Conditions: Alzheimer Disease Dementia of Alzheimer Type
Keywords: Alzheimer's Disease Cognition Dementia ATH-1017 LIFT AD Fosgonimeton
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 554
Healthy volunteers: no

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

Detailed description:
The study is designed to evaluate safety and efficacy of ATH-1017 in mild to moderate AD subjects, with randomized, parallel-arm treatment duration of 26 weeks, and based on clinical diagnostic criteria of Alzheimer's disease. Clinical efficacy is demonstrated by improvement in cognition and global/functional assessments comparing treatment to placebo.

Arms:
arm 1: Daily subcutaneous (SC) injection of 40mg ATH-1017 arm 2: 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 document:
Prot_000.pdf: 
Athira Pharma, Inc.  
Protocol ATH-1017-AD-0201  
Clinical Study Protocol 
CONFIDENTIAL 
 
Version 8 
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Clinical Study Protocol 
A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017 Treatment 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-0201 
IND No.: 
135103 
Investigational Medicinal Product (IMP) 
Name: 
Fosgonimeton (ATH-1017) 
Development Phase: 
Phase 2/3 
Emergency Telephone Number: 
(Refer to the study contacts page) 
SAE Reporting FAX Number/Email: 
 
  
Date of Final Protocol: 
21-MAR-2024 
Version 
8 
 
 
This clinical study will be conducted in accordance with the International Council for 
Harmonisation Tripartite Guideline for Good Clinical Practice (GCP) (E6), the protocol and with 
other applicable regulatory requirements. 
 
 
Confidentiality Statement 
This document contains confidential information of Athira Pharma, Inc. 
Do not copy or distribute without written permission from the Sponsor. 
 
 


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Athira Pharma, Inc. 
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SIGNATURE PAGE - SPONSOR
Declaration of Sponsor or Responsible Medical Expert
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017
Treatment 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.
Sponsor Signatory
 
Date (DD MMM YYYY)


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SIGNATURE PAGE - INVESTIGATOR 
Declaration of the Principal Investigator 
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017 
Treatment in Subjects with 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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PROTOCOL SYNOPSIS 
Protocol Title: 
A Randomized, Placebo-Controlled, Double-Blind Study of ATH-1017 Treatment in 
Subjects with Mild to Moderate Alzheimer’s Disease 
Study Number: 
ATH-1017-AD-0201 
Development Phase: 
Phase 2/3 
Sponsor: 
Athira Pharma, Inc. 
Type of Study 
Interventional 
Study Centers: 
The study will be conducted at a total of approximately 70 centers in the US 
Study Objectives and 
Endpoints: 
 
Primary Efficacy Objectives 
Primary Efficacy Endpoint* 
To evaluate the clinical efficacy of 
ATH-1017 in subjects not on 
background acetylcholinesterase 
inhibitors (AChEIs) 
The Global Statistical Test (GST) score 
(O’Brien, 1984) is a composite of 
cognition and function, calculated as the 
average of two change from baseline 
z-scores; the z-scores are calculated for 
the change from baseline scores for 
cognition (Alzheimer’s Disease 
Assessment Scale-Cognitive Subscale 
[ADAS-Cog11]) and function 
(Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living, 
23-item version [ADCS-ADL23] score) 
at Week 26 
Key Secondary Efficacy Objectives 
Key Secondary Efficacy Endpoints* 
To evaluate the clinical efficacy of 
ATH-1017 in subjects not on 
background AChEIs separately on: 
(1) cognition and 
(2) activities of daily living 
• 
ADAS-Cog11 score: change from 
baseline at Week 26  
• 
ADCS-ADL23 score: change from 
baseline at Week 26  
To determine the effect of ATH-1017 
on plasma neurofilament light chain 
(NfL) levels in subjects not on 
background AChEIs (a biomarker of 
neurodegeneration with literature 
support for being a biomarker of 
Alzheimer’s disease [AD] 
progression) 
Change from baseline in NfL 
concentration at Week 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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change from 
baseline at Week 20 
Safety Objective 
Safety Endpoints 
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) 
* The comparison between ATH-1017 40 mg/once daily (qd) and placebo in 
subjects not on background AChEIs will serve as the primary efficacy comparison 
for the primary and key secondary endpoints.
 
 
 
 
Study Design: 
This is a Phase 2/3 multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study comparing ATH-1017 treatment with placebo in subjects with a 
clinical diagnosis of mild to moderate AD, diagnosed on a ‘probable’ level according 
to the National Institute on Aging – Alzheimer’s Association (NIA-AA; 
McKhann, 2011). The study will be conducted at a total of approximately 70 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. Prior to protocol version 7, subjects meeting all inclusion/exclusion criteria 
were randomized in a ratio of 1:1:1 to 3 parallel arms, either to treatment (ATH-1017 
40 mg/qd or ATH-1017 70 mg/qd or placebo. As of protocol version 7, randomization 
to ATH-1017 70 mg/qd was discontinued, and all subjects will be randomized in a 
ratio of 1:1 to 2 parallel arms, either to receive ATH-1017 40 mg/qd or placebo. 
Subjects randomized to ATH-1017 70 mg/qd prior to protocol version 7 will continue 
their regimen until either study completion or early termination.  
During randomization, subjects will be stratified by screening Mini-Mental State 
Examination (MMSE) severity: mild (MMSE: 20-24) versus moderate 
(MMSE: 14-19). All eligible subjects will be tested for apolipoprotein E (ApoE) 
genotype.  
Study drugs will be administered by subcutaneous (SC) injection qd preferably during 
daytime. Subjects should 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 


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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 
randomized 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 trial at Week 30 (see Table 1 for Schedule 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 of the 
protocol. As marked circadian fluctuations of cognitive performance have been 
observed in AD (Hilt, 2015), ADAS-Cog11, 
 assessments should 
occur at clinic visits in the morning at approximately the same time they were 
performed during the initial Baseline assessment. 
 
