry 
Sodium 
Potassium 
Magnesium 
FSH (post-menopausal females only) a
Calcium  
Chloride 
Glucose 
Creatinine 
ALP  
AST 
ALT 
GGT 
CPK 
Total bilirubin 
Total protein 
Albumin  
Total Cholesterol 
Low-density lipoprotein  
High-density lipoprotein  
Triglycerides 
TSH, fT3 and fT4 a
Coagulation 
INR 
PT 
aPTT 
Serology 
HBsAga
HCV a 
HIV type 1 or type 2 a
Urinalysis  
pH glucose 
ketones 
specific 
gravity  
HCG (females 
of child-
bearing 
potential only) 
nitrite 
protein 
bilirubin 
blood  
AST = aminotransferase; ALP = alkaline phosphatase; ALT = alanine transaminase; CBC = complete blood count; CPK = creatine 
phosphokinase; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; Hb1Ac = glycated hemoglobin; HBsAg 
= hepatitis B surface antigen; HCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; INR = international 
normalized ratio; PT = prothrombin time; aPTT = activated partial thromboplastin time; RBC = red blood cells; fT3 =free tri-
iodothyronine; fT4 =free  thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cells.  
a Measured only at Screening for eligibility; not included in subsequent safety labs.  
Any value outside the normal range will be flagged for clinical interpretation by the investigator 
or designee at the site. In this study, ALT or AST > 2 times the upper limit of normal, or Child-
Pugh Class B and C (i.e., including total bilirubin, albumin, and INR values), will be exclusionary. 
For transaminase liver enzymes, a repeat laboratory assessment may be performed if outside of the 
normal range. If the transaminases remain elevated the investigator should consider stopping study 
medication and withdrawing the subject. 
A medical alert for potential Hy’s laws cases (possible drug-induced liver injury) will be issued 
based on lab values and supported by Medical Monitor interpretation.  
Criteria for potential Hy’s law cases are as follows:   
 
 Total
 
 
 
For the Elevated Liver Tests summary, the list of lab test with criteria will be considered. 


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i) Alanine Aminotransferase (Normal <=ULN, >1 - 3 x ULN, >3 - 5 x ULN, >5 - 10 x ULN, 
>10 - 20 x ULN, >20 x ULN) 
ii) Aspartate Aminotransferase (Normal <=ULN, >1 - 3 x ULN, >3 - 5 x ULN, >5 - 10 x ULN, 
>10 - 20 x ULN, >20 x ULN)
iii) Alkaline Phosphatase (Normal <=ULN, >1 - 2 x ULN, >2 x ULN) 
iv) Bilirubin (Normal <= 2 x ULN, >2 x ULN) 
v) Hy's Law: ALT/AST>=3xULN and BILI>=2xULN (Criteria Not Met, With ALP <2 x 
ULN, With ALP >=2 x ULN)
vi) Alkaline Phosphatase >=2 x ULN (Criteria Not Met, With ALT/AST <2X ULN, With 
ALT/AST >=2X ULN)
 
6.4.4 
Vital Signs  
The following vital signs will be measured:   
 Blood pressure (supine) (systolic and diastolic [mmHg]) 
 Orthostatic blood pressure (systolic and diastolic [mmHg])  
 Heart rate (bpm)  
Body temperature (°C) (oral, tympanic, temporal, or forehead infrared) 
Respiratory rate (breaths per minute) 
Supine BP and HR recordings will be made after the subject has been supine for at least 5 minutes. 
The assessment will be performed as per Appendix 2 Schedule of Assessment. The first blood 
pressure will be the average of 3 measurements recorded after the subject is supine for 5 minutes; 
the second blood pressure will be recorded after the subject has stood for up to 3 minutes. A drop 
abnormal. 
6.4.5
Weight  
Additionally, weight (kg) and BMI (kg/m2) will be measured under the same Vital sign assessment.
6.4.6
12-Lead Electrocardiogram  
The 12-
 The 
assessment will be performed as per Appendix 2 Schedule of Assessment. The ECG will include 
all 12 standard leads and a Lead II rhythm strip on the bottom of the tracing. The following ECG 
parameters will be collected: PR interval, QRS interval, RR interval, QT interval, mean heart rate, 
QTcB and QTcF interval.  
All ECGs must be evaluated by the investigator or qualified designee for the presence of 
abnormalities. Collection and analysis of ECG data will be performed by a central ECG vendor.  


