Clinical trial NCT04491006
Conditions: Alzheimer Disease Dementia of Alzheimer Type
Keywords: Alzheimer's Disease Cognition Dementia ATH-1017 Memory Loss
Sponsor: Athira Pharma
Start date: 2020-11-23; Completion date: 2022-05-20
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate treatment effects of ATH-1017 (fosgonimeton) in mild to moderate Alzheimer's subjects with a randomized treatment duration of 26-weeks.

Detailed description:
This study is designed to assess the correlation of the functional translational biomarker P300 latency and change in ADAS-Cog11 induced by ATH-1017 therapy, over 26-week randomized, double-blind treatment.

Arms: arm 1: Daily subcutaneous (SC) injection of Low Dose ATH-1017 arm 2: Daily subcutaneous (SC) injection of High Dose ATH-1017 arm 3: Daily subcutaneous (SC) injection of Placebo
Interventions: intervention 1: ATH-1017 intervention 2: Placebo
Intervention descriptions: intervention 1: Daily subcutaneous (SC) injection of ATH-1017 in a pre-filled syringe intervention 2: Daily subcutaneous (SC) injection of Placebo in a pre-filled syringe

Protocol documents:
Prot_000.pdf: 
Athira Pharma, Inc.  
Protocol ATH-1017-AD-0202 
Clinical Study Protocol 
CONFIDENTIAL 
Version 3.00 
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Clinical Study Protocol 
A Randomized, Placebo-Controlled, Translational Study of ATH-1017 in Subjects with 
Mild to Moderate Alzheimer’s Disease 
Sponsor: 
Athira Pharma, Inc. 
18706 North Creek Parkway 
Suite 104 
Bothell, WA 98011 
USA 
Protocol No.: 
ATH-1017-AD-0202 
IND No.: 
135103 
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: 
Fax: 1-425-620-8508 
Email: drugsafety@athira.com  
Date of Final Protocol: 
25-MAY-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. 
NCT Number: NCT04491006
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov




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Protocol ATH-1017-AD-0202  
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SIGNATURE PAGE 
Declaration of the Principal Investigator 
Protocol Title: A Randomized, Placebo-Controlled, Translational Study of ATH-1017 in 
Subjects with Mild to Moderate Alzheimer’s Disease 
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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LIST OF STUDY STAFF 
Sponsor: 
Athira Pharma, Inc. 
18706 North Creek Parkway 
Suite 104 
Bothell, WA 98011 
USA 
Contract Research 
Organizations: 
Veristat, LLC (Study Conduct) 
134 Turnpike Road 
Southborough, MA 01772 
USA 
Signant Health, Inc. (Clinical Outcome Assessments) 
785 Arbor Way 
Blue Bell, PA19422 
USA 
MMS Holdings, Inc. (Data Management, Drug Safety and Pharmacovigilance) 
880 Commerce Blvd. 
Canton, MI 48187 
USA 
Pentara Corporation (Statistics) 
2261 East 3300 South 
Suite 200 
Millcreek, UT 84109 
USA 
Medical Monitor Contact: 
Email: 
Central Clinical 
Laboratory: 
Eurofins Central Laboratory 
2430 New Holland Pike. D100 
Lancaster, PA 17601 
USA 
Bioanalytical Laboratory: 
 
Alturas Analytics, Inc. 
1324 Alturas Dr.  
Moscow, ID 83843 
USA 
Central Electrocardiogram 
(ECG) Core Laboratory 
Biotrial 
7-9 rue Jean-Louis Bertrand 
CS 34246 
35042 Rennes CEDEX 
France 
Central 
electroencephalogram 
(EEG) Core Laboratory 
Biotrial 
7-9 rue Jean-Louis Bertrand 
CS 34246 
35042 Rennes CEDEX 
France 


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Biobanking Storage 
Eurofins Central Laboratory 
2430 New Holland Pike. D100 
Lancaster, PA 17601 
USA 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title: 
A Randomized, Placebo-Controlled, Translational Study of ATH-1017 in Subjects with 
Mild to Moderate Alzheimer’s Disease 
Study Number: 
ATH-1017-AD-0202 
Development Phase: 
Phase 2 
Sponsor: 
Athira Pharma, Inc. 
Type of Study 
Interventional 
Study Centers: 
The study will be conducted at a total of approximately 12 centers in Australia and USA 
Study Objectives and 
Endpoints: 
 
Primary Objectives 
Primary Endpoints 
To evaluate the effects of 
ATH-1017 on event-related 
potential (ERP) P300 latency 
ERP P300 latency: changes at Weeks 2, 6, 12, 
16, 20, and 26 compared to placebo 
To determine the safety and 
tolerability of ATH-1017 
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 correlation of ERP 
P300 latency and cognition 
measured by Alzheimer’s Disease 
Assessment Scale-Cognitive 
Subscale (ADAS-Cog11) and/or 
executive memory function 
measured by Controlled Oral 
Word Association test (COWAT) 
Correlation of ERP P300 latency and 
cognition/executive memory function: 
changes at Weeks 2, 6, 12, 20, and 26 
compared to placebo 
To evaluate the clinical efficacy of 
ATH-1017 
The Global Statistical Test (GST) (O’Brien, 
1984) that combines the scores from cognition 
(Alzheimer’s Disease Assessment Scale-
Cognitive Subscale [ADAS-Cog11]) and 
global impression of change (Alzheimer’s 
Disease Cooperative Study-Clinical Global 
Impression of Change [ADCS-CGIC])  
To evaluate the effect of 
ATH-1017 on cognition 
ADAS-Cog11 score: change from baseline at 
Week 26 compared to placebo 
To evaluate the effect of ATH-
1017 on clinical global impression 
of change 
ADCS-CGIC score: change from baseline at 
Week 26 compared to placebo 
To evaluate the effect of 
ATH-1017 on activities of daily 
living 
Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living, 23-item version 


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(ADCS-ADL23) score: change from baseline 
at Week 26 compared to placebo 
To determine the plasma 
pharmacokinetic (PK) profile of 
ATH-1017 and ATH-1001 
• 
Day 1:  post-dose anytime between 30 
minutes and 120 minutes as practical * 
• 
Week 12: pre-dose anytime, and post-
dose anytime between 30 minutes and 
120 minutes as practical * 
• 
Week 26: pre-dose anytime, and post-
dose anytime between 30 minutes and 
120 minutes as practical * 
* Please record the actual time of PK 
sampling. 
To evaluate the effect of 
ATH-1017 on executive memory 
function 
COWAT score: change from baseline at 
Week 26 compared to placebo 
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 mild to moderate 
Alzheimer’s disease (AD), diagnosed on a ‘probable’ level according to McKhann, 
2011. The study will be conducted at a total of approximately 12 centers in Australia 
and the US. 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 be tested for apolipoprotein E (ApoE) 
genotype. Subjects who meet all inclusion/exclusion criteria will undergo baseline 
EEG assessments (ERP P300 and 
) at 2 separate baseline visits. At the first 


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baseline visit, (Visit 2a, Pre-baseline, Day -5 to Day -3), MMSE will be performed to 
first, followed by EEG assessments (ERP P300 and 
) at 2 separate time points 
approximately 2 hours apart. EEG data should be uploaded for quality check 
immediately after the completion of the Pre-baseline visit (Visit 2a). At the second 
baseline visit (Visit 2b, Baseline, Day 1), no more than 6 days after the Pre-baseline 
visit, subjects will be randomized in a ratio of 1:1:1 to 3 parallel arms, either to active 
treatment (ATH-1017 40 mg/day or ATH-1017 70 mg/day) or placebo. During 
randomization, subjects will be stratified by screening Mini-Mental State Examination 
(MMSE) severity: mild (MMSE: 20-24) versus moderate (MMSE: 14-19). At this 
Baseline visit (Visit 2b), subjects will undergo pre-dose baseline and post-dose EEG 
assessments (ERP P300 and 
).  
Study drugs will be administered by subcutaneous (SC) injection once-daily (OD) 
preferably during daytime. Do not take more than one dose within 8 hours. The first 
SC injection of study drug will be performed at 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). Subjects will undergo EEG assessments (ERP P300 and 
) at each 
post-baseline clinic visit (pre- and post-dose timepoints) through Week 26, plus the 
safety follow-up visit at Week 30 (see Table 1 for timing of assessments). On Day 1, 
after completion of the first dose, subjects will remain on-site 2 hours for 
post-treatment clinical observation subject to the conditions in section 5.5. As marked 
circadian fluctuations of cognitive performance have been observed in AD (Hilt, 
2015), ADAS-Cog11 and COWAT assessments shall occur at clinic visits in the 
morning at approximately the same time they were performed during the initial 
Baseline assessment. Similarly, ADCS-CGIC assessments will be organized adjacent 
to the individual EEG assessment times. 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 same assessments as Visit 8/early termination (ET). 
An independent Data Safety Monitoring Board will conduct periodic review and 
assessments of unblinded safety data (AEs, labs, ECG, etc) throughout the study to 
ensure the safety of study subjects. Blood draws will take place at scheduled clinic 
visits for analysis of plasma concentrations of ATH-1017 and ATH-1001. 
A 26-week open-label extension will be offered at participating sites.  


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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 
Investigational 
Medicinal Products: 
Active Treatment: ATH-1017 will be presented in prefilled 1 mL syringes of 40 mg/mL 
and 70 mg/mL 
Placebo: Placebo prefilled 1 mL syringes to match active treatment 
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 subjects in order to include a total of 
approximately 60 evaluable subjects in the analysis of the primary endpoint  
Duration of 
Treatment: 
The study will consist of up to 28 days of screening (Day -28 through Day -6) followed 
by a Pre-baseline period of up to 5 days (Day -5 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, the possibility of an extension can be discussed with the Medical 
Monitor. 
Study Population: 
Inclusion 
1. 
Age 55 to 85 years, inclusive at the time of signing the informed consent. 
2. 
Mild-to-moderate AD dementia subjects 
a) 
MMSE score 14 to 24 inclusive at Screening  
b) 
Clinical Dementia Rating (CDR) Scale global score of 1 or 2 at Screening 
3. 
Clinical diagnosis of dementia, due probably to AD, by Revised National Institute 
on Aging-Alzheimer’s Association criteria (McKhann, 2011): 
a) 
Magnetic resonance imaging (MRI) or computerized tomography (CT) scan 
(for subjects with non-MRI-safe cardiac pacemaker, or other relevant 
medical reason, with Medical Monitor approval) performed within 
12 months before Screening, with findings consistent with the diagnosis of 
dementia due to AD without any other significant comorbid central nervous 
system pathologies. If such scan is unavailable or older than 12 months, it 
should be repeated to ascertain the diagnosis before randomization. 
b) 
Documented clinical decline within 12 months before Screening and onset 
of symptoms at least 12 months before Screening (preferably subject 
medical records; caregiver reports with examples are acceptable) 
4. 
Formal education of 8 or more years; exceptions may be made for subjects with 
less than 8 years of education at the discretion of the investigator. 
5. 
Body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2 at Screening; subjects with BMI 
outside the allowed BMI range but ≥ 16 and ≤ 37 kg/m2 may enroll only with 
prior agreement of the Sponsor. 
6. 
Male subjects 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. Only female subjects of non-childbearing 
potential (i.e., permanently sterilized, postmenopausal) are eligible for 
participation. 


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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 and have 
approximately 4 to 6 hours daytime contact with the subject for at least 
4 days/week. 
8. 
Treatment-free or receiving stable acetylcholinesterase inhibitor (AChEI) 
treatment, defined as: 
a) 
Treatment-naïve, OR 
b) 
Concomitant therapy with AChEI is allowed as long as the dose has been 
stable for 3 months prior to Screening (cf. EC #25b) and no changes are 
planned during the study, OR 
c) 
Subjects who received an AChEI and discontinued 4 weeks prior to 
Screening 
9. 
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. 
10. 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 procedures to evaluate eligibility for the 
study. 
11. 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). 
12. 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. 
13. 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. 
 
Exclusion 
1. 
History of significant neurologic disease, other than AD, that may affect 
cognition, or concurrent with the onset of dementia. 
2. 
History of unexplained loss of consciousness, and epileptic fits (unless febrile). 
3. 
Subject has atypical variant presentation of AD, if known from medical history, 
particularly non-amnestic AD. 


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4. 
History of brain MRI scan indicative of any other significant abnormality, 
including but not limited to multiple (> 10) microhemorrhages, severe white 
matter hyperintensities, history or evidence of a single prior hemorrhage > 1 cm3, 
multiple (> 3) lacunar infarcts or evidence of a single prior infarct > 1 cm3, 
evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular 
malformations, subdural hematoma, or space-occupying lesions (e.g., brain 
tumors). If a known meningioma has been stable for > 1 year and the subject has 
no history of any type of convulsions, this can be allowable after consultation 
with the Medical Monitor. Note: a new MRI scan is required if the scan was 
performed > 12 months prior to Screening; 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 non-MRI-safe cardiac 
pacemaker or other relevant medical reason, with Medical Monitor approval. 
5. 
Inability to hear or differentiate the two different tones necessary for auditory 
ERP P300 assessment, using the centrally provided EEG equipment; hearing aid 
must be removed during the screening hearing test and during EEG recordings. 
6. 
Diagnosis with current symptoms of severe major depressive disorder even 
without psychotic features. Any subject with formalized delusions or 
hallucinations are excluded. 
7. 
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 behaviours). 
9. 
History within 2 years of Screening, or current diagnosis of psychosis (American 
Psychiatric Association 2000) or moderate substance abuse disorder (according to 
the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) 
10. Untreated conditions, including vitamin B12 or folate deficiency, 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 
6 months before Screening. 
11. Abnormal serum electrolytes (potassium, sodium, magnesium) of clinical 
significance. If treated, must be stably treated for at least 30 days before 
Screening. 
12. Active, acute, or chronic infectious disease of any type. 
13. Myocardial infarction or unstable angina within the last 6 months or history of 
more than one myocardial infarction within 5 years before Screening. 
14. Clinically significant (in the judgment of the investigator) cardiac arrhythmia 
(including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: 
pacemaker is acceptable). 


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15. Subject has either hypertension (supine diastolic blood pressure > 95 mmHg), or 
symptomatic hypotension in the judgment of the investigator. 
16. Clinically significant ECG abnormality at Screening , including but not limited to 
a confirmed corrected QT interval using Fridericia’s formula (QTcF) value ≥ 450 
msec for males and ≥ 470 msec for females. 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 
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. 
17. History of or positive results of serology screening for hepatitis B (hepatitis B 
surface antigen), hepatitis C (anti-hepatitis C virus antibodies) or human 
immunodeficiency virus (antibodies type 1 and 2). 
18. Renal insufficiency (serum creatinine > 2.0 mg/dL).  
19. Hepatic impairment with alanine aminotransferase or aspartate aminotransferase 
> 2 times the upper limit of normal, or Child-Pugh class B and C. 
20. Malignant tumor within 3 years before Screening, except for the following 
conditions that are stable in the judgement of the Investigator  
a) Adequately treated squamous and basal cell carcinoma, or squamous and basal 
cell carcinoma in situ 
b) Prostate carcinoma in situ 
21. Clinically significant (in the judgment of the investigator) unintentional weight 
loss within 12 months of Screening. 
22. 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. 
23. Food supplements and nutraceuticals with potential effects on cognition, such as 
Axona and mediumchain triglyceride, are prohibited beginning 7 days prior to the 
first dose of study medication (Day 1) and for the duration of the study. 
24. 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. CBD use should be recorded as concomitant medication. 
25. Prohibited prior and concomitant medications are excluded within 4 weeks prior 
to Screening. 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. (this is 
not an exhaustive list; 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 also]): 
a) 
Memantine in any form, combination or dosage   


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b) 
Donepezil at 23 mg PO  
c) 
Antipsychotics; antipsychotics in low doses (in the judgment of the 
investigator) are allowed only if given for sleep disturbances, agitation 
and/or aggression, and only if the subject has received a stable dose for at 
least 3 months before Screening. If these medications are taken on a PRN 
basis, they should not be taken the night before any cognitive testing. 
d) 
Tricyclic antidepressants, monoamine oxidase 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 
e) 
Anxiolytics at high doses; low doses of benzodiazepines are allowed in the 
judgment of the investigator, but not the night before any cognitive 
assessments. 
f) 
Sedative hypnotics; Zolpidem is allowed 
g) 
Barbiturates (unless given in low doses for benign tremor) 
h) 
Nicotine therapy (including patches), varenicline (Chantix), or similar 
therapeutic agent 
i) 
Peripherally acting drugs with effects on cholinergic neurotransmission. 
Solifenacin is allowed if the subject has received a stable dose for at least 3 
months before Screening.   
j) 
Systemic immunosuppressants if taken in clinically immunosuppressive 
doses in the judgment of the investigator (note: immunosuppressant use for 
allergy or other inflammation, e.g., inhaled steroids, otics, opthalmologics, 
skin creams, and intra-articular injections are allowed) 
k) 
Antiepileptic medication 
l) 
Chronic intake of opioid-containing analgesics; PRN use is allowed (but not 
within 72 hours before any cognitive assessment) 
m) 
Sedating H1 antihistamines; non-sedating H1 antihistamines are allowed and 
preferred 
n) 
Systemic moderate to strong cytochrome P450 3A4 inhibitors or inducers; 
topical applications are allowed 
26. 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 AD 
investigational drug. 
27. The subject has received active amyloid or tau immunization (i.e., vaccination for 
Alzheimer’s disease) at any time, or passive immunization (i.e., monoclonal 
antibodies for Alzheimer’s disease) within 6 months of Screening. FDA approved 
vaccinations or monoclonal antibodies for other indications are allowed. 
28. Subject has known allergy to any component of the investigational medicinal 
product. 
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 


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may interfere significantly with the subject’s compliance or participation in the 
study. 
Statistical Methods: 
General Statistical Methods and Types of Analysis:  
Analysis of pharmacodynamics 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 at least one ERP P300 baseline assessment and 
one post-baseline ERP P300 assessment. A mixed model repeated measures (MMRM) 
analysis to compare the estimated changes in ERP P300 latency between active 
treatment and placebo will be used.  
Correlation of ERP P300 latency and cognition/executive memory function measured 
by (1) ADAS-Cog11 and/or (2) COWAT will be evaluated.  
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 60 evaluable subjects (20 per treatment arm) is based on the 
results of the Phase 1 study, NDX-1017-0101, which demonstrated significant effects 
of ATH-1017 on ERP P300 in n=7 ATH-1017-treated AD subjects compared to 
n=4 placebo-treated AD subjects.  