 
 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. Subjects enrolled at participating sites may seamlessly enroll onto the 
open-label extension (OLEX) study (ATH-1017-0203) following Visit 8, subject to 
meeting all eligibility criteria for that study. For subjects who do not enroll into the 
OLEX, the end of study is defined as either the Safety Follow-up (Visit 9/Week 30) or 
the date of an early termination (ET) visit for those subjects who terminate prior to 
Visit 8. Subjects who terminate prior to Visit 8 are to complete the same assessments 
as Visit 8 at the ET visit. 
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 blood-based biomarkers and for plasma concentrations of 
ATH-1017 and ATH-1001. 
An open-label extension will be offered to eligible subjects at participating sites. 
Treatments 
Administered:  
Subjects will be randomized to one of 2 treatment groups: 
• 
ATH-1017, 40 mg, qd, SC 
• 
Placebo, qd, SC 
Prior to version 7 of this protocol, subjects were also randomized to a 70 mg dose 
group. Randomization to the 70 mg dose group was discontinued, however, subjects 
already randomized to receive ATH-1017 70 mg/qd will continue the following 
regimen until completion or early termination of the study: 
• 
ATH-1017, 70 mg, qd, SC 
Investigational 
Medicinal Products: 
Treatment: ATH-1017 will be presented in prefilled 1 mL syringes of 40 mg/mL or 
70 mg/mL (prior to version 7) 
Placebo: Placebo prefilled 1 mL syringes to match treatment 


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Number of Subjects: 
The study was originally designed to enroll approximately 300 subjects in a 1:1:1 ratio 
to ATH-1017 40 mg/qd, ATH-1017 70 mg/qd, and placebo groups (Protocol versions 
1-3). In version 4, the sample size was increased to 420 subjects in order to increase 
statistical power. After the ATH-1017-AD-0202 ACT-AD readout, the protocol was 
amended (version 5) to: stop enrollment of subjects receiving AChEIs and perform an 
independent, unblinded interim analysis with a pre-specified sample size re-estimation 
(SSR) procedure following a test for futility, based on conditional power (CP) using 
the promising zone approach (Mehta and Pocock, 2011). Prior to version 5, 
approximately 200 subjects who were receiving AChEIs were already enrolled in the 
trial. 
The interim analysis was conducted on approximately 100 subjects not receiving 
AChEIs who had completed participation in the trial or terminated early, and the 
results indicated that a pre-specified sample size re-estimation of up to 275 subjects 
was well powered to meet the primary endpoint of the study. 
The primary purpose of version 6 of the protocol was to add ADAS-Cog11 at screening, 
elevated NfL to be a secondary endpoint, and this did not impact the number of 
subjects to be enrolled. 
In protocol version 7, randomization to the 70 mg dose group was discontinued. In 
order to provide 85% power with two-sided 0.05 testing, a sample size of 298 subjects 
will be randomized in a 1:1 ratio between the two treatment groups, ATH-1017 
40 mg/qd or placebo, for a total of approximately 149 subjects per treatment group 
who are not receiving AChEIs. Approximately 60 subjects not on background AChEIs 
have already been randomized to ATH-1017 70 mg/qd; these subjects will complete 
the study as planned. Therefore, the maximum total enrollment for this study will be 
approximately 558 subjects as outlined in the table below. 
Number of Subjects Planned for Enrollment 
Number of Subjects 
Receiving AChEIs 
Not Receiving AChEIs 
Total 
Plc 
ATH-1017 
40 mg/qd 
ATH-1017 
70 mg/qd 
Plc 
ATH-1017 
40 mg/qd 
ATH-1017 
70 mg/qd 
~200 
~149 
~149 
~60a 
~558 
AChEI = acetylcholinesterase inhibitor; Plc = placebo; qd = once daily. 
a 
Approximate number of subjects who were randomized to ATH-1017 70 mg/qd 
prior to version 7. 
Duration of 
Treatment: 
The study will consist of up to 28 days of screening (Day -28 through Day -1) followed 
by 26 weeks of randomized 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. 


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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. 
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 (subjects not receiving AChEI treatment), defined as: 
a) 
Treatment-naïve, OR 
b) 
Subjects who received an AChEI in the past and discontinued at least 
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 


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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. 
Subject has atypical variant presentation of AD, if known from medical history, 
particularly non-amnestic AD. 
3. 
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. 
4. 
Diagnosis with current symptoms of severe major depressive disorder even 
without psychotic features. Any subject with formalized delusions or 
hallucinations should be excluded. 
5. 
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.  