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6.4.7
Physical and Neurological Examination 
The physical examination includes an assessment of general appearance and a review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric 
systems).  
Neurological components include, but are not limited to, the following assessments: mental status, 
cranial nerves, muscle strength, tone, and bulk, reflexes, coordination, sensory function, and gait. 
The assessment will be performed as per Appendix 2 Schedule of Assessment. 
6.4.8
Columbia-Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS supports suicide risk assessment through a series of simple, plain-language questions. 
The responses assist in identifying whether a subject is at risk for suicide, assesses the severity and 
immediacy of that risk, and gauge the level of support that the subject may require. The assessment 
will be performed as per Appendix 2 Schedule of Assessment.   
6.4.9 
Geriatric Depression Scale (GDS)  
The GDS is a self-report measure of depression in older adults with a “Yes/No” response format; 
The GDS was originally developed as a 30-item instrument. It has since been validated in a 
shortened form comprising 15 items (Sheikh and Yesavage, 1986). The total score range is 0 to 
15, with a higher score indicating more severity. The assessment will be performed as per 
Appendix 2 Schedule of Assessment.   
 
 
 
 
 
 
 
 
  
6.6 
Genotyping  
Blood sample(s) will be collected at Screening for analysis of GBA genotype in subjects who 
consented to genotyping.   
 
 
  
 
  


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7
STUDY POPULATIONS
7.1
Analysis Populations
7.1.1
Intent-to-Treat (ITT) Population 
The ITT population will consist of all randomized subjects regardless of whether or not the subject 
received test article.  A subject is considered randomized when the IxRS provides the test article 
assignment (ie, completes a randomization transaction). Subjects will be analyzed according to the 
dose they were randomized to.   
7.1.2 
Modified Intent-to-Treat (mITT) Population
The modified intent-to-treat (mITT) population will include all randomized subjects who took at 
least one dose of the study medication and who completed both an ADAS-Cog13 and ERP P300 
assessment at Baseline and during at least one post-baseline visit. Subjects will be analyzed 
according to the dose they were randomized to. 
7.1.3 
Per Protocol (PP) Population  
The per protocol population will include all mITT subjects who were medication compliant during 
the 26 weeks of double-blind treatment, completed both an ADAS-Cog13 and ERP P300
assessment during at least one post-baseline visit, and did not have any major protocol deviations. 
Subjects will be analysed based on actual treatment received. 
All criteria for subject removal from PP are identified and confirmed prior to data base lock. 
7.1.4 
Safety Population  
The Safety population will include all randomized subjects who received at least one dose of the 
study medication. Subjects will be analyzed based on actual treatment received.
 
  
 
 
 
 
 


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8
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
The following changes have been made in the analytical strategies:
Since the study is stopped early, minimal analyses will be performed.  
 No interim analysis will be performed.
Alternate statistical comparison tests can be implemented as appropriate.
No statistical conclusion can be made based on the statistical test, if generated.
Other than summary statistics, all exploratory and subgroup analysis are optional.