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Table 1 
Schedule of Assessments 
Assessment 
 
Screening a 
Pre-
baseline 
Double-blind placebo-controlled  
treatment period (26-week) 
Safety 
follow-
up r 
Baseline  
Visit: 
1 
2a 
2b 
3 
4 
5 
6 
7 
8/ET q 
9 
Week: 
-4 to -2 
-1 
1 
2 
6 
12 
16 
20 
26 
30 
Day: 
-28 to  
-6 
-5 to  
-3 
1 
14 
(±7) 
42 
(±7) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
182 
(±7) 
210 
(±7) 
Inclusion/ 
Exclusion 
 
X 
X 
X 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Demographics  
 
X 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
Height and 
Weight 
 
X 
 
X b 
 
 
X b 
 
 
X b 
X b 
Blood c 
 
X 
 
 
 
 
 
 
 
 
 
C-SSRS d * 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
GDS 
 
X 
 
X 
 
 
X 
 
 
X 
X 
MMSE * 
 
X 
X 
 
 
 
 
 
 
 
 
CDR 
 
X 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
 
X 
 
 
 
 
 
 
 
Drug Dispensing e 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Dose of IMP 
in-clinic f 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Drug 
Accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Physical and 
Neurological 
Exam g 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
MRI h 
 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG i 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs j 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs k 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmeds l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hearing Test m 
 
X 
 
 
 
 
 
 
 
 
 
ADAS-Cog11 * 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
COWAT * 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
ADCS-CGIC * 
 
 
 
X 
 
 
X 
 
 
X 
 
ADCS-ADL23 * 
 
 
 
X 
 
 
X 
 
 
X 
 


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Assessment 
 
Screening a 
Pre-
baseline 
Double-blind placebo-controlled  
treatment period (26-week) 
Safety 
follow-
up r 
Baseline  
Visit: 
1 
2a 
2b 
3 
4 
5 
6 
7 
8/ET q 
9 
Week: 
-4 to -2 
-1 
1 
2 
6 
12 
16 
20 
26 
30 
Day: 
-28 to  
-6 
-5 to  
-3 
1 
14 
(±7) 
42 
(±7) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
182 
(±7) 
210 
(±7) 
EEG (ERP P300 
and 
) n 
 
 
X  
(no dosing) 
 
 
 
 
 
 
 
X  
(no dosing) 
Pre-dose  
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Post-dose 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
PK (plasma) o 
 
 
 
X 
 
 
X 
 
 
X 
 
Biobanking 
Plasma p 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
ADCS-ADL23 = Alzheimer’s Disease Cooperative Study-Activities of Daily Living, 23-item version; ADAS-Cog11 = Alzheimer’s 
Disease Assessment Scale-Cognitive Subscale; ADCS-CGIC = Alzheimer’s Disease Cooperative Study-Clinical Global Impression 
of Change; AE = adverse event; CDR = Clinical Dementia Rating Scale; COWAT = Controlled Oral Word Association test; C-
SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ERP = event-related potential; 
 GDS = Geriatric Depression Scale; IMP = investigational medicinal product; 
MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging;
PK = pharmacokinetic;
 
 
a If 28 days is not sufficient to complete the Screening period, the possibility of an extension can be discussed with the 
 
Medical Monitor. 
b. Only weight collected at Baseline/Day 1 (Visit 2b), Week 12 (Visit 5), Week 26 (Visit 8), and Safety follow-up (Visit 9). 
c Blood collection for FSH levels (to confirm post-menopausal state in females), serology, ApoE genotyping, folate, Vitamin B12, 
 
fT3, fT4, and TSH. 
d ‘C-SSRS Baseline/Screening’ version will be administered at Screening and ‘C-SSRS Since Last Visit’ version will be 
 
administered at all post-Screening visits. 
e Dispensing of kits containing study drug will occur every 2 weeks, at the study site or as needed by direct-to-patient  
     shipment; larger provision of study drug is permitted to  accommodate personal need, e.g., vacation; drug returns will be 
     recorded and compliance calculated. IP administration by subject or caregiver will be assessed at Visits 2b through 7, inclusive. 
f First SC injection of IMP will be performed at site under supervision. Subjects will remain at site for 2 hours ± 15 minutes for  
     safety observation follow up. They may be discharged from the clinic at this time absent any systemic AEs (but not for local  
     site reaction). Should they have systemic AEs, they should remain under observation for an additional 2 hours and may be  
     discharged at that time with investigator’s clearance. Subjects should withhold IMP dose on the day of subsequent clinic visits  
     whereupon IMP administration will be done on site under supervision of site staff. There is no specified in-clinic observation  
     period for these subsequent visits but will require investigator discharge from the clinic.  
      It is recommended to contact the subject/caregiver by phone at appropriate intervals to support dosing compliance and injection   
      techniques. 
g. Physical and Neurological Exam should be done post-dose on all visits when dosing applies  
h.  MRI (or CT for subjects with non-MRI-safe cardiac pacemaker, or other relevant medical reason, with Medical Monitor  
     approval) scan must have been performed within 12 months before Screening. If such scan is unavailable or older than  
     12 months, it should be repeated to ascertain the diagnosis before  randomization. 


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Assessment 
 
Screening a 
Pre-
baseline 
Double-blind placebo-controlled  
treatment period (26-week) 
Safety 
follow-
up r 
Baseline  
Visit: 
1 
2a 
2b 
3 
4 
5 
6 
7 
8/ET q 
9 
Week: 
-4 to -2 
-1 
1 
2 
6 
12 
16 
20 
26 
30 
Day: 
-28 to  
-6 
-5 to  
-3 
1 
14 
(±7) 
42 
(±7) 
84 
(±7) 
112 
(±7) 
140 
(±7) 
182 
(±7) 
210 
(±7) 
i. 12-lead ECGs will be performed pre-dose and 30 (± 15) minutes post-dose on Day 1(Visit 2b) and 30 (± 15) minutes post-dose 
 
at all other visits. All ECG assessments will be performed in triplicate approximately 1 minute apart. 
j. Vital signs will be performed pre-dose on all visits. Supine BP and HR recordings will be made after the subject has been supine  
for at least 5 minutes. Orthostatic BP will be recorded as follows: 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 stood for up to 3 
minutes. 
k. Safety labs include chemistry, hematology, and urinalysis. 
l. Prior or concurrent medications. 
m. Subject hearing will be tested to establish suitability for auditory ERP assessment, i.e., ability to hear and differentiate two  
     different tones, using the centrally provided EEG equipment; hearing aid must be removed during the screening hearing test and   
     during EEG recordings. 
n. At Pre-baseline visit (Visit 2a, Day -5 to Day -3, no dosing), EEG assessments (ERP P300 and 
 will be performed twice 
approximately 2 hours apart. EEG data should be uploaded for quality check immediately after the completion of the Pre-baseline 
visit (Visit 2a). If both EEG assessments failed quality check at pre-baseline, the visit will be repeated once and the screening 
window of 28 days can be extended upon approval by Medical Monitor. 
     At Baseline/Day 1 (Visit 2b), EEG assessments (ERP P300 and 
 will be performed at pre-dose following the completion 
of baseline assessments of ADAS-Cog11 and COWAT, and before the ADCS-CGIC assessment, up to 1.5 hour before dose in 
clinic. EEG will be assessed post-dose at approximately 2 (±1) hours after IMP dosing. 
     At Visits 3, 4, 5, 6, 7, and 8, EEG assessments (ERP P300 and 
 will be performed at pre-dose up to 1 hour before dose in 
clinic. EEG will be assessed post-dose following the completion of ADAS-Cog11 and COWAT assessments, and before the ADCS-
CGIC assessment, at approximately 2 (±1) hours after IMP dosing. 
     At safety follow up (Visit 9, no dosing), EEG assessments (ERP P300 and 
 will be performed following the completion of 
ADAS-Cog11 and COWAT. 
o. PK plasma samples will be collected at post-dose on Baseline/Day 1 (Visit 2b); pre-dose and post-dose at Week 12 (Visit 5)  
     and Week 26 (Visit 8). The pre-dose PK sample is collected anytime before dosing. The post-dose PK sample is collected  
     anytime between 30 minutes and 120 minutes after dosing as practical. The actual time of dosing and of PK sampling will be  
     recorded. 
p. Plasma sample will be collected and banked for biomarker analysis (only for subjects who provided consent for plasma 
 
biobanking). Ten aliquots will be created from the plasma sample. 
q. Subjects who terminate prior to Visit 9 are to complete same assessments as Visit 8/ET (early termination). For clinical outcome  
     assessments if completed within 4 weeks of the ET visit they do not need to be repeated; all safety outcomes and drug  
     accountability should be performed regardless of interval. 
r. Safety follow-up visit to be performed for subjects who do not roll over into the optional open-label extension (OLEX) 
 
study; subjects who roll over into the OLEX study will complete the safety follow-up visit at the end of the OLEX study. 
*  At Pre-baseline visit (Visit 2a, Day -5 to Day -3), MMSE should be done first before all other assessments. 
    At Baseline/Day 1 (Visit 2b), ADAS-Cog11, COWAT, and ADCS-CGIC will be performed pre-dose; ADCS-ADL23, 
 C-
SSRS, 
will be performed anytime during the visit.  
   For visits after the baseline (except for safety follow-up when dosing is not applicable), all clinical outcome assessments will be 
performed post-dose, with ADAS-Cog11 and COWAT assessments performed first at approximately 1 hour (± 30 minutes) post-
dose. ADCS-CGIC assessments, when applicable, will be organized at adjacent times shortly after the individual EEG assessments. 


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TABLE OF CONTENTS 
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 ......................................................................... 27 
1.3 
Risk-Benefit Assessment .................................................................................... 27 
2 
STUDY OBJECTIVES AND ENDPOINTS ....................................................... 28 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ......................................... 31 
3.1 
Justification for Study Design ............................................................................ 32 
3.2 
Justification for Dose .......................................................................................... 32 
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 ................................. 41 
4.5 
Screen Failures ................................................................................................... 42 
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 
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 ................................................................. 47 


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6 
VARIABLES AND METHODS OF ASSESSMENT ........................................ 48 
6.1 
Screening Assessments ....................................................................................... 48 
6.1.1 
Mini–Mental State Examination (MMSE) ................................................... 48 
6.1.2 
Clinical Dementia Rating Scale (CDR) ...................................................... 48 
6.1.3 
Audio Screening .......................................................................................... 48 
6.2 
Pharmacodynamic Variables .............................................................................. 48 
6.2.1 
ERP P300 .................................................................................................... 49 
6.2.2 
qEEG ........................................................................................................... 49 
6.3 
Other Variables ................................................................................................... 49 
6.3.1 
Cognitive Variables ..................................................................................... 50 
6.3.2 
Disease Condition ....................................................................................... 50 
 
 
 
 
6.4 
Safety Variables .................................................................................................. 52 
6.4.1 
Adverse Events ............................................................................................ 52 
6.4.2 
Pregnancy .................................................................................................... 59 
6.4.3 
Clinical Laboratory Assessments ................................................................ 60 
6.4.4 
Vital Signs ................................................................................................... 61 
6.4.5 
Weight .......................................................................................................... 62 
6.4.6 
12-Lead Electrocardiogram ........................................................................ 62 
6.4.7 
Physical and Neurological Examination ..................................................... 62 
6.4.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................... 63 
6.4.9 
Geriatric Depression Scale (GDS) .............................................................. 63 
6.5 
Pharmacokinetic Variables ................................................................................. 63 
6.6 
Genotyping ......................................................................................................... 63 
6.7 
Plasma Sample Biobanking ................................................................................ 64 
7 
STUDY CONDUCT .............................................................................................. 65 
7.1 
Schedule and Order of Assessments ................................................................... 65 
7.1.1 
Unscheduled Visit(s) ................................................................................... 66 
7.2 
Pandemic Response ............................................................................................ 66 
7.3 
Data Safety Monitoring Board ........................................................................... 67 
7.4 
Concomitant Medications and Treatments ......................................................... 67 
7.4.1 
Prohibited Treatments During the Study .................................................... 67 
7.4.2 
Permitted Treatments .................................................................................. 69 


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7.4.3 
Other Restrictions ....................................................................................... 70 
7.5 
Subject Withdrawal ............................................................................................ 70 
7.5.1 
Discontinuation of Study Treatment ............................................................ 70 
7.5.2 
Withdrawal from the Study .......................................................................... 70 
7.6 
Lost to Follow-up ............................................................................................... 72 
7.7 
Termination of the Clinical Study ...................................................................... 72 
8 
STATISTICAL METHODS ................................................................................. 73 
8.1 
Populations for Analysis ..................................................................................... 73 
8.1.1 
MITT population ......................................................................................... 73 
8.1.2 
Per protocol population .............................................................................. 73 
8.1.3 
Safety population ......................................................................................... 73 
8.2 
General Considerations ...................................................................................... 73 
8.3 
Analyses ............................................................................................................. 74 
8.3.1 
Primary Analysis – ERP P300 Latency ....................................................... 74 
8.3.2 
Secondary Analysis ..................................................................................... 74 
8.3.4 
Subgroup Analyses ...................................................................................... 74 
8.4 
Safety Summaries ............................................................................................... 74 
8.4.1 
Adverse Events ............................................................................................ 74 
8.4.2 
Laboratory parameters ............................................................................... 75 
8.4.3 
Weight .......................................................................................................... 75 
8.4.4 
12-Lead Electrocardiogram ........................................................................ 75 
8.4.5 
Columbia-Suicide Severity Rating Scale ..................................................... 75 
8.4.6 
Geriatric Depression Scale ......................................................................... 75 
8.5 
Pharmacokinetic Analyses .................................................................................. 75 
8.6 
Determination of Sample Size ............................................................................ 75 
8.7 
Interim Analysis ................................................................................................. 76 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ............................ 77 
9.1 
Data Quality Assurance ...................................................................................... 77 
9.2 
Access to Source Data/Documents ..................................................................... 78 
9.3 
Archiving Study Documents .............................................................................. 78 
9.4 
Good Clinical Practice ........................................................................................ 78 
9.5 
Informed Consent ............................................................................................... 79 


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9.6 
Protocol Approval and Amendment(s) ............................................................... 80 
9.7 
Confidentiality Data Protection .......................................................................... 80 
9.8 
Publication Policy ............................................................................................... 80 
10 
REFERENCE LIST .............................................................................................. 82 
11 
APPENDICES ....................................................................................................... 85 
11.1 
Appendix 1: List of Prohibited Medications ...................................................... 85 
 
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 .................. 56 
Table 4 
Clinical Laboratory Assessments ................................................................................ 60 
 