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6. 
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). 
7. 
History within 2 years of Screening, or current diagnosis of psychosis (American 
Psychiatric Association [APA], 2000) or moderate substance abuse disorder 
(according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition) (APA, 2013). 
8. 
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. 
9. 
Abnormal serum electrolytes (potassium, sodium, magnesium) of clinical 
significance. If treated, must be stably treated for at least 30 days before 
Screening. 
10. Active, acute, or chronic infectious disease of any type. 
11. Myocardial infarction or unstable angina within the last 6 months or history of 
more than one myocardial infarction within 5 years before Screening. 
12. Clinically significant (in the judgment of the investigator) cardiac arrhythmia 
(including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: 
pacemaker is acceptable). 
13. Subject has either hypertension (supine diastolic blood pressure > 95 mmHg), or 
symptomatic hypotension in the judgment of the investigator. 
14. 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. 
15. 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); subjects with a history of positive results for cured 
hepatitis B or hepatitis C may be eligible following discussion with the Medical 
Monitor and prior approval is required. 
16. Chronic kidney disease with estimated glomerular filtration rate (eGFR) 
< 45 mL/min using the Cockcroft and Gault formula with age, sex, and weight 
considered; subjects with moderate to severe impairment (eGFR between 44 and 
30 mL/min inclusive) may be eligible following discussion with the Medical 
Monitor and prior approval is required. 


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17. Hepatic impairment with alanine aminotransferase or aspartate aminotransferase 
> 2 times the upper limit of normal, or Child-Pugh class B and C. 
18. 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; 
c) Fully-excised (biopsy-proven) melanoma in situ; prior Medical Monitor 
approval is required. 
19. Clinically significant (in the judgment of the investigator) unintentional weight 
loss within 12 months of Screening. 
20. 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. 
21. Food supplements and nutraceuticals with potential effects on cognition, such as 
Axona and medium-chain triglyceride, are prohibited beginning 7 days prior to 
the first dose of study medication (Day 1) and for the duration of the study. 
22. 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.  
23. Prohibited prior and concomitant medications are excluded within 4 weeks prior 
to Screening. All allowed medications should remain stable throughout the study 
for medications negatively 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) 
Acetylcholinesterase inhibitors in any dosage form 
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) 


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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, ophthalmologics, 
skin creams, and intra-articular injections are allowed) 
k) 
Antiepileptic medication if taken for control of seizures. Other uses, e.g., 
neuropathy and restless legs, are allowed 
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 
24. 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. 
25. 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. 
26. Subject has known allergy to any component of the investigational medicinal 
product. 
27. The subject has a condition or is in a situation which, in the investigator’s 
opinion, may put the subject at significant risk, may confound the study results, or 
may interfere significantly with the subject’s compliance or participation in the 
study. 
Statistical Methods: 
General Statistical Methods and Types of Analysis:  
The intent-to-treat (ITT) Population will consist of all randomized subjects regardless 
of whether or not the subject received study medication. The modified ITT (mITT) 
Population is a subset of the ITT Population and will consist of all randomized subjects 
who took at least one dose of the study medication and who, during at least one 
post-baseline visit, completed both an ADAS-Cog11 and ADCS-ADL23 assessment, as 
well as at baseline. Statistical tests will use a hierarchical gatekeeping procedure to 
account for multiplicity, with two-sided tests at 0.05 (Dmitrienko, 2013). 
The primary analysis population is comprised of all members of the mITT, who were 
not taking AChEIs during the trial and were randomized to either ATH-1017 40 mg/qd 
or placebo. 
The primary efficacy endpoint is the GST score (a composite of cognition and 
function, calculated as the average of two change from baseline z-scores; the z-scores 


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are calculated for the change from baseline scores for cognition [ADAS-Cog11] and 
function [ADCS-ADL23]) compared to the placebo group at Week 26.  
The primary analysis will use a mixed model for repeated measures (MMRM) with 
GST score as the outcome variable, and terms for baseline value, visit, treatment, visit 
by treatment interaction, ApoE4 carrier status, pooled site as a factor (with 
geographically similar sites grouped and a group of sites using Spanish for clinical 
assessments), baseline age (continuous), and the baseline MMSE stratification factor. 
Least squares means and treatment differences will be estimated from the MMRM 
model. Statistical testing to the key secondary efficacy endpoints continues only if the 
null hypothesis for the primary efficacy endpoint is rejected. 
If the null hypothesis for GST score is rejected, then the key secondary endpoints of 
change from baseline in ADAS-Cog11 and ADCS-ADL23 scores will be analyzed 
using an MMRM as described for the primary analysis. If both of these null hypotheses 
are also rejected, then the key secondary efficacy endpoint of change from baseline in 
NfL concentration will also be analyzed using an MMRM as described for the primary 
analysis. 
Safety analyses will be based on the Safety Population consisting of all randomized 
subjects who received at least one dose of any study medication. All safety parameters 
will be summarized descriptively. 
Sample Size Considerations: 
The sample size for the trial was chosen to provide 85% power for the primary 
endpoint. The following treatment effect premises were made to support sample size 
calculations: 
• 
Change from Baseline to Week 26 in ADAS-Cog11: Mean treatment 
difference (standard deviation): 1.8 (6). 
• 
Change from Baseline to Week 26 in ADCS-ADL23: Mean treatment 
difference (standard deviation): 2.7 (9). 
The sample size of 149 evaluable subjects (subjects in the primary analysis population, 
comprised of mITT subjects randomized to either 40 mg/qd or placebo, and not on 
background AChEIs) per trial arm would yield at least 85% power with a two-sided 
0.05 level. A positive outcome will be achieved in the trial if a significant treatment 
effect based on the primary endpoint is established and power calculations were based 
on successfully meeting the GST score endpoint. 
In view of the overall number of subjects already enrolled prior to version 7 of this 
protocol, including those receiving background AChEI therapy (200 subjects), and 
those already randomized to the 70 mg treatment group not receiving AChEI therapy 
(60 subjects), the maximum number of subjects to be enrolled would be 
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ADCS-ADL23 = Alzheimer’s Disease Cooperative Study-Activities of Daily Living, 23-item version; 
ADAS-Cog11 = Alzheimer’s Disease Assessment Scale-Cognitive Subscale; 
 