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9
OVERALL STATISTICAL CONSIDERATIONS
9.1
General Conventions
Efficacy and safety data will be summarized and presented by disease type (PDD or DLB),
acetylcholinesterase inhibitor (AChEI) usage within disease type, treatment group, and time point 
in summary tables. Continuous variables will be presented by descriptive statistics: n, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical variables will be tabulated 
by frequency count and percentage. Percentages are based on the number of subjects in each 
treatment group in the given population for AE summary tables, and additionally overall for 
medical history, prior and concomitant medications. For all other tables, percentages are based on 
the number of subjects with non-missing data in each treatment group and overall for the given 
population.
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g., standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. P-values will be quoted to 4 decimal places 
consistent with SAS PVALUEw.d format set to PVALUE6.4. P-values < 0.0001 will be presented 
as p<0.0001. 
Listings will include all subjects with defined analysis population for each listing. Listings will 
generally be sorted by disease type, treatment, subject ID, parameter and visit date/study day. 
Unscheduled visits will also be included in the listings. 
Days will be converted to weeks by dividing by seven. Days will be converted to months by 
dividing by 30.44. Days will be converted to years by dividing by 365.25. All data collected during 
the study will be analyzed and reported except as stated otherwise. 
All data will be analyzed using the SAS® Version 9.4 or later.   
9.2 
Baseline Definition 
For safety summaries, the last pre-randomization measurement is defined as the baseline value. 
For clinical effect measures baseline is defined as the last pre-randomization measurement.
GST score, ADCS-CGI-C, and CaGI-C are change scores, so no further calculation is required. 
Appendix 1 describes calculation of the baseline GST score for baseline covariate purposes. For 
all other efficacy measures, baseline is the average of all measurements prior to first dosing, or if 
only one measurement exists that value will be used. 
9.3 
Handling of Partial Dates 
If partial dates are recorded for adverse event and concomitant medications, then partially dates 
will be filled as per Appendix 3. No imputation will be done for other partial dates. 


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9.4 
Interim Analysis 
This is an early closure study; no interim analysis will be performed. 
 
9.5 
Pooling Strategy for Study Sites 
No pooling strategy will be performed due to the smaller number of subjects enrolled in the 
study. 
9.6
Visit Windows / Unscheduled Visits
Visit windowing will be applied for the analyses which use visit categories. For categorical visit 
summaries, all visits including early termination assessments and unscheduled visits will be 
included with the closest scheduled post-baseline visit that includes the efficacy or safety 
assessment, based on number of days since Day 1. For the primary variable of ERP P300 latency
effect, if multiple assessments fall within the same analysis window, pre- and post-dose 
measurement will be averaged within the analysis window for this variable. For all other efficacy 
assessments, if multiple efficacy assessments fall within the same analysis window (other than 
baseline), any non-missing efficacy assessments will be averaged. For all non-efficacy 
assessments, a last-within-window approach will be used. 
The analysis windows for ERP P300, ADAS-Cog13 and COWAT are: 
Analysis Visit
Protocol-Specified 
Day
Analysis-Specified 
Interval 
Week 2
Day 14 
Day 2-63
Week 12 
Day 84 
Day 64-112 
Week 20 
Day 140
Day 113-161 
Week 26 
Day 182
Day 162-196 
Week 30 
Day 210
Day 197-218 
The analysis windows for C-SSRS, Physical and Neurological Exams, EG, Vital Signs, Labs are: 
Analysis Visit
Protocol-Specified 
Day
Analysis-Specified Interval
Week 2
Day 14 
Day 2-28
Week 6
Day 42 
Day 29-63 
Week 12 
Day 84 
Day 64-98 
Week 16 
Day 112 
Day 99-126 
Week 20 
Day 140 
Day 127-161
Week 26 
Day 182 
Day 162-196
Week 30 
Day 210 
Day 197-218
The analysis windows for GDS are: 


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Analysis Visit
Protocol-Specified 
Day
Analysis-Specified Interval
Week 12
Day 84
Day 2-133
Week 26 
Day 182 
Day 134-196
Week 30
Day 210
Day 197-218
The analysis visit windows for MMSE is: 
Analysis Visit
Protocol-Specified 
Day
Analysis-Specified Interval
Week 12
Day 84
Day 2-112
Week 20 
Day 140 
Day 113-161
Week 26 
Day 182 
Day 162-218
The analysis windows for MDS-UPDRS, NMSS, ADCS-ADL23, ADCS-CGIC, ADCS-CaGIC, 
ADCS-CGIS, and PK are: 
Analysis Visit
Protocol-Specified 
Day
Analysis-Specified Interval
Week 12 
Day 84 
Day 2-133 
Week 26 
Day 182 
Day 134-218