 
LIST OF FIGURES 
Figure 1 
Mode of Action of ATH-1017 .................................................................................... 26 
Figure 2 
Dose selection based on PK-PD modeling ................................................................. 34 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
AE 
adverse event 
ADAS-Cog11 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
ADCS-ADL23 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living, 23-item 
version 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression of 
Change 
AKT 
protein kinase B 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoE 
apolipoprotein E 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CBD 
cannabidiol 
CDR 
Clinical Dementia Rating Scale 
CPK 
creatine phosphokinase 
CRO 
Contract Research Organization 
CYP3A4 
cytochrome P450 3A4 
Cmax 
maximum concentration 
CNS 
central nervous system 
COWAT 
Controlled Oral Word Association test 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computerized tomography 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
ERP 
event-related potential(s) 
ET 
early termination 
FSH 
follicle-stimulating hormone 
FWER 
family-wise error rate 
fT3 
free tri-iodothyronine 


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fT4 
free thyroxine 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GST 
Global Statistical Test 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HGF 
hepatocyte 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 
LTP 
long-term potentiation 
MAPK 
mitogen-activated protein kinase 
MCT 
medium-chain triglyceride 
MET 
MET receptor tyrosine kinase 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NMDA 
N-methyl D-aspartate 
OD 
once-daily 
P 
phosphorylated 
PD 
pharmacodynamic(s) 
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetic(s) 
PKC 
protein kinase C 
PLCγ 
phospholipase C-gamma 
PM 
plasma membrane 
PRN 
as needed 


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PSP 
post-synaptic potential 
PT 
prothrombin time 
 
 
QTcF 
corrected QT interval using Fridericia’s formula 
RAC1 
Ras-related C3 botulinum toxin substrate 1 
RAF 
rapidly accelerated fibrosarcoma (protein) 
RAS 
rat sarcoma (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 
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 Alzheimer’s disease (AD) treatment, formulated as a sterile 
solution for subcutaneous (SC) injection. ATH-1017 is a prodrug, which is rapidly converted to 
the active drug 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 active drug 
ATH-1001 acts as an agonist of the hepatocyte growth factor (HGF) receptor and its tyrosine 
kinase, MET. Central nervous system (CNS) MET expression is crucial in maintaining the 
healthy adult brain (Hawrylycz, 2015), and is reduced in AD particularly in the hippocampus 
(Hamasaki, 2014). The HGF/MET system presents a new therapeutic target to treat 
neurodegeneration and restore cognitive function in AD. 
1.1 
Background 
Dementia of the Alzheimer’s type (hereafter referred to as AD) is the most common form of 
dementia and the largest unmet medical need in neurology (Citron, 2010). AD can be further 
classified based on age of onset and genetic risks. Individuals under age 65 have early-onset AD, 
and many of whom have a dominant genetic mutation (i.e., familial AD with known mutations in 
the following genes: amyloid precursor protein, presenilin-1, and presenilin-2). Late-onset AD 
patients have an age of onset at 65 years and older, who typically have no dominant genetic risks 
(i.e., sporadic AD), with disease onset involving a complex interplay of aging, Apolipoprotein E 
(ApoE)-ε4 genotype, environmental, and lifestyle risk factors. The late-onset sporadic cases 
account for about 95% of the total AD population. Although age is the biggest risk factor, AD is 
not a part of normal aging. 
Growing evidence suggests that complex CNS disorders, like AD, 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 AD and other dementias, and 
drugs that stimulate neurotrophic systems have the potential to address neurodegeneration and 
improve cognition by protecting existing neurons, promoting connectivity, inducing 
neuro-regenerative mechanisms, as well as addressing multiple aspects of the AD pathology, 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 Parkinson’s disease 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 


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the brain, presents a superior therapeutic strategy for targeting neurotrophic factors to treat 
neurodegenerative disorders.  
ATH-1017 represents a new approach to treat AD in a systemic approach. The mode of action of 
ATH-1017 is augmentation of HGF function and facilitation of signal transduction through MET 
phosphorylation (Figure 1).  
Figure 1 
Mode of Action of ATH-1017 
 
AKT = protein kinase B; EEG = electroencephalogram; HGF = hepatic growth factor; LTP = long-term potentiation; 
MAPK = mitogen-activated protein kinase; MET = MET receptor tyrosine kinase; NMDA = N-methyl D-aspartate; 
P = phosphorylated; PI3K = phosphoinositide 3-kinase; PKC = protein kinase C; PLCγ = phospholipase C-gamma; 
PM = plasma membrane; PSP = post-synaptic potential; RAC1 = Ras-related C3 botulinum toxin substrate 1; 
RAF = rapidly accelerated fibrosarcoma (RAF) kinase; STAT3 = signal transducer and activator of transcription 3. 
 
After SC injection, the prodrug ATH-1017 is rapidly converted to the active drug ATH-1001, 
which binds to HGF and enhances MET activation. Interaction of the ligand HGF with its 
receptor MET induces MET phosphorylation (activation) and recruitment of effector proteins 
that potentiate downstream signaling through the PI3K/AKT and RAS/RAF/MAPK pathways, 
among others (Organ, 2011). In the CNS, HGF/MET activity has neuroprotective and 
neurotrophic effects and modulates neurogenesis and neuronal maturation (Ebens, 1996; Maina, 
1999; Shang, 2011). As a critical regulator of inflammation, HGF/MET activity reduces the 
expression of the pro-inflammatory cytokine interleukin-6 and promotes expression of the 


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anti-inflammatory interleukin -10 (Molnarfi, 2015). HGF/MET activity also leads to protein 
kinase C (PKC)-mediated potentiation of N-methyl D-aspartate (NMDA) receptor current, 
synaptic localization of NMDA receptors, and long-term potentiation (Tyndall, 2007), processes 
important for memory formation. 
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 (PD) based on 
electroencephalogram  (EEG), including quantitative electroencephalogram (qEEG) and event-
related potentials (ERP) was established. 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 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. This finding suggests ATH-1017 treatment has potential effects on 
cognitive processing and working memory access in AD. 
This study (ATH-1017-AD-0202) is designed to provide evidence for the functional translational 
biomarker P300 latency as being predictive of pro-cognitive effects induced by ATH-1017 
therapy. In addition, this study will determine time to onset and degree of maintenance of P300 
latency reduction over 26 weeks. Eligible participants will receive once-daily (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. Subjects who complete the double-blind study will have the option to 
roll over into a long-term (26-week) open-label extension study. 
1.3 
Risk-Benefit Assessment 
Whilst ERP P300 and qEEG results in humans are indicative of CNS penetration and target 
engagement, efficacy in subjects with AD (in terms of cognitive, functional, or behavioral 
improvement) has not been established. Therefore, the benefit to study subjects of participating 
in this clinical trial are not yet known. 
In human 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 effects of 
ATH-1017 on event-related 
potential (ERP) P300 latency 
ERP P300 latency: changes at Weeks 2, 6, 12, 16, 20, 
and 26 compared to placebo 
To determine the safety and 
tolerability of ATH-1017 
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 correlation of ERP 
P300 latency and cognition 
measured by Alzheimer’s Disease 
Assessment Scale-Cognitive 
Subscale (ADAS-Cog11) and/or 
executive memory function 
measured by Controlled Oral Word 
Association test (COWAT) 
Correlation of ERP P300 latency and cognition/ 
executive memory function: changes at Weeks 2, 6, 12, 
20, and 26 compared to placebo 
To evaluate the clinical efficacy of 
ATH-1017 
The Global Statistical Test (GST) (O’Brien, 1984) that 
combines the scores from cognition (Alzheimer’s 
Disease Assessment Scale-Cognitive Subscale 
[ADAS-Cog11]) and global impression of change 
(Alzheimer’s Disease Cooperative Study-Clinical 
Global Impression of Change [ADCS-CGIC])  
To evaluate the effect of ATH-1017 
on cognition 
ADAS-Cog11 score: change from baseline at Week 26 
compared to placebo 
To evaluate the effect of ATH-1017 
on clinical global impression of 
change 
ADCS-CGIC score: change from baseline at Week 26 
compared to placebo 
To evaluate the effect of ATH-1017 
on activities of daily living 
Alzheimer’s Disease Cooperative Study – Activities of 
Daily Living, 23-item version (ADCS-ADL23) score: 
change from baseline at Week 26 compared to placebo 
To determine the plasma PK profile 
of ATH-1017 and ATH-1001 
• 
Day 1:  post-dose anytime between 30 minutes and 
120 minutes as practical* 


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• 
Week 12: pre-dose anytime, and post-dose anytime 
between 30 minutes and 120 minutes as practical* 
• 
Week 26: pre-dose anytime, and post-dose anytime 
between 30 minutes and 120 minutes as practical* 
* Please record the actual time of PK sampling. 


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To evaluate the effect of ATH-1017 
on executive memory function 
COWAT score: change from baseline at Week 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 mild to moderate AD, diagnosed on a ‘probable’ level 
according to McKhann, 2011. The study will be conducted at a total of approximately 12 centers 
in Australia and the US. 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 be tested for ApoE genotype. Subjects who meet all 
inclusion/exclusion criteria will undergo baseline EEG assessments (ERP P300 and 
) at 2 
separate baseline visits. At the first baseline visit (Visit 2a, Pre-baseline, Day -5 to Day -3), 
Mini-Mental State Examination (MMSE) will be performed to first, followed by EEG 
assessments (ERP P300 and 
) at 2 separate timepoints approximately 2 hours apart (no 
dosing). EEG data should be uploaded for quality check immediately after the completion of the 
Pre-baseline visit (Visit 2a). At the second baseline visit (Visit 2b, Baseline, Day 1), no more 
than 6 days after the Pre-baseline visit, subjects will be randomized in a ratio of 1:1:1 to 3 
parallel arms, either to active treatment (ATH-1017 40 mg/day or ATH-1017 70 mg/day) or 
placebo. During randomization, subjects will be stratified by screening MMSE severity: mild 
(MMSE: 20-24) versus moderate (MMSE: 14-19). At this Baseline visit (Visit 2b), subjects will 
undergo pre-dose baseline and post-dose EEG assessments (ERP P300 and 
). 
Study drugs will be administered by SC injection OD preferably by during daytime. Do not take 
more than one dose within 8 hours. The first SC injection of study drug will be performed at 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). Subjects will 
undergo EEG assessments (ERP P300 and 
) at each post-baseline clinic visit (pre- and 
post-dose timepoints) through Week 26, plus the safety follow-up visit at Week 30 (see Table 1 
for timing of assessments). On Day 1, after completion of the first dose, subjects will remain on-
site 2 hours for post-treatment safety observation. As marked circadian fluctuations of cognitive 
performance have been observed in AD (Hilt, 2015), ADAS-Cog11 and COWAT assessments 
shall occur at clinic visits in the morning at approximately the same time they were performed 
during the initial Baseline assessment. Similarly, ADCS-CGIC assessments will be organized at 
adjacent times to the individual EEG assessment times. 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 


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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 same assessments as Visit 8/early 
termination (ET). 
An independent Data Safety Monitoring Board (DSMB) will conduct periodic review and 
assessments of unblinded safety data (AEs, labs, ECG, etc.) throughout the study to ensure the 
safety of study subjects (see Section 7.2). 
Blood draws will take place at scheduled clinic visits (Day 1, Week 12 and Week 26) for 
analysis of plasma concentrations of ATH-1017 and ATH-1001 (see Table 1 for schedule of 
assessments). 
A 26-week open-label extension will be offered at participating sites. 
3.1 
Justification for Study Design 
The study is designed to primarily explore the correlation and extended time course of changes 
of the functional pharmacodynamic biomarker ERP P300 and cognitive performance, as well as 
establishing further long-term safety in mild to moderate AD subjects (based on clinical 
diagnostic criteria of AD [McKhann, 2011] and the inclusion/exclusion criteria), with 
double-blind, parallel-arm treatment duration of 26 weeks. An option to roll over into a 
long-term (26-week) open-label extension study will be available to subjects who complete the 
double-blind study; the purpose of the open-label extension is to continue to collect long-term 
safety. 
The study is additionally designed to explore treatment effects using validated outcome scales 
for cognitive function, executive memory function, activities of daily living, and behavioral 
changes, this study will collect pharmaco-economic data using validated scales for 
 
. 
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). This study will employ an independent 
DSMB who will conduct periodic review and assessments of unblinded safety data (AEs, labs, 
ECG, etc.) throughout the study. 
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 qEEG and nonclinical studies in animal models, together with 
the qEEG and ERP P300 results of a completed Phase 1a/b study. 


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In the randomized placebo-controlled Phase 1a/b study, ATH-1017 has been evaluated for safety, 
PK, and PD in a total of 88 subjects (of whom 65 were exposed to active study drug), including 
healthy young, healthy elderly, and AD subjects. ATH-1017 was evaluated over a wide dose 
range to understand the safety profile and PD effects based on qEEG and ERP P300 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 nonclinical 
qEEG studies in mouse, nonclinical efficacy studies in animal models (i.e., scopolamine-induced 
amnesia in rat and aged dementia rat), and Phase 1a/b human clinical study. The results were 
compared based on equivalent PK exposures, based on Cmax, to inform dose selection for the next 
proposed study. Given the mode of action of ATH-1017 is via pulsatile activation of a growth 
factor system, the PD of ATH-1017 are primarily driven by concentration (Cmax). Upon 
activation, MET phosphorylation persists for some time before the active complex is 
internalized, and either degraded or dephosphorylated and recycled back to the membrane. This 
pulsatile method of ATH-1017 (prodrug) administration is aligned with the natural regulatory 
mechanisms of HGF/MET activity, and suggests a steady-state level of ATH-1001 (active drug) 
exposure is not necessary for a therapeutic effect. 
As summarized in Figure 2, the active PD 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 PD 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 PD range. 


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Figure 2 
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 PD 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 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 PD 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),  


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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 
PD 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. The 
doses of ATH-1017 used in this study will support selection of an appropriate dose for 
registration of ATH-1017 as a potential treatment for mild to moderate AD. 


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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 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 in order to include a total of approximately 60 evaluable 
subjects in the analysis of the primary endpoint. 
4.2 
Inclusion Criteria 
1. Age 55 to 85 years, inclusive at the time of signing the informed consent. 
2. Mild-to-moderate AD dementia subjects: 
a) MMSE score 14 to 24 inclusive at Screening  
b) Clinical Dementia Rating (CDR) Scale global score of 1 or 2 at Screening 
3. Clinical diagnosis of dementia, due probably to AD, by Revised National Institute on 
Aging-Alzheimer’s Association criteria (McKhann, 2011): 
a) Magnetic resonance imaging (MRI) or computerized tomography (CT) scan (for subjects 
with non-MRI-safe cardiac pacemaker, or other relevant medical reason, with Medical 
Monitor approval) performed within 12 months before Screening, with findings 
consistent with the diagnosis of dementia due to AD without any other significant 
comorbid CNS pathologies. If such scan is unavailable or older than 12 months, it should 
be repeated to ascertain the diagnosis before randomization. 
b) Documented clinical decline within 12 months before Screening and onset of symptoms 
at least 12 months before Screening (preferably subject medical records; caregiver reports 
with examples are acceptable) 
4. Formal education of 8 or more years; exceptions may be made for subjects with less than 
8 years of education at the discretion of the investigator. 
5. Body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2 at Screening; subjects with BMI outside the 
allowed BMI range but ≥ 16 and ≤ 37 kg/m2 may enroll only with prior agreement of the 
Sponsor 
6. Male subjects 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 


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potential. Only 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 and have approximately 4 to 6 hours daytime contact with the subject for 
at least 4 days/week. 
8. Treatment-free or receiving stable acetylcholinesterase inhibitor (AChEI) treatment, defined 
as: 
a) Treatment-naïve, OR 
b) Concomitant therapy with AChEI is allowed as long as the dose has been stable for 3 
months prior to Screening (cf. EC #25b) and no changes are planned during the study, 
OR 
c) Subjects who received an AChEI in the past and discontinued 4 weeks prior to Screening 
9. 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. 
10. Written informed consent from the 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. 
11. 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). 
12. 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. 
13. 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. History of significant neurologic disease, other than AD, that may affect cognition, or 
concurrent with the onset of dementia. 
2. History of unexplained loss of consciousness, and epileptic fits (unless febrile). 