AE = adverse event; CDR = Clinical Dementia Rating Scale; 
 C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; 
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 2), 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 2 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. 
i. 
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 ECG assessments will be performed in triplicate sequentially. 
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. PK plasma samples will be collected at pre-dose and post-dose on 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 any time 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. 
n. 
Plasma samples will be collected for biomarker analysis. Prior to version 7 this was optional for subjects. 
o. 
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. 
p. 
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. 
q. 
At Baseline/Day 1 (Visit 2), MMSE should be done first before all other assessments pre-dose. ADAS-Cog11, 
 
 will be performed pre-dose; 
 
 
. For visits after the baseline (except for safety follow-up when 




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TABLE OF CONTENTS 
SIGNATURE PAGE - SPONSOR .............................................................................................. 3 
SIGNATURE PAGE - INVESTIGATOR .................................................................................. 4 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
TABLE OF CONTENTS ........................................................................................................... 19 
LIST OF TABLES ...................................................................................................................... 22 
LIST OF FIGURES .................................................................................................................... 22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 23 
1 
INTRODUCTION ............................................................................................ 26 
1.1 
Background ......................................................................................................... 26 
1.2 
Rationale for the Clinical Study ......................................................................... 28 
1.3 
Risk-Benefit Assessment .................................................................................... 29 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................. 31 
3 
OVERALL DESIGN AND PLAN OF THE STUDY .................................... 34 
3.1 
Justification for Study Design ............................................................................ 35 
3.2 
Justification for Dose .......................................................................................... 36 
4 
STUDY POPULATION ................................................................................... 39 
4.1 
Number of Subjects ............................................................................................ 39 
4.2 
Inclusion Criteria ................................................................................................ 40 
4.3 
Exclusion Criteria ............................................................................................... 41 
4.4 
Caregiver / Support Person Eligibility and Responsibility ................................. 45 
4.5 
Screen Failures ................................................................................................... 46 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ........................................ 47 
5.1 
Identity of the Investigational Medicinal Products ............................................ 47 
5.2 
Supply, Packaging, Labeling, and Storage ......................................................... 47 
5.3 
Drug Accountability, Dispensing, and Destruction ............................................ 47 
5.4 
Subject Identification and Randomization ......................................................... 48 
5.4.1 
Screening Numbers ..................................................................................... 48 
5.4.2 
Randomization Numbers ............................................................................. 48 
5.5 
Administration of Investigational Medicinal Products ....................................... 48 
5.6 
Compliance with Investigational Medicinal Products ........................................ 48 
5.7 
Blinding and Breaking the Blind ........................................................................ 49 
5.8 
Stopping Criteria ................................................................................................ 49 


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5.9 
Treatment of Overdose ....................................................................................... 50 
5.10 
Treatment after the End of the Study ................................................................. 51 
6 
VARIABLES AND METHODS OF ASSESSMENT .................................... 52 
6.1 
Screening Assessments ....................................................................................... 52 
6.1.1 
Mini–Mental State Examination (MMSE) ................................................... 52 
6.1.2 
Clinical Dementia Rating Scale (CDR) ...................................................... 52 
6.2 
Efficacy Variables .............................................................................................. 52 
6.2.1 
Primary Efficacy Variable: Composite of Cognition and Function ........... 52 
6.2.2 
Cognitive Variables ..................................................................................... 53 
6.2.3 
Disease Condition ....................................................................................... 54 
 
 
 
 
6.3 
Safety Variables .................................................................................................. 56 
6.3.1 
Adverse Events ............................................................................................ 56 
6.3.2 
Pregnancy .................................................................................................... 63 
6.3.3 
Clinical Laboratory Assessments ................................................................ 63 
6.3.4 
Vital Signs ................................................................................................... 65 
6.3.5 
Weight .......................................................................................................... 65 
6.3.6 
12-Lead Electrocardiogram ........................................................................ 65 
6.3.7 
Physical and Neurological Examination ..................................................... 66 
6.3.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................... 66 
6.3.9 
Geriatric Depression Scale (GDS) .............................................................. 66 
6.4 
Pharmacokinetic Variables ................................................................................. 67 
6.5 
Genotyping ......................................................................................................... 67 
6.6 
Plasma Sample Collection (Biomarker Analyses) ............................................. 67 
7 
STUDY CONDUCT ......................................................................................... 68 
7.1 
Schedule and Order of Assessments ................................................................... 68 
7.1.1 
Unscheduled Visit(s) ................................................................................... 69 
7.2 
Pandemic Response ............................................................................................ 69 
7.3 
Data Safety Monitoring Board ........................................................................... 70 
7.4 
Supportive Care Measures for Potential Adverse Events ................................... 70 
7.5 
Concomitant Medications and Treatments ......................................................... 71 
7.5.1 
Prohibited Treatments During the Study .................................................... 71 