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10 STATISTICAL ANALYSIS METHODS
10.1
Subject Disposition
A summary table will be provided for all patients to display the number of subjects randomized, 
Safety Population, mITT Population, Per Protocol population, and patients who completed or 
discontinued the study with reason of study discontinuation, by treatment and overall. This 
summary will be produced for each disease type and AChEI usage within disease type. 
Listings will present all information on the End of Study eCRF page and the Protocol Deviations. 
Another supportive listing will display patients excluded from any analysis population along with 
the reason(s) for exclusion. 
Screen failure data will be listed by reason subjects were found to not be eligible for the study. 
Randomization data will also be listed by subject, country, site, randomization number and 
randomization date. 
10.2 Demographics and Baseline Characteristics 
A summary table will be provided for demographic and baseline characteristics for safety
population, presented by treatment and overall. This summary will be produced for each disease 
type and AChEI usage within disease type.
Variables to be summarized in this table are: 
 Gender (male/female)
 Race (white, black or African American, American Indian or Alaska native, Native 
Hawaiian or other Pacific Islander, Asian, Other) 
 Years of Education (years) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
Age (years)
Age group (<=55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85)
Disease Type (Dementia with Lewy bodies, Parkinson's Disease Dementia)
Baseline MMSE total score
Baseline MMSE group (Mild (MMSE>=20), Moderate (MMSE<20)),
Baseline GBA Genotype 
Baseline Weight (kg)
Baseline Height (cm)
Baseline Body mass index (BMI, kg/m2) 
 AChEI usage (Yes, No) 
 
Listings will present all data on the demographics, baseline characteristics, clinical diagnosis, medical 
history CRF pages for safety population. 


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10.3 Prior and Concomitant Medications and Procedures 
Medications received prior to the date of first dose of double-blind study medication are considered as 
prior medications. Medications will be considered as concomitant if the start date of the medication is 
on or after the date of first intake of investigational product or if the start date is prior to the first date 
of investigational product but the medication is ongoing during the treatment period in the study. 
Concomitant medications will be coded using the World Health Organization (WHO) dictionary 
and will be summarized by generic name and Anatomical Therapeutic Chemical (ATC) 
classification system level 3 for safety population, by treatment group and overall. This summary 
will be produced for each disease type and AChEI usage within disease type. 
A listing will be generated for prior and concomitant medications. A separate listing will be 
generated for surgical procedures.
10.4 Treatment Compliance and Exposure 
Duration of exposure, number of days dosed, compliance and drug holiday duration will be 
tabulated descriptively as per CRF response for safety population, by treatment and overall. This 
summary will be produced for each disease type and AChEI usage within disease type. 
Duration of exposure for the treatment will be calculated as follows: 
 
Duration of exposure in days = (Last dose date – First dose date) + 1 
 
Duration of exposure also will be categorized as:  
i) 
0 to 2 weeks 
ii) 
 >2 to 6 weeks  
iii) 
>6 to 12 weeks 
iv) 
>12 to 16 weeks 
v) 
>16 to 20 weeks 
vi) 
>20 to 26 weeks 
vii) 
>26 weeks 
Drug compliance will be categorized as:  
i) 
< 80% 
ii) 
>=80% 
 
10.5 Efficacy 
Summary statistics will include change from baseline comparison of ATH-1017 with placebo 
using a two-sample t-test without baseline adjustment. All statistical tests will be carried out using 
a one-sided 2.5% significance level and all comparisons will be reported with 95% confidence 
intervals for mITT population unless otherwise stated. The comparison between ATH-1017 (40 
mg and 70 mg pooled) and placebo will serve as the primary efficacy comparison. This summary 
will be produced for each disease type and AChEI usage within disease type also. 