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3. Subject has atypical variant presentation of AD, if known from medical history, particularly 
non-amnestic AD. 
4. History of brain MRI scan indicative of any other significant abnormality, including but not 
limited to multiple (> 10) microhemorrhages, severe white matter hyperintensities, history or 
evidence of a single prior hemorrhage > 1 cm3, multiple (> 3) lacunar infarcts or evidence of 
a single prior infarct > 1 cm3, evidence of a cerebral contusion, encephalomalacia, 
aneurysms, vascular malformations, subdural hematoma, or space-occupying lesions (e.g., 
brain tumors). If a known meningioma has been stable for > 1 year and the subject has no 
history of any type of convulsions, this can be allowable after consultation with the Medical 
Monitor. Note: a new MRI scan is required if the scan was performed > 12 months prior to 
Screening; 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 non-MRI-safe cardiac pacemaker or other relevant medical reason, with Medical 
Monitor approval. 
5. Inability to hear or differentiate the two different tones necessary for auditory ERP P300 
assessment, using the centrally provided EEG equipment; hearing aid must be removed 
during the screening hearing test and during EEG recordings. 
6. Diagnosis with current symptoms of severe major depressive disorder even without 
psychotic features. Any subject with formalized delusions or hallucinations are excluded. 
7. Geriatric Depression Scale (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 Columbia-Suicide 
Severity Rating Scale (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 behaviours). 
9. History within 2 years of Screening, or current diagnosis of psychosis (American Psychiatric 
Association, 2000) or moderate substance abuse disorder (according to the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition). 
10. Untreated conditions, including vitamin B12 or folate deficiency, 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 6 months before Screening. 
11. Abnormal serum electrolytes (potassium, sodium, magnesium) of clinical significance. If 
treated, must be stably treated for at least 30 days before Screening. 
12. Active, acute, or chronic infectious disease of any type.  


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13. Myocardial infarction or unstable angina within the last 6 months or history of more than 
one myocardial infarction within 5 years before Screening. 
14. Clinically significant (in the judgment of the investigator) cardiac arrhythmia (including 
atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: pacemaker is 
acceptable). 
15. Subject has either hypertension (supine diastolic blood pressure > 95 mmHg), or 
symptomatic hypotension in the judgment of the investigator. 
16. Clinically significant ECG abnormality at Screening, including but not limited to a 
confirmed corrected QT interval using Fridericia’s formula (QTcF) value ≥ 450 msec for 
males and ≥ 470 msec for females. 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 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. 
17. History of or 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). 
18. Renal insufficiency (serum creatinine > 2.0 mg/dL). 
19. Hepatic impairment with alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 2 times the upper limit of normal, or Child-Pugh class B and C. 
20. Malignant tumor within 3 years before Screening, except for the following conditions that 
are stable in the judgement of the Investigator. 
a) Adequately treated squamous and basal cell carcinoma, or squamous and basal cell 
carcinoma in situ 
b) Prostate carcinoma in situ 
21. Clinically significant (in the judgment of the investigator) unintentional weight loss within 
12 months of Screening. 
22. 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. 
23. Food supplements and nutraceuticals with potential effects on cognition, such as Axona and 
mediumchain triglyceride (MCT), are prohibited beginning 7 days prior to the first dose of 
study medication (Day 1) and for the duration of the study. 
24. 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 


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allowed but not on the clinical visit days except for topical applications. CBD use should be 
recorded as concomitant medication. 
25. Prohibited prior and concomitant medications are excluded within 4 weeks prior to 
Screening. 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. (this is not an exhaustive list; 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 also]): 
a) Memantine in any form, combination or dosage 
b) Donepezil at 23 mg PO  
c) Antipsychotics; antipsychotics in low doses (in the judgment of the investigator) are 
allowed only if given for sleep disturbances, agitation and/or aggression, and only if the 
subject has received a stable dose for at least 3 months before Screening. If these 
medications are taken on a PRN basis, they should not be taken the night before any 
cognitive testing. 
d) Tricyclic antidepressants, monoamine oxidase inhibitors, and Sketamine; all other 
antidepressants are allowed only if the subject has received a stable dose for at least 
3 months before Screening 
e) Anxiolytics at high doses; low doses of benzodiazepines are allowed in the judgment of 
the investigator, but not the night before any cognitive assessments. 
f) Sedative hypnotics; Zolpidem is allowed  
g) Barbiturates (unless given in low doses for benign tremor) 
h) Nicotine therapy (including patches), varenicline (Chantix), or similar therapeutic agent 
i) Peripherally acting drugs with effects on cholinergic neurotransmission. Solifenacin is 
allowed if the subject has received a stable dose for at least 3 months before Screening.   
j) Systemic immunosuppressants if taken in clinically immunosuppressive doses in the 
judgment of the investigator (note: immunosuppressant use for allergy or other 
inflammation, e.g., inhaled steroids, otics, opthalmologics, skin creams, and intra-
articular injections are allowed) 
k) Antiepileptic medications  
l) Chronic intake of opioid-containing analgesics; PRN use is allowed (but not within 72 
hours before any cognitive assessment) 
m) Sedating H1 antihistamines; non-sedating H1 antihistamines are allowed and preferred 


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n) Systemic moderate to strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers; 
topical applications are allowed 
26. 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 AD investigational drug. 
27. The subject has received active amyloid or tau immunization at any time (i.e., vaccination 
for Alzheimer’s disease), or passive immunization (i.e., monoclonal antibodies for 
Alzheimer’s disease) within 6 months of Screening. FDA approved vaccinations or 
monoclonal antibodies for other indications are allowed. 
28. Subject has known allergy to any component of the investigational medicinal product (IMP). 
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 
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: 
• Study drug administration and disposal of empty syringes 
• Study drug storage requirements 


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• The nature of expected AEs 
• How to report AEs 
• 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 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 and has 
discussed the reason for this with the Medical Monitor. Individuals who are rescreened will 
receive a new screening number. (Note: clinical 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% NaCl. 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% NaCl. 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) during storage 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. A stratified permuted block randomization procedure will be used 
(stratification will be by screening MMSE severity: mild (MMSE: 20-24) versus moderate 
(MMSE: 14-19). 
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 judgement 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 absent any systemic AEs at the 2-hour timepoint. 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 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 Sponsor. However, subjects who are off drug for ≥ 14 consecutive 
days may be prematurely discontinued from the study, in discussion with the Sponsor. 


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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 Contract Research 
Organization (CRO) standard operating procedure (SOP) will be followed for blind breaking 
procedures. 
In the event that an interim analysis would be performed by the DSMB employing an 
independent statistician, adequate measures will be defined in the final 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 if any of the following criteria/AEs do not resolve: 
• 
ALT or AST > 8 × upper limit of normal (ULN) 
• 
ALT or AST > 5 × ULN for more than 2 weeks 
• 
ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN, or international normalized ratio 
[INR] > 1.5) 
• 
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%) 
• 
AEs: 
− Any AE of severe intensity and related causality  
− Any SAE of related causality 
(Note: causality as determined by the Sponsor) 
• 
Other clinical laboratory criteria: 
− Creatine phosphokinase (CPK) ≥ 3 × ULN (that cannot be attributed to causes other than 
the study treatment; i.e., vigorous exercise) 
− Serum creatinine > 1.5 × ULN 


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− A decrease from baseline in hemoglobin concentration > 2 g/dL 
− Absolute neutrophil count < 1,000/µL 
− Platelets < 50,000/µL 
• Vital sign criteria: 
− Hypotension (systolic blood pressure [SBP] < 90 mmHg and symptomatic). If 
hypotension is observed during the study and the subject is symptomatic, then a 
minimum of 2 repeat blood pressure measurements should be obtained approximately 
5 minutes apart. The mean of the 3 SBP measurements will be used to determine stopping 
criteria. 
− Tachycardia defined as heart rate (HR) > 120 beats per minute (bpm) lasting longer than 
30 minutes or with impaired consciousness 
• ECG criterion: 
− QTcF > 500 msec (if prolonged QTcF interval is observed during the study, then a 
minimum of 2 sets of repeat ECGs in triplicate should be obtained over a brief period. 
The mean of the 3 sets of ECGs will be used to determine 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. The 
conditions of determining eligibility should be taken into account when considering the 
ECG stopping criterion. 
In addition, if any of the above criteria are met, the event must be reported and discussed with 
the Medical Monitor. 
The responsibilities of the independent DSMB will be defined in a DSMB Charter and shall 
include making recommendations regarding continuation of any dose groups (as described in 
Section 7.3), and of the study itself. 
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. 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. 


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5.10 
Treatment after the End of the Study 
Access to study treatment will be limited to the period of participation in this study and (if 
subjects decide to participate and are eligible) for the duration of their participation in the 
optional open-label extension study. 
Subjects who decide not to roll over into the open-label extension study will return to their 
original medication upon discontinuation of double-blind treatment; 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 
Mini–Mental State Examination (MMSE) 
The Mini–Mental State Examination (MMSE) (Folstein, 1975) is a widely used test of overall 
cognitive function, assessing memory, orientation and praxis in a short series of tests. The score 
is from 0 to 30 with 30 being the best possible and 0 being the worst possible score. The MMSE 
is administered at Screening with a score of 14 to 24 inclusive for subject eligibility and at the 
Pre-baseline visit (Visit 2a, Day -5 to Day -3). At Pre-baseline visit (Visit 2a, Day -5 to Day -3), 
MMSE should be done first before all other assessments. 
6.1.2 
Clinical Dementia Rating Scale (CDR) 
The Clinical Dementia Rating Scale (Hughes, 1982) is a global rating of the function of AD 
subjects assessed in 6 categories: memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care. It is based on a semi-structured 
interview conducted with the subject and caregiver. Each category has scores from 0 (no 
symptoms) to 3 (severe) from which the overall CDR global score is derived. The CDR is 
administered at the Screening visit with a score of 1 or 2 required for subject eligibility. 
6.1.3 
Audio Screening 
A brief hearing test will be performed at the Screening visit for the purpose of documenting that 
subjects have adequate hearing to participate in the auditory ERP P300 procedure, i.e., ability to 
hear and differentiate the two different tones, using the centrally provided EEG equipment; 
hearing aid must be removed during the screening hearing test and during EEG recordings. 
6.2 
Pharmacodynamic Variables 
Pharmacodynamic variables will consist of EEG assessments (ERP P300 and 
) performed 
over approximately 20 minutes, with ERP P300 performed prior to 
.  
At Pre-baseline visit (Visit 2a, Day -5 to Day -3, no dosing), EEG assessments (ERP P300 and 
) will be performed twice approximately 2 hours apart. EEG data should be uploaded for 
quality check immediately after the completion of the Pre-baseline visit (Visit 2a). 
At Baseline/Day 1 (Visit 2b), EEG assessments (ERP P300 and 
) will be performed at pre-
dose following the completion of baseline assessments of ADAS-Cog11 and COWAT, and before 
the ADCS-CGIC assessment, up to 1.5 hour before dose in clinic. EEG will be assessed post-
dose at approximately 2 (±1) hours after IMP dosing. 
At Visits 3, 4, 5, 6, 7, and 8, EEG assessments (ERP P300 and 
) will be performed at pre-
dose up to 1 hour before dose in clinic. EEG will be assessed post-dose following the completion 


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of ADAS-Cog11 and COWAT assessments, and before the ADCS-CGIC assessment, at 
approximately 2 (±1) hours after IMP dosing. 
At safety follow up (Visit 9, no dosing), EEG assessments (ERP P300 and 
) will be 
performed following the completion of ADAS-Cog11 and COWAT. 
6.2.1 
ERP P300 
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 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. 
6.2.2 
6.3 
Other 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-Cog11 and COWAT assessments shall occur at clinic visits in the morning at 
approximately the same time they were performed during the initial Baseline/Day 1 assessment. 


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6.3.1 
Cognitive Variables 
6.3.1.1 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog11) 
The ADAS-Cog11 is designed to measure cognitive symptom change in subjects with AD 
(Rosen, 1984). The standard 11 items are 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 test includes 7 performance items and 4 clinician-rated items, with a total score ranging from 
0 (no impairment) to 70 (severe impairment). Therefore, higher scores indicate more severe 
cognitive impairment. 
Due to known circadian fluctuations of cognitive capacity (Hilt, 2015), ADAS-Cog11 will be 
assessed in the morning at approximately the same time of day as the baseline assessment for all 
applicable visits. 
ADAS-Cog11 assessments will be performed pre-dose at Visit 2b (Baseline/Day 1), and post-
dose at approximately 1 hour (± 30 minutes) at Visit 3 (Week 2), Visit 4 (Week 6), Visit 5 
(Week 12), Visit 7 (Week 20), Visit 8/ET (Week 26), and Visit 9 (Safety follow-up; no dosing). 
6.3.1.2 
Controlled Word Association Test (COWAT) 
The Controlled Oral Word Association Test (COWAT) is an oral verbal fluency test in which the 
subject is required to make verbal associations to different letters of the alphabet by saying all 
the words which they can think of beginning with a given letter. Individuals are given 1 minute 
to name as many words as possible beginning with each of the letters. The procedure is then 
repeated for the remaining two letters (Benton, 1994; Strauss, 2006). The test score is the total 
number of different words produced for all 3 letters. 
The COWAT will be performed adjacent to the ADAS-Cog11 assessment, i.e., pre-dose at Visit 
2b (Baseline/Day 1), and post-dose at approximately 1 hour (± 30 minutes) at Visit 3 (Week 2), 
Visit 4 (Week 6), Visit 5 (Week 12), Visit 7 (Week 20), Visit 8/ET (Week 26), and Visit 9 
(Safety follow-up; no dosing). 
6.3.2 
Disease Condition 
6.3.2.1 
Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change 
(ADCS-CGIC) 
The Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change 
(ADCS-CGIC) scale is a 7-point scale that requires the clinician to assess how much the 
subject’s illness has improved or worsened relative to a baseline state at the beginning of the 
intervention and rated as: 1, markedly improved; 2, moderately improved; 3, minimally 
improved; 4, no change; 5, minimally worse; 6, moderately worse; or 7, markedly worse. The 


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ADCS-CGIC consists of 3 parts: a guided baseline interview administered to the subject and 
caregiver/support person, a follow-up interview administered to the subject and caregiver/ 
support person, and a clinician’s rating review (Schneider, 1997). At study start, using the 
ADCS-CGIC baseline form as a guideline, the ADCS-CGIC rater will obtain an integral clinical 
impression of the subject’s status, can apply any formal testing at his/her discretion, and take 
personal notes regarding the subject’s condition; these will serve as a reference for future change 
ratings. The ADCS-CGIC will be administered by an experienced clinician who will remain 
independent of the subject’s safety, cognitive and functional outcomes, and will be trained and 
certified for this study. The ADCS-CGIC rater will ideally remain the same individual for all 
ADCS-CGIC ratings. 
ADCS-CGIC assessments will be performed adjacent to ADAS-Cog11 and COWAT assessments 
pre-dose at Visit 2b (Baseline/Day 1), post-dose at Visit 5 (Week 12), and post-dose at 
Visit 8/ET (Week 26). 
6.3.2.2 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living, 23-item Version 
(ADCS-ADL23) 
The ADCS- ADL23 (Galasko, 1997) is a 23-item assessment of functional impairment in terms 
of activities of daily living administered to the support person/caregiver. It comprises 
23 questions about the subject’s involvement and level of performance across items representing 
daily living. The questions range from basic to instrumental activities of daily living. Each item 
is rated from the highest level of independent performance to complete loss. The total score 
range is from 0 to 78, with lower scores indicating greater functional impairment. ADCS-ADL23 
assessments will be performed pre-dose at Visit 2b (Baseline/Day 1), post-dose at Visit 5 (Week 
12), and post-dose at Visit 8/ET (Week 26). 


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6.3.3 
Health-related Quality of life 
6.3.3.1 
6.3.4 
Caregiver Burden/Resource Utilization/Pharmacoeconomic Variables 
6.3.4.1 
6.3.4.2 
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 


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(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), 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 
• New condition detected or diagnosed after Screening even though it may have been 
present in the medical history before the start of the study 
• 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 (eg, 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: 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. 
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. 


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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: 
• 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 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. 
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. 


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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 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. 
 
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 
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• 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 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. 
• 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. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
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6.4.1.4 
Reporting of Serious Adverse Events 
Prompt (within 24 hours) notification by the investigator to 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 the MMS 
Drug Safety and Pharmacovigilance of any SAE, whether deemed IMP-related or not, that a 
subject experience during their participation in study within 24 hours of becoming aware of the 
event to: 
Email: drugsafety@athira.com 
Fax: 1-425-620-8508 
The 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: 
• Identifiable subject 
• Identifiable event (including causality assessment) 
• Identifiable IMP 
• Identifiable reporter 
The 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 the MMS Drug Safety and 
Pharmacovigilance within 24 hours of the request. 