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7.5.2 
Permitted Treatments .................................................................................. 72 
7.5.3 
Other Restrictions ....................................................................................... 73 
7.6 
Subject Withdrawal ............................................................................................ 73 
7.6.1 
Discontinuation of Study Treatment ............................................................ 74 
7.6.2 
Withdrawal from the Study .......................................................................... 74 
7.7 
Lost to Follow-up ............................................................................................... 75 
7.8 
Termination of the Clinical Study ...................................................................... 76 
8 
STATISTICAL METHODS ............................................................................ 77 
8.1 
Populations for Analysis ..................................................................................... 77 
8.1.1 
ITT Population ............................................................................................ 77 
8.1.2 
MITT Population ......................................................................................... 77 
8.1.3 
Primary Analysis Population ...................................................................... 77 
8.1.4 
Per Protocol Population ............................................................................. 77 
8.1.5 
Safety Population ........................................................................................ 77 
8.2 
General Considerations ...................................................................................... 77 
8.3 
Statistical Analyses ............................................................................................. 78 
8.3.1 
Primary Efficacy Analysis - GST Score ...................................................... 78 
8.3.2 
Key Secondary Efficacy Analysis – ADAS-Cog11, ADCS-ADL23, and 
Biomarkers (NfL) ......................................................................................... 78 
 
 
 
 
8.4 
Safety Summaries ............................................................................................... 80 
8.4.1 
Adverse Events ............................................................................................ 81 
8.4.2 
Laboratory parameters ............................................................................... 81 
8.4.3 
12-Lead Electrocardiogram ........................................................................ 81 
8.4.4 
Columbia-Suicide Severity Rating Scale ..................................................... 81 
8.4.5 
Geriatric Depression Scale ......................................................................... 81 
8.5 
Pharmacokinetic Analyses .................................................................................. 81 
8.6 
Determination of Sample Size ............................................................................ 82 
8.7 
Interim Analysis ................................................................................................. 82 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................... 84 
9.1 
Data Quality Assurance ...................................................................................... 84 
9.2 
Access to Source Data/Documents ..................................................................... 85 
9.3 
Archiving Study Documents .............................................................................. 85 


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9.4 
Good Clinical Practice ........................................................................................ 85 
9.5 
Informed Consent ............................................................................................... 86 
9.6 
Protocol Approval and Amendment(s) ............................................................... 87 
9.7 
Confidentiality Data Protection .......................................................................... 87 
9.8 
Publication Policy ............................................................................................... 87 
10 
REFERENCE LIST ......................................................................................... 89 
11 
APPENDICES ................................................................................................... 92 
11.1 
Appendix 1: List of Prohibited Medications ...................................................... 92 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ............................................................................................ 16 
Table 2 
Number of Subjects Planned for Enrollment .............................................................. 40 
Table 3 
Identity of Investigational Medicinal Products ........................................................... 47 
Table 4 
Assessment of Relationship of Adverse Events to IMP/Study Procedure .................. 59 
Table 5 
Clinical Laboratory Assessments ................................................................................ 63 
Table 6 
Supportive Care Measures and Follow-up of Potential Adverse Events .................... 70 
 
LIST OF FIGURES 
Figure 1 
Mechanism of ATH-1017 ........................................................................................... 27 
Figure 2 
Dose selection based on PK-PD modeling ................................................................. 37 
Figure 3 
Hierarchical Statistical Gatekeeping Strategy ............................................................ 79 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
  
 
AChEI 
Acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADAS-Cog11 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
ADCS-ADL23 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living, 
23-Item Version 
 
 
AE 
Adverse event 
AEC 
Absolute eosinophil count 
AKT 
Protein kinase B 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
ApoE 
Apolipoprotein E 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CBC 
Complete blood count 
CBD 
Cannabidiol 
CDR 
Clinical dementia rating scale 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
 
 
CP 
Conditional power 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
C-SSRS 
Columbia-suicide severity rating scale 
CT 
Computerized tomography 
CYP3A4 
Cytochrome P450 3A4 
DDI 
Drug-drug interaction 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
EQ-5D-5L 
EuroQol group 5-dimension 5 level questionnaire 


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ERP 
Event-related potentials 
ET 
Early termination 
FSH 
Follicle-stimulating hormone 
fT3 
Free tri-iodothyronine 
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 
Hepatic growth factor 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
IRT 
Interactive response technology 
iSAP 
Interim Statistical Analysis Plan 
ISR 
Injection site reaction 
ITT 
Intent-to-treat 
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 
NfL 
Neurofilament light chain 


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NIA-AA 
National Institute on Aging – Alzheimer’s Association 
NMDA 
N-methyl-D-aspartate 
 
 
OLEX 
Open-label extension 
P 
Phosphorylated 
PD 
Pharmacodynamic(s) 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic(s) 
PKC 
Protein kinase C 
Plc 
Placebo 
PLCγ 
Phospholipase C-gamma 
PM 
Plasma membrane 
PRN 
As needed 
PSP 
Post-synaptic potential 
PT 
Prothrombin time 
 
 
qEEG 
Quantitative electroencephalogram 
qd 
Once daily 
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 
SSR 
Sample size re-estimation 
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) 
 