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No adjustments will be made for multiple comparisons. 
10.5.1 
Primary Analysis 
NOTE: The following description for the primary analysis was prepared to implement the intention 
of the protocol, however in view of the early stopping of the trial this analysis will not be 
performed, unless the simple summary statistics suggest a finding of interest, in which case this 
would be performed as an exploratory analysis. 
The primary analysis will use a mixed model with repeated measures (MMRM) to compare the 
GST score between ATH-1017 and placebo at 26 weeks. In this MMRM model, GST score (a 
composite of the standardized change from baseline variables) will be considered as the outcome 
variable and the following fixed terms: baseline value, treatment arm, visit, treatment by visit 
interaction, baseline by visit by treatment interaction, GBA genotype, and baseline age. The 
correlations among repeated observations within a patient will be accounted for by specifying an 
unstructured covariance matrix. The least squares mean, and treatment differences will be 
estimated from the MMRM model.  
The MMRM model summary will contains LSMEAN, Standard Error (SE), 95% CI at each visit 
by treatment (ATH-1017, Placebo) will be displayed. Also, LSMEAN for ATH-1017 difference 
from placebo, SE, 95% CI, and p-value at Week 26.   
If convergence not met for the MMRM model, GST score between ATH-1017 and placebo at 
Week 26 will be compared using one sided t-test 2.5% significance level. 
Additionally, the GST score will be listed and summarized for all visits. This summary will be 
produced for each disease type and AChEI usage within disease type also. A line plot with mean 
GST score and 95% CI over visit by treatment arm (40 mg ATH-1017, 70 mg ATH-1017 and 
placebo) will be displayed.  
 
10.5.1.1 
Subgroup Analyses 
NOTE: These analyses are not planned due to the early termination of the trial but may be 
performed as exploratory if deemed worthwhile by the sponsor. 
The analyses may be performed for subgroups of interest such as subgroups based on key 
demographic or clinical characteristics, e.g., gender, age group (< 65 years and >= 65 years of 
age), AChEI usage, and GBA genotype. The subgroup analyses will be applied to the mITT 
population. 
No subgroup analyses are planned due to limited subjects enrolled in this study. 


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10.5.2
Secondary Analysis 
NOTE: The following description for the secondary analyses was prepared to implement the 
intention of the protocol, however in view of the early stopping of the trial this analysis will not 
be performed, unless the simple summary statistics suggest a finding of interest, in which case 
these would be performed as exploratory analysis. 
The separate key secondary variables ADAS-Cog13 and ERP P300 latency will be analyzed using 
the MMRM model. Change form baseline ADAS-Cog13 score and change form baseline ERP 
P300 latency will be used as the outcome variable and the following fixed terms: baseline value, 
treatment arm, visit, treatment by visit interaction, baseline by visit by treatment interaction, GBA 
genotype, and baseline age. in the MMRM model. Similar summary statistics will be presented
that was used for analysis of the primary endpoint. If MMRM model do not converge, active 
treatment and placebo groups will be compared using one sided t-test 2.5% significance level at 
Week 26 for change for baseline secondary variables. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.5.5
Interim Analysis
An interim analysis was planned to be performed when at least 30 subjects had completed the 
Week 2 visit. The analysis would have focused on the ERP P300 results and would be used to 
determine whether one or other of the 2 active doses of ATH-1017 (40 mg or 70 mg) is superior 
to the other (difference of 2 standard deviations). Based on the analysis, subjects would be enrolled 
with the superior dose.
In view of the early stopping of the trial, no interim analysis will be performed. 
10.5.6
Final Analysis 
 This is an early closure study; other than summary statistics, all analyses are optional. 
10.6 Safety and Tolerability 
All safety analyses will be performed on the safety population. 
10.6.1
Adverse Events 
All adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). A treatment-emergent adverse event (TEAE) is defined as any 
adverse event that begins or worsens in severity on or after the first study drug dose date until 
follow-up period. Treatment Related AE includes probably related, possibly related or related 
AEs. Injection Site Reactions will be identified from high level term (HLT) as ‘Injection Site 
Reactions’. 
The number and percentage of subjects experiencing one or more adverse events in the following 
adverse event categories will be summarized for each treatment group, and overall. No 
comparisons of treatment groups will be performed. 
 Any AE 
 Any TEAE 
 Any Treatment Related TEAE (possibly related; probably related; related) 
 Any severe TEAE 