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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 SAE Report Form. Additional information (copy 
of lab reports, consultant reports, copy of discharge summaries, etc.) should be provided on 
request of MMS Drug Safety and Pharmacovigilance.  
If a new 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 Investigator will be reviewed by study Sponsor and assessed for 
meeting criteria of Suspected Unexpected Serious Adverse Reactions (SUSARs). All SUSARs 
will be reported by Sponsor to Competent National Authorities and Investigators according to 
local regulatory requirements and Sponsor policy. 
An investigator who receives an Individual Case Safety Report (ICSR) 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 7.6). 
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. 
6.4.2 
Pregnancy 
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. Only female subjects 
of non-childbearing potential (i.e., permanently sterilized, postmenopausal) are eligible for 
participation.  
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
MMS Drug Safety and Pharmacovigilance within 24 hours of learning of the partner’s 


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pregnancy. The 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 by a central laboratory, 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) 
Calcium 
Chloride 
Glucose 
Creatinine 
ALP 
AST 
ALT 
GGT 
CPK 
Total bilirubin 
Total protein 
Albumin 
Total Cholesterol 
Low-density lipoprotein  
High-density lipoprotein 
Triglycerides 
Vitamin B12 a 
Folate a 
TSH, fT3 and fT4 a 
Coagulation 
INR 
PT 
aPTT 
Serology 
HBsAg 
HCV 
HIV type 1 or type 2 
Urinalysis  
pH 
glucose 
ketones 
specific gravity 
nitrite 
protein 
bilirubin 
blood 
CBC = complete blood count; RBC = red blood cells; WBC = white blood cells; AST = aminotransferase; ALT = alanine 
transaminase; ALP = alkaline phosphatase; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; 
HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; INR = international normalized ratio; 
PT = prothrombin time; aPTT = activated partial thromboplastin time; fT3 = free tri-iodothyronine; T4 = free thyroxine; TSH = 
thyroid-stimulating hormone 
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 


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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 lab values and supported by Medical Monitor interpretation. Investigators, the Sponsor, 
Medical Monitor 
, and MMS - Sponsor’s designated CRO for Drug 
Safety and Pharmacovigilance (drugsafety@athira.com) 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:  
• 
ALT or AST ≥ 3 × ULN AND  
• 
Total bilirubin ≥ 2 × ULN AND  
• 
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). 
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:  
• 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) 


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• 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 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 approximately 1 minute apart, 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. 
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. 
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, in discussion with the Medical 
Monitor. 
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 body mass index using the following formula: weight (kg)/[height (m)]2. 


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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 7 (Week 20), Visit 8/ET, and Visit 9 (Safety follow-up) 
(Week 26) (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 more severity. A GDS score of ≤ 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, Baseline/Day 1 (Visit 2b), Visit 5 (Week 12), 
Visit 8/ET (Week 26), and Visit 9 (Safety follow-up). 
6.5 
Pharmacokinetic Variables 
Blood will be collected for PK analyses at the timepoints detailed in Table 1. The actual time of 
PK sampling will be recorded. 
Blood sample collection, processing, and shipping details will be outlined in a separate 
laboratory manual. In brief, blood will be processed and plasma analyzed by a validated method 
for concentrations of ATH-1017 and ATH-1001. PK parameters will be calculated from the 
plasma concentration-actual time profiles. The noncompartmental analysis, if feasible, will be 
performed using WinNonlin version 7.0. Plasma concentrations may also be used for population 
PK analysis, the results of which will be reported separately. 
6.6 
Genotyping 
Blood sample(s) will be collected at Screening for analysis of ApoE genotype.  


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6.7 
Plasma Sample Biobanking 
Collection of samples for fluid biomarker research is also part of this study. Plasma samples for 
biomarker research will be collected, if consented to, pre-dose at Baseline (Day 1) and at the last 
scheduled visit (Week 26) from all subjects in this study (Table 1). 
Samples will be stored for up to 5 years; analysis may be performed on biomarkers thought to 
relate to AD progression/pathology including, but not limited to, neurofilament light chain to 
evaluate their association with observed clinical responses to ATH-1017. 


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7 
STUDY CONDUCT 
• Study procedures and their timing are summarized in the Schedule of Assessments (Table 
1). 
• Protocol exemptions related to enrollment criteria are only allowed with prior 
Investigator and Sponsor approval, supported by documented agreement from the 
IRB/IEC. 
• 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. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. 
• 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. 
• 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 -28 through Day -6), a Pre-baseline 
visit (Visit 2a, Day -5 to Day -3), during which subjects will undergo an MMSE assessment, and 
2 baseline EEG assessments (ERP P300 and 
) approximately 2 hours apart, 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 key endpoints, the general order post-dose should be followed: 
(1) ADAS-Cog11 
(2) COWAT 


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(3) EEG assessments (ERP P300 and 
) 
(4) ADCS-CGIC 
At Pre-baseline visit (Visit 2a, Day -5 to Day -3), MMSE should be done first before all other 
assessments. 
ADAS-Cog11 and COWAT assessments shall occur at clinic visits in the morning at 
approximately the same time they were performed during the initial Baseline/Day 1 assessment. 
ADAS-Cog11 and COWAT 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 6 (Visit 4) 
Week 12 (Visit 5), Week 20 (Visit 7), and Week 26 (Visit 8); and additionally at Safety follow 
up (visit 9; no dosing). 
EEG assessments shall occur shortly after the completion of ADAS-Cog11 and COWAT 
assessments, and before the ADCS-CGIC assessment at applicable visits. EEG assessments will 
be performed at Pre-baseline (Visit 2a), Baseline/Day 1 (Visit 2b), Week 2 (Visit 3), Week 6 
(Visit 4), Week 12 (Visit 5), Week 16 (Visit 6), Week 20 (Visit 7), Week 26 (Visit 8), and safety 
follow up (Visit 9, no dosing). 
ADCS-CGIC assessments will be organized at adjacent times to the individual EEG assessment 
times at Baseline/Day 1 (Visit 2), and post-dose at Week 12 (Visit 5), and Week 26 (Visit 8). 
PK plasma samples will be collected at post-dose at Baseline/Day 1 (Visit 2); pre-dose and post-
dose at Week 12 (Visit 5) and Week 26 (Visit 8). The pre-dose PK sample is collected anytime 
before dosing. The post-dose PK sample is collected anytime between 30 minutes and 120 
minutes after dosing as practical.. The actual time of dosing and of PK sampling will be 
recorded. 
The order of assessments for all other endpoints is 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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• Visits 1 (Screening), 2 (Pre-baseline, Day -5 to Day -3; Baseline/Day 1), 5 (Week 12), 
8 (Week 26), and 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) 
• Visits 3 (Week 2), 4 (Week 6), 6 (Week 16), and 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 
7.3 
Data Safety Monitoring Board 
An independent DSMB will conduct periodic review and assessments of unblinded safety data 
(AEs, labs, ECG, etc) throughout the study to ensure the safety of study subjects. Based on 
unblinded safety data review, the DSMB may recommend terminating the study. 
The DSMB is composed of at least a study-independent non-Sponsor physician and a 
study-independent statistician. Additional members have been included and ad hoc members 
may also be invited depending on the safety findings and required scope of expertise. 
Details regarding the DSMB are included in the DSMB charter, including committee 
membership, data review procedures, frequency of review, and communication between the 
DSMB and others. 
7.4 
Concomitant Medications and Treatments 
7.4.1 
Prohibited Treatments During the Study 
Concomitant use of the following drugs is excluded within 4 weeks prior to Screening. 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.: 
• Memantine, in any form, combination or dosage 
• Donepezil at 23 mg PO  


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The following drugs are prohibited during the study: 
• 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 7.4.2). 
• Nicotine therapy (including patches), varenicline (Chantix), or similar therapeutic agent 
• Peripherally acting drugs with effects on cholinergic neurotransmission. Solifenacin is 
allowed if the subject has received a stable dose for at least 3 months before Screening 
• Systemic immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses in the judgment of the investigator (for exceptions see 
Section 7.4.2) 
• Antiepileptic medication 
• Chronic intake of opioid containing analgesics; PRN use is allowed (but not within 72 
hours before any cognitive assessment) 
• Sedating H1 antihistamines; non-sedating H1 antihistamines are allowed and preferred 
• Systemic moderate to strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
fluconazole, cimetidine, clarithromycin, erythromycin, troleandomycin); topical 
applications are allowed (see Appendix 1: List of Prohibited Medications for 
non-exhaustive list) 
• Systemic moderate to strong CYP3A4 inducers (e.g., carbamazepine, rifabutin, ritonavir, 
and St. John’s wort); topical applications are allowed (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. 


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7.4.2 
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: 
• Indication 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
In this study, subjects may be taking a stable dose of AChEI, as long the dose has been stable for 
3 months prior to Screening (cf. EC #25b) and no changes are planned during the study.  
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 7.4.1, 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 only if given for sleep disturbances, agitation and/or aggression, and 
only if the subject has received a stable dose for at least 3 months before Screening. If these 
medications are taken on a PRN basis, they should not be taken the night before any cognitive 
testing. 
Low doses (in the judgement 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, monoamine oxidase inhibitors, and S-ketamine, 
all other antidepressant medications are allowed. 
Immunosuppressant use for allergy or other inflammation, e.g., inhaled steroids, otics, 
opthalmologics, skin creams, and intra-articular injections are allowed. 
If the permissibility of a specific medication/treatment is in question, please contact the Medical 
Monitor. 


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7.4.3 
Other Restrictions 
7.4.3.1 
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 and 
MCT are excluded during the study, beginning 7 days prior to the first dose of study medication 
(Day 1). THC is prohibited beginning 4 weeks prior to the first dose of study medication (Day 1) 
and for the duration of the study. CBD without THC is allowed but not on the clinical visit days 
except for topical applications. CBD use should be recorded as concomitant medication. 
7.4.3.2 
Contraceptives 
Sexually active males with female 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. 
7.5 
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 contact 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. 
7.5.1 
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). 
7.5.2 
Withdrawal from the Study 
• 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 
• Subjects must be discontinued from the study and/or receive no further study treatment, if 
any of the following criteria are met: 


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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 
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 
• 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. 
• 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. 
• 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. 
• 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. 


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7.6 
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: 
• 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 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• 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. 
• 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. 
7.7 
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: 
• 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 
• Inadequate recruitment of participants by the investigator 
• 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 at least one ERP P300 baseline 
assessment and one post-baseline ERP P300 assessment. 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 took the assigned medication 
during the 26 weeks of treatment, completed at least one ERP P300 plus ADAS-Cog11 and/or 
COWAT post-baseline assessment, 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 the primary variable of ERP P300, Pre-baseline and Baseline visit 
assessments will be used for change from baseline comparisons. For other 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 
Analyses 
8.3.1 
Primary Analysis – ERP P300 Latency 
The primary analysis will use a mixed model for repeated measures (MMRM) to compare the 
estimated changes between active treatment and placebo in ERP P300 latency. These analyses 
will assess whether or not there is a difference in estimated changes between treatment groups 
and placebo at Weeks 2, 6, 12, 16, 20, and 26. Further details relating to the primary analysis will 
be described in the SAP. 
8.3.2 
Secondary Analysis  
8.3.2.1 
Correlation of ERP P300 with ADAS-Cog11 and COWAT 
Secondary analyses will include an evaluation of the correlation of ERP P300 latency with 
cognition/executive memory function, and comparison of treatment and placebo for the Global 
Statistical Test (GST), ADAS-Cog11, ADCS-CGIC, and ADCS-ADL23, which will be described 
in the SAP. 
8.3.3 
Exploratory Analyses 
8.3.4 
Subgroup Analyses 
Subgroup analyses (e.g., gender, age, MMSE score, ApoE genotype) will be performed in the 
mITT population. 
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. 
8.4.1 
Adverse Events 
AEs occurring after the start of study drug dosing at 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 percent within each category will be generated for each of the 
following types of AEs:  
• 
All events 


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• 
Serious events 
• 
Deaths 
• 
Events leading to study discontinuation 
• 
Events related to study treatment (study drug and injection procedure separately) 
• 
Severe events 
8.4.2 
Laboratory parameters 
Laboratory parameters and vital signs will be summarized by scheduled and unscheduled 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 
Weight 
Weight 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 
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.  
8.4.5 
Columbia-Suicide Severity Rating Scale 
Results from the C-SSRS questionnaire will be listed and summarized using descriptive statistics 
by treatment group and visit. 
8.4.6 
Geriatric Depression Scale 
Results from the GDS questionnaire will be listed and summarized using descriptive statistics by 
treatment group and visit. 
8.5 
Pharmacokinetic Analyses 
PK analyses will be described in a separate document finalized before database lock. The PK 
analyses will be presented separately from the main clinical study report. 
8.6 
Determination of Sample Size 
A total sample size of 60 evaluable subjects (20 per treatment arm) is based on the results of the 
Phase 1 study, NDX-1017-0101, which demonstrated significant effects of ATH-1017 on ERP 
P300 in n=7 ATH-1017-treated AD subjects versus n=4 placebo-treated AD subjects.  


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8.7 
Interim Analysis 
No interim analysis is planned for this study. 
 


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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 MMSE, CDR, ADAS-Cog11, and 
ADCS-CGIC will take place for rating quality control purpose. 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 clinical 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 x-rays 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 
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.  
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. 


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9.6 
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. 
9.7 
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. 
9.8 
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 
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. 


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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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development of a shorter version. Clinical Gerontologist: The Journal of Aging and Mental 
Health, 5(1-2), 165–173. 
Strauss, E., Sherman, E. M. S., & Spreen, O. (2006). Compendium of neuropsychological tests: 
Administration, norms, and commentary (3rd ed., p. 502). Oxford: Oxford University Press.  
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. 
Wimo A, Wetterholm AL, Mastey V, Winblad B. Evaluation of the resource utilization and 
caregiver time in Anti-dementia drug trials – a quantitative battery. In: Wimo A, Karlsson G, 
Jönsson B, Winblad B (eds). The Health Economics of Dementia, 1998. Wiley’s, London, UK. 
Zarit, SH, Reever, KE, Back-Peterson, J. Relatives of the impaired elderly: correlates of feelings 
of burden. The Gerontologist. 1980;20:649-655. 


Athira Pharma, Inc.  
Protocol ATH-1017-AD-0202  
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 3.00 
Page 85 of 87 
25-MAY-2021 
 
11 
APPENDICES 
11.1 
Appendix 1: List of Prohibited Medications 
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  
High-dose donepezil 
• Donepezil (Aricept) at 23 mg PO 
•  
Peripherally acting anticholinergics 
• 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, 
anti-depressants (tricyclic), anxiolytics 
or sedative hypnotics. 
Antipsychotics (Please refer to Exclusion 25c 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) 
• Aripiprazole (Abilify)  
• Asenapine (Saphris, Sycrest)  
• Clozapine (Clozaril)  
• Iloperidone (Fanapt, Fanapta) 
• Lurasidone (Latuda) 
• Olanzapine (Zyprexa)  
• Paliperidone (Invega) 
• Quetiapine (Seroquel)  
• Risperidone (Risperdal)  
• Trimipramine (Surmontil) 


Athira Pharma, Inc.  
Protocol ATH-1017-AD-0202  
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 3.00 
Page 86 of 87 
25-MAY-2021 
 
Category of Prohibited Medications 
Examples: General Name (Trade Name) 
• Ziprasidone (Geodon, Zeldox)  
Tricyclic antidepressants 
• 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 
• Sedating H1 antihistamines 
• Chronic opioids 
• S-ketamine 
• Anti-epileptics 
Systemic moderate or strong CYP3A4 
inhibitors 
• Boceprevir (Victrelis) 
• Cannabidiol 
• 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) 
• Troleandomycin 
• Verpamil 
• Voriconazole (Vfend) 


Athira Pharma, Inc.  
Protocol ATH-1017-AD-0202  
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 3.00 
Page 87 of 87 
25-MAY-2021 
 
Category of Prohibited Medications 
Examples: General Name (Trade Name) 
Systemic 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: 
Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 1 of 45
A Randomized, Placebo-Controlled, Translational Study of
ATH-1017 in Subjects with Mild to Moderate Alzheimer’s 
Disease
Pentara Corporation
2261 East 3300 South
Millcreek, UT 84109
Protocol:
ATH-1017-AD-0202 v3.00 dated 25-May-2021
SAP Version: 1.1, 02-Jun-2022
NCT Number: NCT04491006
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov




Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 3 of 45


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 4 of 45
Modification History
Unique 
Identifier 
for 
this Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from 
Previous Authorized Version 
0.1
05-APR-2021
not applicable—first version
0.2
12-APR-2022
- specifying pooled
treatment arm vs placebo as primary
- removing hierarchy for secondary
- primary outcome as change from 
baseline to all post baseline, post-dose 
P300 latencies
-
alpha control only for primary 
endpoint
- specify acute and sustained analysis 
of p300 latency as additional endpoints
- covariance structure for MMRM 
model updated
- update covariates list for primary and 
secondary models
-
specify 
 
(subgroup analyses) of +/- ACHEI and 
for disease severity (mild/moderate)
- clarify that a Pearson correlation will 
be used for the secondary outcome 
(between change in P300 latency and 
cognitive measures
-
specify outcomes of all GST 
combinations of interest
- removed all sensitivity analysis as 
outcomes of interest are specified as 
secondaries
- rename 
 to 
additional outcomes
-7.5.1.2 changed to use the same model 
as 7.4.1 except with time and time 
interactions 
included 
for 
the 
correlations.
-sections describing primary analysis 
changed to prioritize pooled active 
treatment vs. placebo.