 
WBC 
White blood cells 
 
 
 


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1 
INTRODUCTION 
Fosgonimeton (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 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 hepatic 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. 
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)-4 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 


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small molecule approach capable of passing the blood brain barrier and entering all regions of 
the brain, presents a superior therapeutic strategy for targeting neurotrophic factors to treat 
neurodegenerative disorders.  
ATH-1017 represents a new approach to treat AD in a systemic approach. The mechanism of 
action of ATH-1017 via its active metabolite is augmentation of HGF function and facilitation of 
signal transduction through MET phosphorylation (Figure 1).  
Figure 1 
Mechanism 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 in plasma to the active 
metabolite 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 


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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 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 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 11 AD subjects with 40 mg/once daily 
(qd) SC significantly reduced P300 latency (p=0.027) after 8 days of treatment when compared 
to placebo (Hua, 2022). This finding suggests ATH-1017 treatment has potentially beneficial 
effects on cognitive processing and working memory access in AD. 
The sponsor has completed a Phase 2 study (ATH-1017-AD-0202 [ACT-AD]) study of 
ATH-1017 in 77 mild to moderate Alzheimer’s subjects over 6 months of treatment. The results 
of the study suggested ATH-1017 had positive effects on measures of cognition, function and 
neurodegeneration in subjects taking ATH-1017 alone compared to placebo at 26 weeks (data on 
file). 
This study (ATH-1017-AD-0201) is designed to demonstrate efficacy in mild to moderate AD 
subjects and establish long-term safety information. Eligible subjects prior to version 7 will 
receive qd SC injections of ATH-1017 (40 mg or 70 mg) or placebo, over a 26-week randomized 
period, followed by a 4-week safety follow-up. Subjects who complete the study will have the 
option to roll over into a long-term open-label extension study. 
Based on the results of the ATH-1017-AD-0202 ACT-AD study, as of version 5 of this protocol 
no additional subjects on acetylcholinesterase inhibitor (AChEI) therapy will be enrolled, and, as 
of version 7 of this protocol, subjects are no longer randomized to receive 70 mg of ATH-1017, 
since 40 mg/qd is the dose intended for further development. The 70 mg/qd dose was tested in 
the ATH-1017-AD-0202 study; clinical and biomarker endpoints did not consistently favor 
70 mg/qd when compared to 40 mg/qd. While ATH-1017 has demonstrated a favorable safety 


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profile in all completed and ongoing studies to date, there appears to be better tolerability in the 
40 mg cohort when compared to 70 mg. By discontinuing the 70 mg cohort, with no further 
plans to develop the 70 mg formulation, it will also decrease the burden on clinical trial 
healthcare resources (e.g., clinical site utilization, availability of eligible subjects, caregiver 
commitments), and subjects will be randomized to ATH-1017 40 mg/qd or placebo, in a 
1:1 ratio. Subjects already randomized to receive the 70 mg dose will complete the study as 
planned. The primary analysis population will include modified intent-to-treat (mITT) subjects 
randomized to ATH-1017 40 mg/qd or placebo who are not receiving AChEI treatment (see 
Sections 8.1.1 and 8.1.3 for details). The comparison between ATH-1017 70 mg/qd and placebo, 
between ATH-1017 70 mg/qd and ATH-1017 40 mg/qd, and between pooled ATH-1017 
(70 mg/qd + 40 mg/qd subjects) and placebo will be treated as exploratory comparisons. In 
addition, exploratory analyses for the effect of ATH-1017 in the presence of background AChEIs 
will be performed for subjects who enrolled prior to protocol version 5. 
1.3 
Risk-Benefit Assessment 
Whilst qEEG and ERP results in humans are indicative of CNS penetration and target 
engagement, ATH-1017 efficacy in subjects with AD (in terms of cognitive, functional, or 
behavioral improvement) has not been established. Therefore, the benefits to study subjects of 
participating in this clinical trial are not yet known. 
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, qd, over 
9 consecutive days) in healthy elderly subjects, and 40 mg (SC, qd, over 9 consecutive days) in 
AD subjects were safe and well tolerated.   
Injection site reactions (ISRs), eosinophilia, and transaminase elevations are considered as 
nonserious adverse drug reactions to ATH-1017. 
Injection site reactions have been observed commonly in clinical trials and are characterized by 
localized symptoms including swelling, erythema, pruritus, pain, and/or irritation around the 
injection site. They have usually been mild, appear during the first weeks of injections, though in 
some cases ISRs may appear later. Most ISRs were mild and recovered shortly without 
treatment, while some were more persistent. 
Transient absolute eosinophil count (AEC) elevations without signs of clonality and without 
associated clinical symptoms have been observed in subjects. The majority of these elevations 
stayed below 3 × 103/μL and resolved without intervention during continued IMP administration. 
Very few subjects experienced elevations above 5 × 103/μL. No AEs potentially associated with 
eosinophilia were reported. None of the subjects fulfilled the criteria for a hyper-eosinophilic 
syndrome. All AEC elevations have resolved without sequela, and the vast majority of subjects 
continued in the trials. 