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 Any serious TEAE 
Any TEAE that led to discontinuation of study drug
Any fatal TEAE
All deaths
Treatment emergent adverse event (TEAE) incidence will be summarized and presented using 
primary MedDRA system organ classes (SOCs), and preferred terms (PTs).
All TEAE
Any Treatment Related-TEAE 
Study Drug Related Treatment-Emergent Adverse Events by Worst Severity 
 Any serious TEAE by Worst Severity
 Any TEAE that led to discontinuation of study drug 
 Treatment-Emergent Adverse Events Leading to Death  
 Injection Site Reactions Treatment-Emergent Adverse Events 
The following listings of adverse events will be prepared. 
 All adverse events 
 Drug Related Treatment-Emergent Adverse Events
 Injection Site Reactions Treatment-Emergent Adverse Events
 Serious Treatment-Emergent Adverse Events  
 Treatment-Emergent Adverse Events Leading to Study Discontinuation
 Death listing 
10.6.2 
Clinical Laboratory 
Continuous blood clinical laboratory analytes observed values and change from baseline values 
will be summarized by analyte and visit using descriptive statistics (n, mean, median, SD, 
minimum, maximum) by treatment group. The denominators for calculating the percentages will 
be based on the number of subjects with non-missing assessments in each treatment group at a 
particular visit for the safety population. The latest non-missing clinical laboratory tests collected 
prior to dosing will be used as the baseline values.  


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Clinical laboratory results will be provided in data listings by treatment group, subject, lab 
category, visit and parameter. 
10.6.3 
Electrocardiograms 
ECG values will be summarized by visit and treatment group using descriptive statistics (n, mean, 
median, SD, minimum, maximum) for PR interval, QT interval, QTcB interval, QTcF interval, RR 
interval, mean heart rate, and QRS duration.  
The latest non-missing ECG value collected prior to dosing will be used as the baseline value. The 
baseline values will usually be the vital signs recorded at the Day 1 30 min pre-dose visit. In the 
case of repeated ECG parameters, the last collected values within that visit will be used for the 
summary tables.  
ECG will be provided in a data listing by subject, treatment group, subject, visit, timepoint and 
parameter.  
10.6.4 
Vital Signs 
Each vital sign will be summarized by treatment and by visit, using descriptive statistics (n, mean, 
median, SD, minimum, maximum) for the safety population for diastolic blood pressure, systolic 
blood pressure for both standing and supine position, heart rate and respiratory rate. 
The latest non-missing vital sign value collected prior to dosing will be used as the baseline values. 
The baseline values will usually be the vital signs recorded at the baseline visit. In the case of 
repeated vital signs, the last collected values within that visit will be used for the summary tables.  
Vital signs will be provided in a data listing by treatment group, subject, visit and parameter.   
10.6.5
Physical and Neurological Examination
The physical and neurological examination normal/abnormal results will be listed by treatment 
group, subject, visit and parameter.  
10.6.6
Columbia-Suicide Severity Rating Scale 
Count and percentage of C-SSRS responses will be generated over the visit. This summary will 
also be produced for each disease type and AChEI usage within disease type.
10.6.7
Geriatric Depression Scale  
Descriptive statistics for the results of GDS will be presented over the visit. This summary will 
also be produced for each disease type and AChEI usage within disease type.


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11 REFERENCES
Ally, B.A., et al. (2006). The P300 component in patients with Alzheimer’s disease and their 
biological children. Biol Psychol 72, 180-187.
Benton, A.L., et al. (1994). Multilingual Aphasia Examination (3rd ed). Iowa City, IA: AJA 
Associates. 
Busner, J., and Targum, S.D. (2007). The Global Clinical Impressions Scale: applying a research 
tool in clinical practice. Psychiatry 4, 28-37. 
 
  
Emre M., et al. (2004). Rivastigmine for dementia associated with Parkinson’s disease. N. Eng. 
J. Med. 351, 2509-2518.  
Emre M., et al. (2007). Clinical diagnostic criteria for dementia associated with Parkinson’s 
disease. Mov. Disord. 22, 1689-1707.
 
  
 
s disease Cooperative Study. Alzheimer’s Disease and 
Associated Disorders, 11, S33–S39.  
 
 
  
 
 
  
McKeith, I., et al. (2017). Diagnosis and management of dementia with Lewy bodies: Fourth 
consensus report of the DLB Consortium. Neurology 89, 88-100.  
Mohs, R.C., et al. (1997). Development of cognitive instruments for use in clinical trials of 
antidementia drugs: Additions to the Alzheimer’s Disease Assessment Scale that broaden its 
scope. Alzheimer’s Disease and Associated Disorders, 11, S13-S21.  
O’Brien, P.C. (1984). Procedures for comparing samples with multiple endpoints. Biometrics 40, 
1079-1087.  