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 5 of 45
0.3
28-APR-2022
- define ROI (region of interest) as 
average of CZ, FC1, FC2, CP1, and 
CP2 electrodes as primary efficacy 
endpoint
- update language in SAP to define 
primary efficacy endpoint as the 
average of pre-dose and post-dose 
records within an analysis window
- update language regarding baseline 
definition, pre-dose (sustained) and 
pre-to-post (acute) to be more explicit
1.0
11-MAY-
2022
-Clarified that all visits are used in the 
covariance modeling but that visits at 
week 12, 16, 20, and 26 are averaged 
for the primary endpoint and key 
secondary.
-Changed the key secondary to match 
the paragraph text of the protocol, 
which does not include COWAT, so 
the GST is ADASCog and CGIC 
instead.
-Ordering of secondary objectives is 
changed and some are moved to 
exploratory.
-Pooled treatment changed to active 
and a paragraph added to general 
section that describes the pooling of 
active treatments.
-Allowed for keeping data if there is 
only pre or post, eliminating sentence 
that stated must have both a pre and 
post for a visit to be included.
-Key secondary now uses neither the 
model of the primary nor a Pearson 
correlation, instead has its own model.
Region of interest defined in general 
section.
-Removed duplicated descriptions by 
moving as many as possible to the 
general section.
-COWAT and ADASCog version of 


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 6 of 45
the GST removed since it is only 
mentioned in the summary and 
heading of the protocol but that 
contradicts the text of the protocol.
-Concurrent 
medication 
coding 
described.
-Clarified primary analysis not using 
weeks 2 and 6 in the endpoint.
-Clarified 
averaging 
of 
primary 
endpoint visits.
-Removed unneeded explanation of 
overall effect of treatment.
-Added treatment descriptions in the 
general section.
-Significant differences defined as p < 
.05 in the general section.
1.1
02-Jun-2022
-added GST of (COWAT + ADCS-
ADL) as secondary analysis


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 7 of 45
Table of Contents
1 Abbreviations ............................................................................................. 9 
2 Introduction..............................................................................................16 
3 Trial Overview..........................................................................................17 
3.1 Design ..............................................................................................................17 
3.2 Study Objectives..............................................................................................18 
3.2.1 Primary Objectives........................................................................... 18 
3.2.2 Key Secondary Objectives............................................................... 18 
3.2.3 Other Secondary Objectives ............................................................ 18 
3.3 Sample Size Determination..............................................................................19 
3.4 Blinding and Unblinding..................................................................................19 
4 Patient Chronology ..................................................................................20 
5 General Conditions for the Final Analysis ............................................ 20 
5.1 Definitions........................................................................................................20 
5.2 General Considerations for the Final Analysis................................................20 
5.3 Visit Windowing..............................................................................................22 
5.4 Procedures for Handling Missing Data............................................................23 
5.5 Interim Analysis...............................................................................................23 
5.6 Changes to Statistical Analysis........................................................................23 
5.7 Analysis Populations/Sets................................................................................23 
5.7.1 Modified Intent-to-Treat (mITT) Population................................... 23 
5.7.2 Per Protocol Population ................................................................... 24 
5.7.3 Safety Population............................................................................. 24 
5.8 Primary Estimand.............................................................................................24 
5.9 Data Review.....................................................................................................24 
5.10 Missing Data..................................................................................................25 
6 Study Conduct..........................................................................................26 
6.1 Treatment Assignments ...................................................................................26 
6.2 Enrollment, Demographics, and Baseline Characteristics...............................26 
6.3 Patient Disposition and Protocol Deviations ...................................................26 
6.4 Extent of Exposure to Study Drug...................................................................26 
6.5 Medical History / Concomitant Medication ....................................................26 
6.6 General Comments...........................................................................................27 
7 Efficacy Endpoints...................................................................................28 
7.1 Primary Variable..............................................................................................28 
7.2 Secondary Efficacy Endpoints.........................................................................28 
7.2.1 Global Statistical Tests .................................................................. 28 
7.2.2 Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-
Cog11)............................................................................................ 29 




Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 9 of 45
1 Abbreviations
AChEl
Acetylcholinesterase inhibitor
AD
Alzheimer’s disease
AE
Adverse event
ADAS-Cog11
Alzheimer’s disease assessment scale – cognitive subscale
ADCS-ADL23
Alzheimer’s disease cooperative study-activities of daily living, 23-item
version
ADCS-CGIC
Alzheimer’s disease cooperative study-clinical global impression of 
change
AKT
Protein kinase B
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ApoE
Apolipoprotein E
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CBC
Complete blood count
CBD
Cannabidiol
CDR
Clinical dementia rating scale
CFB
Change from baseline
CPK
Creatine phosphokinase
CRO
Contract research organization
CYP3A4
Cytochrome P450 3A4
Cmax
Maximum concentration
CNS
Central nervous system
COWAT
Controlled oral word association test
C-SSRS
Columbia-suicide severity rating scale
CT
Computerized tomography
DSMB
Data safety monitoring board
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEG
Electroencephalogram
ERP
Event-related potentials


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 10 of 45
ET
Early termination
FSH
Follicle-stimulating hormone
fT3
Free tri-iodothyronine
fT4
Free thyroxine
FWER
Family-wise error rate
GCP
Good clinical practice
GDS
Geriatric depression scale
GGT
Gamma-glutamyl transferase
GLP
Good laboratory practice
GST
Global statistical test
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HGF
Hepatocyte 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
LTP
Long-term potentiation
MAPK
Mitogen-activated protein kinase
MCT
Medium-chain triglyceride
MET
MET receptor tyrosine kinase
mITT
Modified intent-to-treat
MMRM
Mixed model with repeated measures
MMSE
Mini-mental state examination
MRI
Magnetic resonance imaging


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 11 of 45
NMDA
N-methyl D-aspartate
OD
Once daily
P
Phosphorylated
PD
Pharmacodynamic(s)
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetic(s)
PKC
Protein kinase C
3/&Ȗ
Phospholipase C-gamma
PM
Plasma membrane
PRN
As needed
PSP
Post-synaptic potential
PT
Prothrombin time
QTcF
Corrected QT interval using Fridericia’s formula
RAC1
Ras-related C3 botulinum toxin substrate 1
RAF
Rapidly accelerated fibrosarcoma (protein)
RAS
Rat sarcoma (protein)
RBC
Red blood cells
ROI
Region of interest
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SC
Subcutaneous
SE
Standard error
SOP
Standard operating procedure
STAT3
Signal transducer and activator of transcription 3
THC
Tetrahydrocannabinol
TSH
thyroid-stimulating hormone
ULN
Upper limit of normal
D


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Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 12 of 45
US(A)
United States (of America)
VAS
Visual analog scale
WBC
White blood cells






Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 15 of 45
h. MRI (or CT for subjects with non-MRI-safe cardiac pacemaker, or other relevant medical reason, with Medical Monitor
approval) scan must have been performed within 12 months before Screening. If such scan is unavailable or older than
12 months, it should be repeated to ascertain the diagnosis before randomization.
i. 12-lead ECGs will be performed pre-dose and 30 (± 15) minutes post-dose on Day 1(Visit 2b) and 30 (± 15) minutes post-dose 
at all other visits. All ECG assessments will be performed in triplicate approximately 1 minute apart.
j. Vital signs will be performed pre-dose on all visits. Supine BP and HR recordings will be made after the subject has been supine 
for at least 5 minutes. Orthostatic BP will be recorded as follows: 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 stood for up to 3 
minutes.
k. Safety labs include chemistry, hematology, and urinalysis.
l. Prior or concurrent medications.
m. Subject hearing will be tested to establish suitability for auditory ERP assessment, i.e., ability to hear and differentiate two
different tones, using the centrally provided EEG equipment; hearing aid must be removed during the screening hearing test and 
during EEG recordings.
n. At Pre-baseline visit (Visit 2a, Day -5 to Day -3, no dosing), EEG assessments (ERP P300 and 
) will be performed twice 
approximately 2 hours apart. EEG data should be uploaded for quality check immediately after the completion of the Pre-
baseline visit (Visit 2a). If both EEG assessments failed quality check at pre-baseline, the visit will be repeated once and the 
screening window of 28 days can be extended upon approval by Medical Monitor.
At Baseline/Day 1 (Visit 2b), EEG assessments (ERP P300 and 
) will be performed at pre-dose following the completion 
of baseline assessments of ADAS-Cog11 and COWAT, and before the ADCS-CGIC assessment, up to 1.5 hour before dose in 
clinic. EEG will be assessed post-dose at approximately 2 (±1) hours after IMP dosing.
At Visits 3, 4, 5, 6, 7, and 8, EEG assessments (ERP P300 and 
) will be performed at pre-dose up to 1 hour before dose in 
clinic. EEG will be assessed post-dose following the completion of ADAS-Cog11 and COWAT assessments, and before the 
ADCS-CGIC assessment, at approximately 2 (±1) hours after IMP dosing.
At safety follow up (Visit 9, no dosing), EEG assessments (ERP P300 and 
) will be performed following the completion of 
ADAS-Cog11 and COWAT.
o. PK plasma samples will be collected at post-dose on Baseline/Day 1 (Visit 2b); pre-dose and post-dose at Week 12 (Visit 5) and 
Week 26 (Visit 8). The pre-dose PK sample is collected anytime before dosing. The post-dose PK sample is collected anytime 
between 30 minutes and 120 minutes after dosing as practical. The actual time of dosing and of PK sampling will be recorded.
p. Plasma sample will be collected and banked for biomarker analysis (only for subjects who provided consent for plasma 
biobanking). Ten aliquots will be created from the plasma sample.
q. Subjects who terminate prior to Visit 9 are to complete same assessments as Visit 8/ET (early termination). For clinical outcome 
assessments if completed within 4 weeks of the ET visit they do not need to be repeated; all safety outcomes and drug 
accountability should be performed regardless of interval.
r. Safety follow-up visit to be performed for subjects who do not roll over into the optional open-label extension (OLEX) study; 
subjects who roll over into the OLEX study will complete the safety follow-up visit at the end of the OLEX study.
*  At Pre-baseline visit (Visit 2a, Day -5 to Day -3), MMSE should be done first before all other assessments.
At Baseline/Day 1 (Visit 2b), ADAS-Cog11, COWAT, and ADCS-CGIC will be performed pre-dose; ADCS-ADL23, 
, 
C-SSRS, 
 will be performed anytime during the visit. 
For visits after the baseline (except for safety follow-up when dosing is not applicable), all clinical outcome assessments will be 
performed post-dose, with ADAS-Cog11 and COWAT assessments performed first at approximately 1 hour (± 30 minutes) post-
dose. ADCS-CGIC assessments, when applicable, will be organized at adjacent times shortly after the individual EEG 
assessments.


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 16 of 45
2 Introduction
ATH-1017 is an experimental Alzheimer’s disease (AD) treatment. ATH-1017 is a prodrug, 
which is rapidly converted to the active metabolite 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 active metabolite ATH-1001 acts as a positive modulator at the 
hepatocyte growth factor (HGF) and its tyrosine kinase, MET, receptor system. Central 
nervous system (CNS) MET expression is crucial in maintaining the healthy adult brain 
(Hawrylycz, 2015), and is reduced in AD particularly in the hippocampus and frontal cortex 
(Hamasaki, 2014). The HGF/MET system presents a new therapeutic target to treat 
neurodegeneration and restore cognitive function in AD and other neurodegenerative 
disorders.


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 17 of 45
3 Trial Overview
3.1 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 mild to moderate AD, diagnosed on a ‘probable’ level 
according to McKhann, 2011. 
The study will be conducted at a total of 6 centers in Australia and 8 centers in the US. 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 be tested for ApoE genotype. 
Subjects who meet all inclusion/exclusion criteria will undergo baseline EEG assessments 
(ERP P300 and 
) at 2 separate baseline visits. At the first baseline visit (Visit 2a, Pre-
baseline, Day -5 to Day -3), EEG assessments (ERP P300 and 
) will be performed at 2 
separate timepoints approximately 2 hours apart (no dosing). EEG data should be uploaded for 
quality check immediately after the completion of the Pre-baseline visit (Visit 2a). At the 
second baseline visit (Visit 2b, Baseline, Day 1), no more than 6 days after the Pre-baseline 
visit, subjects will be randomized in a ratio of 1:1:1 to 3 parallel arms, either to active treatment 
(ATH-1017 40 mg/day or ATH-1017 70 mg/day) or placebo. During randomization, subjects 
will be stratified by baseline MMSE severity: mild (MMSE: 20-24) versus moderate (MMSE: 
14-19). At this Baseline visit (Visit 2b), subjects will undergo pre-dose baseline and post-dose 
EEG assessments (ERP P300 and 
).
Study drugs will be administered by SC injection once daily (OD) preferably during daytime. 
It is not recommended to take more than one dose within 8 hours. At the baseline visit, the first 
SC injection of study drug will be performed at 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). 
Subjects will undergo EEG assessments (ERP P300 and 
) at each post-baseline clinic 
visit (pre- and post-dose timepoints) through Week 26, plus the safety follow-up visit at Week 
30 (see Table 1 for timing of assessments). On Day 1, after completion of the first dose, 
subjects will remain onsite 2 hours for post-treatment safety observation. As marked circadian 
fluctuations of cognitive performance have been observed in AD (Hilt, 2015), ADAS-Cog11
and COWAT assessments shall occur at clinic visits in the morning at approximately the same 
time they were performed during the initial Baseline assessment. 


Athira Pharma, Inc.
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Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 18 of 45
Similarly, ADCS-CGIC assessments will be organized at adjacent times to the individual EEG 
assessment times. 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 same assessments as Visit 8/early termination (ET).
An independent Data Safety Monitoring Board (DSMB) will conduct periodic review and
assessments of unblinded safety data (AEs, labs, ECG, etc.) throughout the study to ensure the
safety of study subjects.
Blood draws will take place at scheduled clinic visits (Day 1, Week 12 and Week 26) for
analysis of plasma concentrations of ATH-1017 and ATH-1001 (see Table 1 for schedule of
assessments).
An open label extension will be offered at participating sites.
3.2 Study Objectives
3.2.1 Primary Objectives
1. To evaluate the effects of ATH-1017 on event-related potential (ERP) P300 
latency; change from baseline to post-baseline measurements compared to 
placebo.
2. To determine the safety and tolerability of ATH-1017.
3.2.2 Key Secondary Objectives
1. To evaluate the correlation of ERP P300 latency and cognition measured by 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11)
and/or executive memory function measured by Controlled Oral Word 
Association test (COWAT); changes
from baseline to post-baseline
measurements comparing ATH-1017 to placebo.
3.2.3 Other Secondary Objectives
1. To evaluate the clinical efficacy of ATH-1017; Global Statistical Tests (GSTs)
(O’Brien, 1984) that combine the scores from various clinical assessments into 
a single measure of overall symptomology. The various combinations of clinical 
outcomes combined for the GSTs are described in Section 7.
2. To evaluate the efficacy of ATH-1017 compared to placebo based on changes 
from baseline in:
a)
clinical efficacy, measured separately by
the ADAS-Cog11
(cognition), ADCS-CGIC (global impression of change), and 
COWAT (executive memory function) questionnaires
b)
Functional ability, measured by ADCS-ADL23


Athira Pharma, Inc.
Statistical Analysis Plan
Protocol ATH-1017-AD-0202; 
SAP version 1.1, 02-Jun-2022
Page 19 of 45
3. To further evaluate the effects of ATH-1017 on ERP P300 latency; (i) evaluation 
of the acute effects of ATH-1017 on ERP P300 latency change from pre-dose to 
within-visit post-dose measurement,(ii) evaluation of the sustained effects of 
ATH-1017 on ERP P300 latency change from pre-dose baseline to pre-dose 
measurement across visits, (iii) evaluation of persistence of change in ERP P300 
latency at Week 30 compared to placebo.
 
 
5. To determine the plasma PK profile of ATH-1017 and ATH-1001.
3.3 Sample Size Determination
A total sample size of 60 evaluable subjects (20 per treatment arm) is based on the results of 
the Phase 1 study, NDX-1017-0101, which demonstrated significant effects of ATH-1017 on 
ERP P300 in n=7 ATH-1017-treated AD subjects versus n=4 placebo-treated AD subjects,
with 8 days of daily SC injection.
3.4 Blinding and Unblinding
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 standard operating 
procedures (SOPs) at the applicable vendors will be followed for blind breaking procedures.
After database lock, the overall randomization code will be broken only for reporting purposes.