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Non-clinical data identified a potential risk for hepatotoxicity and will be closely monitored in 
this study. The sponsor reviewed clinical data from the Phase 1 trial ATH-1017-0103, and 
6 healthy subjects in the 140 mg cohort had elevated transaminases. Repeat testing showed 
resolution towards normal in all subjects, with no reports of associated complications. No serious 
events of transaminase elevations have been reported and there have been no cases meeting Hy’s 
Law criteria. 
In the completed translational Phase 2 study (ATH-1017-AD-0202), an apparent and unexpected 
pharmacodynamic drug-drug interaction (DDI) with background AChEIs was observed. The 
suspected pharmacodynamic DDI did not affect safety in ATH-1017-AD-202 or the present 
study. A pre-specified ERP P300L analysis, and post-hoc unadjusted summary statistical 
analysis, as well as post-hoc Mini-Mental State Examination (MMSE) data collected during the 
study and during an open-label extension, consistently suggest favorable effects of ATH-1017 in 
the “no AChEI” group. In addition, analysis of biomarkers in the Phase 2 study showed 
statistically significant reduction in Neurofilament light chain (NfL) concentration, a 
well-established biomarker of neurodegeneration, among subjects not using AChEIs, and 
congruent trends in improvement in all other blood-based biomarkers. 
The safety of ATH-1017 is monitored by an independent unblinded Data Safety Monitoring 
Board (DSMB), which continues to recommend that Study ATH-1017-AD-0201 continue 
without modification. ATH-1017 has demonstrated a favorable safety profile in all completed 
and ongoing studies to date. 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Efficacy Objective 
Primary Efficacy Endpoint* 
To evaluate the clinical efficacy of ATH-1017 
in subjects not on background 
acetylcholinesterase inhibitors (AChEIs) 
The Global Statistical Test (GST) score 
(O’Brien, 1984) is a composite of cognition 
and function, calculated as the average of two 
change from baseline z scores; the z-scores 
are calculated for the change from baseline 
scores for cognition (Alzheimer’s Disease 
Assessment Scale-Cognitive Subscale 
[ADAS-Cog11]) and function (Alzheimer’s 
Disease Cooperative Study – Activities of 
Daily Living, 23-item version 
[ADCS-ADL23] score) at Week 26 
Key Secondary Efficacy Objectives 
Key Secondary Efficacy Endpoints* 
To evaluate the clinical efficacy of ATH-1017 
in subjects not on background AChEIs 
separately on: 
(1) cognition and 
(2) activities of daily living 
• 
ADAS-Cog11 score: change from baseline 
at Week 26 
• 
ADCS-ADL23 score: change from 
baseline at Week 26 
To determine the effect of ATH-1017 on 
plasma neurofilament light chain (NfL) levels 
in subjects not on background AChEIs 
(a biomarker of neurodegeneration with 
literature support for being a biomarker for 
Alzheimer’s disease [AD] progression) 
Change from baseline in the NfL 
concentration at Week 26 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety Objective 
Safety Endpoints 
To determine the safety and tolerability of 
ATH-1017 
Analysis of 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) 
* The comparison between ATH-1017 40 mg/qd and placebo in subjects not on background 
AChEIs will serve as the primary efficacy comparison for the primary and key secondary 
endpoints.
 
 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
This is a Phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study comparing ATH-1017 treatment with placebo in subjects with a clinical diagnosis of mild 
to moderate AD, diagnosed on a ‘probable’ level according to the National Institute on 
Aging – Alzheimer’s Association (NIA-AA; McKhann, 2011). The study will be conducted at a 
total of approximately 70 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. Up to protocol version 7, subjects meeting all inclusion/exclusion 
criteria were randomized in a ratio of 1:1:1 to 3 parallel arms, either to treatment (ATH-1017 
40 mg/qd or ATH-1017 70 mg/qd) or placebo group. As of protocol version 7, randomization to 
ATH-1017 70 mg/qd was discontinued, and subjects will be randomized in a ratio of 1:1 to 
2 parallel arms, either to receive ATH-1017 40 mg/qd or placebo. Subjects randomized to 
ATH-1017 70 mg/qd prior to protocol version 7 will continue that treatment regimen until either 
study completion or early termination (ET).  
During randomization, subjects will be stratified by screening MMSE severity: mild (MMSE: 
20-24) versus moderate (MMSE: 14-19). All eligible subjects will be tested for ApoE genotype. 
Study drugs will be administered by SC injection qd preferably during daytime. Subjects should 
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 randomized 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 trial at Week 30 (see Table 1 for schedule of assessments). On Day 1, after 
completion of the first dose, subjects will remain on-site 2 hours (±15 minutes) 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, 
 assessments should occur at clinic visits in the morning at approximately 
the same time they were performed during the initial Baseline
 
ubjects 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. Subjects 
enrolled at participating sites may seamlessly enroll onto the open label extension (OLEX) study 
(ATH-1017-0203) following Visit 8, subject to meeting all eligibility criteria for that study. For 