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Olichney, J.M., et al. (2011). Cognitive event-related potentials: Biomarkers of synaptic 
dysfunction across the stages of Alzheimer’s disease. Journal of Alzheimer’s Disease 26, 
215228.  
Postuma, R.B., et al. (2015). MDS clinical diagnostic criteria for Parkinson’s disease. Mov. 
Disord. 30, 1591-1599.  
Rubin D. Inference and Missing Data. Biometrika, Vol. 63, No. 3 (Dec., 1976), pp. 581-592.
Sheikh, J.I., and Yesavage, J.A. (1986). Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontologist: The Journal of Aging and Mental 
Health, 5, 165-173. 
Strauss, E., et al. (2006). Compendium of neuropsychological tests: Administration, norms, and 
commentary (3rd ed., p. 502). Oxford: Oxford University Press.   


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12 APPENDICES




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baseline. Those baseline measurements are standardized using the overall baseline mean and 
baseline pooled standard deviation for each variable. 










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Appendix 3. 
Imputation of Partial Dates 
Table 4.
Imputation Rules for Partial Dates – Adverse Events
Parameter
Missing 
Additional Condition
Imputation
Start Date
D only
M and Y are prior to first study drug dose 
First day of indicated month
 
M and Y is same as first study drug dose 
Date of first study drug dose
 
M and Y are after first study drug dose 
First day of indicated month
M and D 
Y is prior to first study drug dose 
01 Jan of indicated year 
 
Y is same as first study drug dose
Date of first study drug dose
 
Y is after first study drug dose
01 Jan of indicated year 
M, D, and Y
-
assumed to be TEAE  
End Date 
D only
M and Y are prior to last study drug dose
Last day of indicated month
 
M and Y is same as last study drug dose 
Date of last observation 
 
M and Y are after last study drug dose 
First day of indicated month
M and D 
Y is prior to last study drug dose 
31 Dec of indicated year 
 
Y is same as last study drug dose 
Date of last observation 
 
Y is after last study drug dose
01 Jan of indicated year 
M, D, and Y
-
TEAE is ongoing 
- 
Estimated end date is before a complete or 
imputed AE start date 
Last day of the month of AE start 
date 
D = day; M = month; Y= year; TEAE = treatment-emergent adverse event
Note: The imputation of end date must be later than start date
Table 5.
Imputation Rules for Partial Dates – Prior and Concomitant Medications
Parameter
Missing
Additional Condition
Imputation
Start Date
D only
M and Y same as M and Y of first study 
drug dosing
Date of first study drug dose
M and/or Y not the same as M and Y of 
first study drug dosing
First day of indicated month
M and D
Y same as Y of first study drug dosing
Date of first study drug dose
Y not the same as Y of first study drug 
dosing 
01 Jan of indicated year 
M, D, and Y
none – date completely missing
Date of first study drug dose
End Date 
D only
M and Y same as M and Y of last study 
drug dosing
Date of last study drug dose
M and/or Y not the same as M and Y of 
last study drug dosing 
Last day of indicated month
M and D 
Y same as Y of last study drug dosing
Date of last study drug dose
Y not the same as Y of last study drug 
dosing 
31 Dec of indicated year 
M, D, and Y
none – date completely missing
Date of last study drug dose
D = day; M = month; Y= year


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Appendix 4. 
Summary of Efficacy Analyses 
Table 6.
Analyses of Efficacy Parameters
Parameter 
Population
Statistical 
Method
Missing Data 
Interpretation 
Table Number
GST Score
mITT
t-test/MMRM
NA
Primary analysis
Table 14.2.3.1
CFB ADAS-
Cog13 score
mITT
t-test/MMRM
NA
Secondary
analysis
Table 14.2.3.2
CFB ERP 
P300 latency
mITT 
t-test/MMRM 
NA
Secondary 
analysis
Table 14.2.3.3
 
mITT = Modified intent-to-treat; MMRM = Mixed Model Repeated Measures; CFB = change from baseline