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4 Patient Chronology
Study days will be numbered from Day 1, the first day of IMP administration. The duration of 
events, such as the duration of treatment, will be taken as the end date minus the start date
(Day 1), plus 1.
5 General Conditions for the Final Analysis
5.1 Definitions
Safety endpoints representing the change from baseline at a particular visit will be defined as 
the result at the visit minus the last non-missing result prior to the first dose of study 
medication. Should a baseline value be missing, then the corresponding screening value, if 
available, may be used.
Efficacy endpoints representing the change from baseline at a particular visit will be defined 
as the result at the visit minus the baseline value. Baseline for the primary analysis is defined 
as the average of all non-missing ERP P300 values measured prior to the first dose. Unless 
otherwise specified, similar definitions for baseline will be used for other efficacy analyses. 
Change from baseline will be missing for data collected prior to the first dose of study 
medication. Patients with a missing score for either baseline or the applicable visit will have a 
missing value for the change from baseline at that visit.
Whether an improvement is represented by a positive or negative change from baseline will 
depend on the endpoint.
5.2 General Considerations for the Final Analysis
All analyses will be carried out in SAS version 9.3 and R version 3.4 or higher.
Visits will be designated as Visit 1 (Screening), Visit 2a (Pre-baseline), Visit 2b 
(Baseline/Week 1 (Day 1)), Visit 3 (Week 2), Visit 4 (Week 6), Visit 5 (Week 12), visit 6 
(Week 16), Visit 7 (Week 20), Visit 8/ET (Week 26), and Visit 9 (Safety Follow-up; Week 30) 
as defined in Table 1.
For all efficacy analyses, unless otherwise specified, active treatment refers to pooled treatment 
arms (40mg arm and 70mg arm). After this pooled comparison, the 70 mg versus placebo 
comparison (first) and the 40 mg versus placebo comparison (second) will be performed. A
one-sided alpha of 0.05 will be used for all comparisons.
Regarding ERP P300 endpoint, 18 electrodes in the 10-20 system are collected for this 
endpoint, but not all of them will be used in the analysis. Because the design of the auditory 
task requires reference and ground electrodes to be in the front and back of the head, 
respectively, the average of the central electrodes available, CZ, FC1, FC2, CP1, and CP2, 
known as the region of interest (ROI) offers the best signal to noise ratio for identifying a 
potential ERP P300 effect and will be used for this endpoint analysis.
Summaries will be shown with columns for each treatment group as well as a column for all 
patients in the study and applicable population. The number of subjects in the treatment group 
and population will be shown in the column header. Continuous data will be summarized with 
the number of non-missing values and their mean, standard deviation, median, minimum and 


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maximum. Categorical data will be summarized as the count and percentage of distinct patients 
with each value. Unless noted otherwise and for a given analysis population, the denominator 
will be the number of subjects with non-missing assessments in this analysis population who 
belong to the treatment group. Summaries by visit will include both unscheduled and regularly 
scheduled visits.
All data collected in the clinical database will be listed. Listings will include all subjects with 
analysis population flags included to designate which population each subject is included with.
Listings will generally be sorted by subject ID, parameter and visit date/study day.
Unscheduled visits will be included in the listings.
If it happens that no patients qualify for a display, the display will be produced with a note that 
“No patients qualify for the display.” For example, if there are no deaths then the applicable 
displays will be so noted.
For safety summaries, the last pre-dose measurement is defined as the baseline value. For 
MMSE, the mean of the pre-dose measurements (obtained at Screening and Pre-baseline) will 
be used as the baseline value . ADCS-CGIC is a change score, so no further calculation is 
required.  For all other efficacy masures, baseline is the average of all measurements prior to 
first dosing, or if only one measurement exists that value will be used.
Visit windowing will be applied for 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.
Assessments will be considered on-treatment after first dose of study drug and up to the last 
day of dosing +35 days for all safety assessments. For ERP and efficacy assessments, on 
treatment will include all assessments after the first dose of study drug and up to the last day 
of dosing +3 days.
If partial dates are recorded for safety outcomes, then partially missing start/beginning date 
(e.g. AE/Concomitant medication start date) will fill in the missing month with January and 
missing day with 1. For example, if month and day were both missing, then the date would be 
filled in with January 1st. Partially missing end/finishing date (e.g. AE/Concomitant 
medication end date) will be filled in with December and missing day with the last day of the 
month. For example, if month and day were both missing, then the date would be filled in with 
December 31st. For other outcomes (e.g. date of vital signs collection), if only the day is 
missing it will be imputed as the 15th.  When both month and day are missing, the missing 
month and day will be July 1st. For safety outcomes, (e.g. AE/Concomitant medication start 
date) if the start date is entirely missing, it will be filled in with study start date as a conservative 
approach.


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Days will be converted to weeks by dividing by seven. Days will be converted to months by 
dividing by 30.417. Days will be converted to years by dividing by 365.25. All data collected 
during the study will be analyzed and reported unless stated otherwise.
5.3 Visit Windowing
Analysis Windows for ADAS-Cog11 and COWAT
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 64-112
Week 20
Day 140
Day 113-161
Week 26
Day 182
Day 162-196
Week 30
Day 210
Day 197-217
Analysis Windows for EEG (ERP P300 and 
), CSSRS, Physical and Neurological 
Exams, EG, Vital Signs, Labs
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 197-217
Analysis Windows for GDS, Height, Weight
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 197-217
Analysis Windows for ADCS-CGIC, ADCS-ADL23, 
, PK
Analysis Visit
Protocol-Specified Day
Analysis-Specified Interval
Week 12
Day 84
Day 2-133
D


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Week 26
Day 182
Day 134-217
Analysis Windows for MMSE
Analysis Visit
Protocol-Specified Day
Analysis-Specified Interval
Week 20
Day 140
Day 2-161
Week 26
Day 182
Day 162-217
5.4 Procedures for Handling Missing Data
Patients who drop out will have all available post-baseline data included in the analysis,
unless otherwise specified. The mixed model is based on an assumption of Missing
at Random (MAR) and is designed to handle right censored data for subjects who
drop out of the study.
5.5 Interim Analysis
No interim analysis of the data is planned.
5.6 Changes to Statistical Analysis
The statistical analysis plan clarifies that comparison between treatment and placebo will be 
performed first by evaluating differences between pooled active treatment (40 mg and 70 mg 
ATH-1017 arms combined) followed by comparisons of individual treatment groups (40 mg 
ATH-1017 versus placebo and 70 mg ATH-1017 versus placebo).
The primary esstimand and analysis were amended to reflect use of a treatment treatment contrast 
that averages the difference between treatments in mean CFB across Weeks 12, 16, 20, and 26,
whereas the original, protocol-specified approach was the difference at Week 26.
5.7 Analysis Populations/Sets
5.7.1 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 at 
least one ERP P300 baseline assessment and one post-baseline ERP P300. Subjects 
will be analyzed according to the dose they were randomized to.


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5.7.2 Per Protocol Population
The per protocol population will include all mITT subjects who took the assigned 
medication during the 26 weeks of treatment, completed at least one ERP P300 plus
ADAS-Cog11 or COWAT post-baseline assessment, and did not have any major 
protocol deviations. Subjects will be analyzed based on actual treatment received.
5.7.3 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.
5.8 Primary Estimand
The primary estimand for this study is the mean difference between drug and placebo based 
on post-baseline changes in ERP P300 latency using a hypothetical strategy to assess the 
results expected if all patients had completed the treatment period. 
The rationale for this as the primary estimand is based on the aim of this study to evaluate a 
measure suggestive of treatment benefit in support of establishing proof of concept. 
Specific details of this estimand are:
Treatment regimen: ATH-1017 40 mg/day and ATH-1017 70 mg/day pooled compared 
versus placebo.
Population: Patients in the mITT analysis set (see Section 5.7.1) with mild to moderate AD 
as specifically definded by the protocol inclusion / exclusion criteria.
Variable: ERP P300 latency as defined in Section 7.1.
Population summary measure: The LS mean difference in CFB between pooled ATH-1017
treatment arms and placebo averaged across Weeks 12, 16, 20, and 26 (see Section 8.1).
Handling of intercurrent events. The intercurrent events (ICEs) of missed or modified 
doses, drug discontinuation and concurrent treatment will be handled using a treatment 
policy strategy which ignores these ICEs. Deaths are not expected during the 26-week 
double-blind phase follow-up in the enrolled subject population. A hypothetical strategy 
will be used to handle the ICE of early study discontinuation in order to estimate the effect 
anticipated if all patients had completed treatment.
5.9 Data Review
Classification of deviations from the protocol as minor or major, and decisions regarding 
patient population assignments will be decided on a case-by-case basis without knowledge 
of the treatment assigned and before the database lock in a blinded data review meeting.


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After database lock, the responsible statistician will request the treatment codes, the study 
will be unblinded, and the statistical analysis will be conducted.
5.10 Missing Data
Patients that lack information at a visit due to early termination, etc. will not be imputed 
for the primary analysis. In each of the following listings, patients missing the applicable 
data will have the following entry listed for that data point “No Data”: Analysis Population 
Exclusions (Listing 16.1.4), General Comments (Listing 16.1.7), Serious AEs (Listing 
16.3.1.2), AEs Leading to Discontinuation or Death (Listing 16.3.2), and Clinically 
Significant Laboratory Abnormalities (Listing 16.3.4). 
In the event that an ADAS-Cog11 total score is partially collected, but missing some 
individual items, a last z-score carried forward (LZCF) or straight line imputation will be 
performed at the item level to fill in missing values prior to calculating total scores. 


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6 Study Conduct 
6.1 Treatment Assignments
Upon locking the database the study will be unblinded. The treatment assignment will be 
given to each patient and 100% verified.
6.2 Enrollment, Demographics, and Baseline Characteristics
A summary table that includes all patients will be provided to show the study timelines: 
the earliest and latest date of screening visit, of study drug intake, and study participation 
as well as the duration in days of screening, treatment and study participation.
A summary table will be provided for the Safety Population to summarize demographics, 
i.e. age, sex, race, height and weight at baseline. The table will be repeated for the mITT 
and PP Populations. The equality between treatment groups for each of these parameters 
will be tested with a t-test or Fisher’s exact test, as appropriate.
The supportive listings will present all data on the Informed Consent / Demographics CRF 
page. The listings of disposition, IMP dispensing and return, and vital signs also partly 
support these tables. 
6.3 Patient Disposition and Protocol Deviations
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. Listings will be provided for the different 
reasons for screen failure, discontinuation, and exclusion from the analysis populations. 
Reasons for discontinuation will be presented as displayed in the eCRF.
A summary table will be provided for all randomized patients to include those with one or 
more major protocol deviations. Major deviations as reported on corresponding eCRF will 
be classifed by category and summarized; within each classification the count and percent 
of each category that appears on the CRF will be displayed. 
Supportive listings will present all information on the Study Completion / Early 
Termination eCRF page and the Protocol Deviations page. Another supportive listing will 
display patients excluded from any analysis population along with the reason(s) for 
exclusion.
6.4 Extent of Exposure to Study Drug
A summary table will be provided for the Safety Population stratified by treatment group 
to summarize the duration of treatment, total dose received, average dose per week and 
compliance. The count and percentage of subjects with compliance below 80% and above 
110% will be provided as an assessment of under/overdosing. 
The supportive listing will present all data on the Drug Accountability CRF page. 
6.5 Medical History / Concomitant Medication
Concomitant medications will be coded according to WHODDrug (WHO Drug 
dictionary). Medical history findings will be coded with the Medical Dictionary for 
Regulatory Affairs (MedDRA). The version number will be shown as a footnote in the 


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displays. A listing will be provided of these data and will include all patients in the study. 
A summary table will be provided to show the count and percentage of patients with any 
medical history by system organ class and preferred term. Patients will be counted at most 
once per term.
6.6 General Comments
A listing will be provided of all general comments recorded on the corresponding CRF 
page.


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7 Efficacy Endpoints
7.1 Primary Variable
The primary variable is change from baseline in ERP P300 latency. Each post-baseline 
assessment of ERP P300 latency  will be calculated as the average across the pre-dose and 
post-dose values at each respective visit. The primary estimand and analysis are based on 
combining results across Weeks 12, 16, 20, and 26 via a contrast statement that in essence 
averages the LS mean treatment group differences across these assessment times (see Section 
8.1).
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 component (latency and amplitude), the subject 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.
7.2 Secondary Efficacy Endpoints
7.2.1 Global Statistical Tests
Global statistical tests (GST) facilitate assessment of a overall change in disease 
status/trajectory into a single measure by standardizing and then combining individual 
clinical and/or functional measures. Several combinations of clinical measures will be used 
to create multiple GSTs. Each GST is a specific combination of outcomes that are measured 
at then standardized at each visit. Standardization is based on using the mean score from 
baseline (across all arms) as the mean value and standard deviation is calculated on all 
residual values (across all arms) per visit, where the residuals are calculated as the distance 
between inidivual outcomes and the mean outcome within that treatment arm.  The GST 
will be determined for each subject by calculating the z-score on the individual level for 
each of the component endpoints and taking the mean z-score across GST component 
measures for each individual at each time point. This individual patient mean z-scores will 
be the efficacy outcome variable used in the analyses.
GST scores will be computed using the following combinations (See definitions of GST 
components below):


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Protocol-specified GST
ADAS-Cog11 and COWAT
ADAS-Cog11 and ADCS-CGIC
Additional exploratory GSTs
ADCS-ADL23 and COWAT
ADAS-Cog11 and ADCS-ADL23
ADAS-Cog11 and ERP P300 (no correlation analysis)
ADAS-Cog11, ERP P300, and ADCS-CGIC (no correlation analysis)
For ex-US purposes, the activities of daily living endpoint, comparison of active to placebo for 
the first GST may include the ADCS-ADL23 instead of ADCS-CGIC.
7.2.2 Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog11)
The ADAS-Cog11 is designed to measure cognitive symptom change in subjects with AD
(Rosen, 1984). The standard 11 items are 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 test includes 7 performance items and 4 clinician-rated 
items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). 
Therefore, higher scores indicate more severe cognitive impairment.
Due to known circadian fluctuations of cognitive capacity (Hilt, 2015), ADAS-Cog11 will 
be assessed in the morning at approximately the same time of day as the baseline 
assessment for all applicable visits.
ADAS-Cog11 assessments will be performed pre-dose at Visit 2 (Baseline/Day 1), and post-
dose at approximately 1 hour (± 30 minutes) at Visit 3 (Week 2), Visit 4 (Week 6), Visit 5 
(Week 12), Visit 7 (Week 20), Visit 8/ET (Week 26), and Visit 9 (Safety follow-up; no 
dosing).
7.2.3 Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change
(ADCS-CGIC)
The Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change 
(ADCS-CGIC) scale is a 7-point scale that requires the clinician to assess how much the 
subject’s illness has improved or worsened relative to a baseline state at the beginning of 
the intervention and rated as: 1, markedly improved; 2, moderately improved; 3, minimally 
improved; 4, no change; 5, minimally worse; 6, moderately worse; or 7, markedly worse. 
The ADCS-CGIC consists of 3 parts: a guided baseline interview administered to the 
subject and caregiver/support person, a follow-up interview administered to the subject and 


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caregiver/ support person, and a clinician’s rating review (Schneider, 1997). At study start, 
using the ADCS-CGIC baseline form as a guideline, the ADCS-CGIC rater will obtain an 
integral clinical impression of the subject’s status, can apply any formal testing at his/her 
discretion, and take personal notes regarding the subject’s condition; these will serve as a 
reference for future change ratings. The ADCS-CGIC will be administered by an 
experienced clinician who will remain independent of the subject’s safety, cognitive and 
functional outcomes, and will be trained and certified for this study. The ADCS-CGIC rater 
will ideally remain the same individual for all ADCS-CGIC ratings.
ADCS-CGIC assessments will be performed adjacent to ADAS-Cog11 and COWAT 
assessments pre-dose at Visit 2 (Baseline/Day 1), post-dose at Visit 5 (Week 12), and post-
dose at Visit 8/ET (Week 26).
7.2.4 Controlled Oral Word Association Test (COWAT)
The Controlled Oral Word Association Test (COWAT) is an oral verbal fluency test in 
which the subject is required to make verbal associations to different letters of the 
alphabet by saying all the words which they can think of beginning with a given letter. 
Individuals are given 1 minute to name as many words as possible beginning with each of 
the letters. The procedure is then repeated for the remaining two letters (Benton, 1994; 
Strauss, 2006). The test score is the total number of different words produced for all 3 
letters.
The COWAT will be performed adjacent to the ADAS-Cog11 assessment, i.e., pre-dose at 
Visit 2 (Baseline/Day 1), and post-dose at approximately 1 hour (± 30 minutes) at Visit 3 
(Week 2), Visit 4 (Week 6), Visit 5 (Week 12), Visit 7 (Week 20), Visit 8/ET (Week 26), 
and Visit 9 (Safety follow-up; no dosing).
7.2.5 Alzheimer’s Disease Cooperative Study – Activities of Daily Living, 23-item Version
(ADCS-ADL23)
The ADCS-ADL23 (Galasko, 1997) is a 23-item assessment of functional 
impairment in terms of activities of daily living administered to the support 
person/caregiver. It comprises 23 questions about the subject’s involvement and 
level of performance across items representing daily living. The questions range 
from basic to instrumental activities of daily living. Each item is rated from the 
highest level of independent performance to complete loss. The total score range is 
from 0 to 78, with lower scores indicating greater functional impairment. ADCS-
ADL23 assessments will be performed pre-dose at Visit 2 (Baseline/Day 1), post-
dose at Visit 5 (Week 12), and post-dose at Visit 8/ET (Week 26).


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7.2.10 Pharmacokinetic Variables
Blood will be collected for analysis of ATH-1017 and ATH-1001 in plasma at the 
timepoints detailed in Table 1. The actual time of blood sampling will be recorded.
Blood sample collection, processing, and shipping details will be outlined in a separate
laboratory manual. In brief, blood will be processed and plasma analyzed by a validated 
method for concentrations of ATH-1017 and ATH-1001. Concentrations of ATH-1017 and 
ATH-1001 will be listed by treatment, subject, day, and time of sample. Plasma 
concentration summary statistics will be presented.


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8 Statistical Analyses
Efficacy analyses will be performed in the mITT and PP populations, based on pooling of 
active doses and with  by individual dose.
8.1 Primary Analysis
The primary analysis will use a likelihood-based mixed model for repeated measures 
(MMRM) to compare the estimated changes across post-baseline visits (CFB) between 
pooled active treatment and placebo in ERP P300 latency. These analyses will assess the 
magnitude and statistical significance of mean CFB between placebo and the pooled active
treatment groups. All post baseline visits will be included in the model. Because the 
difference between treatments in ERP P300 latency is not expected to vary significantly 
over time, the primary analysis will be based on the contrast between LS means averaged 
across Weeks 12, 16, 20, and 26.
Baseline for the primary analysis is defined as the average of all non-missing ERP P300 
values measured prior to the first dose.
An ERP risk score will be calculated and used as a covariate in the model, combining 
known contributors to AD severity. The ERP risk score will be calculated on a per-person 
basis and is equal to the predicted value from OLS regression of the average of all post-
baseline ERP P300 latenecy measurements as the dependent variable. The following 
covariates are used as explanatory variables:  age, sex, screening (stratifying) MMSE score, 
AChEI treatment status, APOE4 genotype (E4/E4 versus non-E4/E4), baseline 
ADAS-Cog11 total score, baseline ADCS-ADL23 total score, baseline NPI total score, and 
baseline COWAT total score.
The MMRM analysis of the primary outcome will have CFB in ERP P300 latency as the 
response variable and will include the following covariates and fixed effects:
x
Baseline Test Score (covariate)
x
ERP Risk Score (covariate)
x
Time (aka visit, categorical)
x
Site (random effect)
x
Subject (random effect)
x
Baseline Test Score by time interaction
Visitwise LS means, the main effect LS mean, and contrasts between LS means are
interpreted as the expected mean difference between treatment groups (pooled/separate 
active doses versus placebo) in CFB. In addition to treatment group differences, output 
will include p-values, 95% confidence intervals for the difference, effect size, 95% 
confidence interval for the effect size, and an effect size based upon Cohen’s D.
Effect size will be calculated by taking the difference between LS means and dividing by 
the standard deviation (i.e. the standard error of the estimated difference multiplied by the 
squared degrees of freedom).  The equations below show how effect size and Cohen’s D 


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effect size will be calculated. In the following formulas p stands for placebo and t stands 
for treatment, and SE for standard error:
ܧ݂݂݁ܿݐܵ݅ݖ݁= ܮܵܯܧܣܰ௉െܮܵܯܧܣܰ௧
ܮܵܯܧܣܰ௉
For assessments where a higher score indicates worse performance (i.e. ADAS-Cog11)
Cohen’s d will be calculated using the following equation:
ܥ݋݄݁݊ᇱݏ ܦ= ܮܵܯܧܣܰ௉െܮܵܯܧܣܰ௧
(݌݋݋݈݁݀ܵܦ)
and for assessments where a higher score indicates better performance (i.e. COWAT)
Cohen’s d will be calculated using the following equation:
ܥ݋݄݁݊ᇱݏ ܦ=
௅ௌொ஺ே೟ି௅ௌொ஺ேು
(௣௢௢௟௘ௗௌ஽)
where the pooled standard deviation (pooled SD) is 
defined as follows:
ܲ݋݋݈݁݀ܵܦ= ඩ(݊௧െ1) ቀܵܧ௧ඥ௡೟ቁ
ଶ
+ ൫݊௣െ1൯ቀܵܧ௣ඥ௡೛ቁ
ଶ
൫݊௧+ ݊௣െ1൯
.
The number of subjects with an observed efficacy outcome, mean, standard deviation, 
median, 25th percentile (Q1), 75th percentile (Q3), minimum and maximum will all be 
reported and accompany the estimates from the MMRM outlined in this section. A
compound symmetry (CS) covariance structure will be used for this analysis.
8.2 Key Secondary Analysis
The correlation (association) between CFB in ERP P300 with the GST that includes 
ADAS-Cog11 and ADCS-COWAT will be established using an MMRM analysis. In these 
analyses CFB in GST will be the response variable of interest and CFB to each post-
baseline visit in ERP P300 latency will be the primary independent (explanatory) variables
of interest, with other covariates fit to isolate the association between ERP P300 latency 
and GST. Treatment will not be fit in the model. A clinical risk score will be created using 
the same method described for the primary analysis in section 8.1, but using the average of 
all post-baseline ADAS-Cog11 measurements as the dependent variable instead of ERP 
P300 Latency. 
The covariates for the MMRM analysis will include:
x
Baseline value ERP P300 (covariate)
x
Clinical Risk Score (covariate)
x
Time (aka visit, categorical)
x
Site (random effect)
x
Subject (random effect)
x
Baseline value ERP P300 by time interaction   


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The covariance structure for the repeated measures in this model will be
unstructured (UN). If UN does not converge for the model, the MMRM model will
be simplified to allow convergence as described in the following paragraph.
Variance components will be used as the covariance structure for the random site
effect in the model.
If the MMRM does not converge, using the model described above, the analysis will be
rerun
using a first-order heterogeneous autoregressive (ARH[1]) covariance
structure, and then a compound symmetric (CS) structure. If convergence is still
not achieved then the model will be simplified to exclude the baseline by time
interaction and rerun first with the UN and then with ARH[1], followed by CS. If
convergence is still not achieved, the following terms will be excluded from the
model: age, first with the UN and then ARH[1], followed by CS. If convergence is 
still not achieved, then these models will have all covariates removed except
center/site and visitwise CFBs in ERP P300 latency.
A partial Pearson correlation that controls for treatment will also be calculated by 
including data from all treatment arms but will account for variance due to 
treatment (e.g., using the partial statement in SAS PROC CORR).
8.3 Other Secondary Analyses
8.3.1 Global statistical tests
Each of the GSTs defined in Section 7.2.1 will be analyzed as follows: 
The MMRM analysis will include the respective CFB to each post-baseline visit in GSTs as the 
repeatedly measured response variable, with treatment as an explanatory variable along with 
other covariates, fixed, and random effects, including:
•
Baseline Test Scores of the Efficacy Parameter (covariate)
•
AD Risk Score (covariate)
•
Time (aka visit, categorical)
•
Site (random effect)
•
Subject (random effect)
•
Time by Baseline Test Score
The same covariance structure process will be used as described for the primary analysis.
A Clinical risk score will be created using the same method described for the secondary 
analysis in section 8.2. For GSTs that involve the CGIC, which is inherently a measure of 
change and hence no baseline value exists, the baseline value to be used as a covariate in that 
analysis will be the baseline values of the other component(s) of that GST.  When more than 
one component of a GST exists besides the CGIC, the baseline covariate will be a combined 


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statistical test of those components defined as the mean of baseline z-scores for those 
components, where each z-score is defined based on the mean and standard deviation for that 
outcome at baseline irrespective of treatment group.
8.3.2 Individual clinical, functional, health economic, and biomarker assessments
The ADCS-ADL23, ADAS- Cog11, ADCS-CGIC, 
, COWAT, 
 will be 
analyzed using the MMRM analysis as described for the primary analysis, with the exception that 
for the ADCS-CGIC, which is inherently a measure of change, the baseline ADAS-Cog11 score
will be used as the baseline covariate. These analyses will use the clinical risk score in place of 
the ERP risk score as a covariate. Output from these analyses will focus on visitwise contrast at 
Week 26 (the primary ERP P300 latency analysis was based on a contrast combining results 
across post-baseline visits).
An additional analysis will be performed on the change in ERP P300 latency from pre-dose to 
within-visit post-dose measurements averaged across all post-dose measurements within post-
baseline analysis windows to estimate the acute effect estimate. In addition, change in ERP P300 
latency from pre-dose baseline to pre-dose measurements averaged across all pre-dose 
measurements within post-baseline analysis windows across visits will be analyzed to estimate 
the sustained effect.
8.3.3 Subgroup analyses
The following subgroups will be assessed for ERP P300 latency:
x
AChEI (subjects taking anti-cholinesterase inhibitors / not taking anti-
cholinesterase inhibitors);
x
MMSE stratification variable (mild/moderate).
x
APoE status (carrier/non-carrier)


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Subgroup analyses will be implemented by using the MMRM model as described 
for the primary analysis with the addition of the treatment-by-subgroup and 
treatment-by-visit-by subgroup interaction terms. 
8.3.4 Additional Analyses
The persistence of the treatment effect on ERP P300 latency will be evaluated by repeating 
the primary analysis with the addition of the Week 30 (off treatment) data.  
Simple correlations will also be evaluated between visitwise post-dose ERP P300 latency 
and the following outcomes: ADAS-Cog11, ADCS-ADL23, COWAT, GST, and ADCS-
CGIC. These correlation will be assessed using partial Pearson correlations that control for 
treatment. That is, the analyses will include data from all treatment arms but will account for 
variance due to treatment (e.g., using the partial statement in SAS PROC CORR).
8.3.5 PK Analyses
PK will be analyzed using the mITT population. Descriptive statistics will be provided for the 
each treatment group.  Additionally, correlations of exposure values to clinical outcomes may be 
assessed, if possible, by correlation to concentration data as well as summarization of outcomes 
data in the upper and lower PK tertiles.
The PK concentration data collected prior to each dose will be used in a concentration-response 
relationship analysis to assess correlation with each outcome which will mirror the primary 
analysis but replace the treatment variable with PK concentration. Analysis will be performed 
separately for each PK collection time as well as using the highest of the PK timepoints.


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9 Safety
9.1 Safety Endpoints
Primary endpoint
x
incidence of treatment-emergent adverse events
Additional endpoints
x
Incidence and severity of treatment-emergent adverse events (AEs)
x
Clinical laboratory tests 
x
Vital signs 
x
Physical/neurological examinations
x
ECGs
x
Use of concomitant medications for treatment of AEs
x
C-SSRS
x
GDS
9.2 Analysis Populations Evaluated for Safety
All analyses of safety will be performed on the Safety Population.
9.3 Statistical Methods for Safety Endpoints
A summary table will be provided for the Safety Population of the count and percentage of 
subjects with any safety endpoint. No hypothesis testing will be performed for safety variables.
Adverse Events
AEs reported on CRFs will be coded into system organ classes and preferred terms using
the Medical Dictionary for Regulatory Activities (MedDRA v23.1). A treatment-emergent 
adverse event (TEAE) is defined as an AE with an onset date on or after the start of dosing.
The adverse event summary will include only TEAEs. Any AEs that are not considered 
treatment-emergent will be provided in data listings only. 
The incidence of AEs will be summarized for the safety population. Although a preferred term 
or system organ class may be reported more than once for a subject, each subject will only be 
counted once in the incidence count for each category. If a subject has the same AE on multiple 
occasions, the highest severity (severe > moderate > mild) or drug relationship (definite > 
probable > possible > unlikely > not related) recorded for the event will be presented.
Severity levels include: mild, moderate and severe. Relationships will be grouped into two
categories for analysis: related and unrelated. Not related and unlikely will be categorized as 
“unrelated.” Possible, probable and definite will be categorized as “related.” If severity or drug 
relationship is missing no data imputation will be performed and no category of missing will 
be presented.


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Summary tables showing the number of subjects and percent within each category will be 
generated for each of the following types of adverse events:
x
All AEs;
x
Serious Adverse Events;
x
Fatal Adverse Events;
x
AEs by causality 
x
AEs by severity
x
AEs for Subjects who Died.
These summaries will present the number and percentage of subjects reporting an adverse 
event for each classification level. The denominators for calculating the percentages overall 
will be based on the number of subjects in the safety population. The denominators for 
calculating the percentages by treatment will be based on the number of subjects exposed to 
each treatment in the safety population. In addition to these summaries, all AEs will be 
summarized by action taken, seriousness, severity, and relationship to study drug.
All AEs that occurred in 5% or more of all subjects (active and placebo) will be tabulated for 
the safety population. These results will be analyzed descriptively and their incidence rate will 
be summarized.
All SAEs, AEs, AEs leading to premature discontinuation from the study, and AEs with fatal 
outcome will also be provided in data listings by subject, treatment group, verbatim term and 
preferred term.
9.2
Vital Signs 
Each vital sign will be summarized by treatment and by visit, using descriptive statistics (mean, 
median, SD, minimum, maximum, and number of subjects) for the safety population.
Additionally, descriptive summaries will be provided for CFB values for each treatment by 
visit for vital sign measurements collected during the study.
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 subject, treatment group, visit, and parameter.
9.3
Electrocardiogram
ECG values and change from baseline values will be summarized by visit using descriptive 
statistics for PR interval, QT interval, QTcB interval, QTcF interval, RR interval, mean heart 
rate, and QRS duration. ECG abnormalities will be summarized as the count and percentage 
of subjects in each treatment group. CFB will be summarized in a shift table crossing baseline 
and each visit result. The denominators for calculating the percentages will be the number of 


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subjects in each treatment group who have an evaluation for both the screening and each post-
baseline visit in the safety population. These results will be analyzed descriptively and their 
incidence rate and two-sided 95% confidence intervals will be summarized.
9.4
Clinical Laboratory Evaluations
Continuous blood clinical laboratory analytes absolute values and change from baseline values 
will be summarized by analyte and visit using descriptive statistics (mean, median, SD, 
minimum, maximum, and number of subjects). Mean line plots over time will be displayed for 
each analyte with separate lines for each treatment. Categorical laboratory analytes, classified 
as normal or abnormal, will be summarized by analyte and visit using the number and 
percentage of subjects in each category and in each 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.
Shifts to values outside of the normal range will be presented by analyte and will be 
summarized by the number and percentage of subjects with shifts. Shifts will be determined 
for analytes in which both the baseline value and the termination value are recorded. The 
denominators for calculating the percentages will be based on the number of subjects with non-
missing assessments for a particular analyte.
Clinical laboratory results will be provided in data listings by subject, visit and analyte. 
Abnormal lab results (either below LLN or above ULN) will be provided in a separate listing 
by subject, center, analyte, treatment group and visit.
9.5
Physical and Neurological Exams
Physical and neurological examination findings will be summarized as the count and 
percentage of subjects in each treatment group.
9.6
C-SSRS
The C-SSRS responses will be tabulated by visit, treatment group, question and response. All 
C-SSRS responses will also be provided in a data listing.
9.7
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 
D KLJKHU VFRUH LQGLFDWLQJ PRUH VHYHULW\ $ *'6 VFRUH RI   LV UHTXLUHG DW 6FUHHQLQJ ,Q
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.


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GDS assessments will be performed at Screening, Baseline/Day 1, Visit 5 (Week 12), Visit 
8/ET (Week 26), and Visit 9 (Safety follow-up). A listing will be provided, showing responses 
across all outcomes and timepoints.


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9
OTHER LISTINGS 
The following additional listings will be provided:
x
Subjects excluded from the safety, mITT, and PP populations;
x
Clinical laboratory results for hematology, blood chemistry and urinalysis; 
x
Abnormal laboratory results;
x
Physical examination assessments;
x
Neurological examination assessments;
x
Concomitant medications;
x
Dose administration dates and times.


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x
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