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subjects who do not enroll into the OLEX, the end of study is defined as either the Safety 
Follow-up (Visit 9/Week 30) or the date of an ET visit for those subjects who terminate prior to 
Visit 8. Subjects who terminate prior to Visit 8 are to complete the same assessments as Visit 8 
at the ET visit. 
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 blood-based biomarkers (optional prior to version 7 of the protocol), and for plasma 
concentrations of ATH-1017 and ATH-1001 (see Table 1 for schedule of assessments). 
An open-label extension will be offered to eligible subjects at participating sites. 
3.1 
Justification for Study Design 
The study is designed to demonstrate efficacy and safety of ATH-1017 in mild to moderate AD 
subjects, with double-blind, parallel-arm treatment duration of 26 weeks, and based on clinical 
diagnostic criteria of AD (McKhann, 2011) and the inclusion/exclusion criteria. An option to roll 
over into a long-term open-label extension study will be available to subjects who complete this 
study; the purpose of the open-label extension is to continue to collect long-term safety. 
Clinical efficacy in the target patient population is demonstrated by improvement in cognition 
and global/function assessments comparing treatment to placebo. Based on the results of the 
ATH-1017-AD-0202 ACT-AD study, only subjects not receiving AChEI treatment will be 
included in the primary analysis population. Following protocol version 7, only subjects 
randomized to either ATH-1017 40 mg/qd or placebo will be included in the primary analysis 
population. The Global Statistical Test (GST) score combines the change from baseline scores 
from efficacy endpoints ADAS-Cog11 (i.e., cognition) and ADCS-ADL23 (i.e., function) into a 
single primary efficacy endpoint, allowing an assessment of the overall treatment effects of 
ATH-1017 in this complex disorder. Assessment of NfL, a biomarker of neurodegeneration, will 
provide objective data to support the clinical evaluations of benefit. 
As well as providing efficacy data 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 caregiver burden and healthcare 
resource utilization. 
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. 


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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. 
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 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 metabolite) 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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1 placebo), with PK results in keeping with dose-linearity, and supportive safety data. The 70 mg 
dose is therefore selected in reference to the high dose range defined as 60 mg to 90 mg.  
The selection of the 40 mg and 70 mg doses is supported by the 6- and 9-month 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 6- and 9-month GLP nonclinical toxicology studies in animals at equivalent 
doses.  
Based on the results of the ATH-1017-AD-0202 ACT-AD study, no additional subjects on 
AChEI therapy will be enrolled (version 5) and, as of version 7, subjects will no longer be 
randomized to receive 70 mg of ATH-1017. The ATH-1017 70 mg/qd dose is not intended for 
further clinical development. The 70 mg/qd dose was tested in the ATH-1017-AD-0202 study, 
where there was no clear suggestion of added clinical benefit of 70 mg/qd when compared to 
40 mg/qd. In addition, there appears to be better tolerability in the 40 mg cohort when compared 
to 70 mg. By discontinuing the 70 mg cohort, with no further plans to develop the 70 mg 
formulation, it will also decrease the burden on clinical trial healthcare resources (e.g., clinical 
site utilization, availability of eligible subjects, caregiver commitments). Subsequently, as of 
version 7, subjects will be randomized to ATH-1017 40 mg/qd or placebo, in a 1:1 ratio. 
Subjects already randomized to receive the 70 mg dose will complete the study as planned. The 
doses of ATH-1017 used for evaluation of efficacy and safety 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 was originally designed to enroll approximately 300 subjects in a 1:1:1 ratio to 
ATH-1017 40 mg/qd, ATH-1017 70 mg/qd, and placebo groups (Protocol versions 1-3). In 
version 4, the sample size was increased to 420 subjects in order to increase statistical power. 
After the ATH-1017-AD-202 ACT-AD read out (data on file, peer-reviewed publication is in 
preparation), the protocol was amended (version 5) to: stop enrollment of subjects receiving 
AChEIs, and perform an independent, unblinded interim analysis with a pre-specified sample 
size re-estimation (SSR) procedure following a test for futility based on conditional power (CP), 
using the promising zone approach (Mehta and Pocock, 2011). Prior to version 5, approximately 
200 subjects who were receiving AChEIs were already enrolled in the trial. 
The interim analysis was conducted on approximately 100 subjects not receiving AChEIs who 
completed participation in the trial (either completion of Week 26 assessments or terminated 
early). The results indicated that a pre-specified sample size of up to 275 subjects was well 
powered to meet the primary endpoint of the study. The primary purpose of version 6 of the 
protocol was to add ADAS-Cog11 at screening, and to elevate NfL to be a secondary endpoint. 
These changes did not impact the number of subjects to be enrolled. 
With version 7 of this protocol, randomization to the 70 mg dose group was discontinued. In 
order to provide 85% power with two-sided 0.05 testing, a sample size of 149 subjects will be 
randomized in a 1:1 ratio to each of the two treatment groups, ATH-1017 40 mg/qd or placebo, 
for a total of approximately 298 subjects who are not receiving AChEIs. Approximately 
60 subjects have already been randomized to ATH-1017 70 mg/qd; these subjects will complete 
the study as planned. Therefore, the maximum total enrollment for this study will be 
approximately 558 subjects as outlined in Table 2 below. 


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Table 2 
Number of Subjects Planned for Enrollment 
Number of Subjects 
Receiving AChEIs 
Not Receiving AChEIs 
Total 
Plc 
ATH-1017 
40 mg/qd 
ATH-1017 
70 mg/qd 
Plc 
ATH-1017 
40 mg/qd 
ATH-1017 
70 mg/qd 
~200 
~149 
~149 
~60a 
~558 
AChEI = acetylcholinesterase inhibitor; Plc = placebo; qd = once daily. 
a 
Approximate number of subjects who were randomized to ATH-1017 70 mg/qd prior to version 7. 
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 
potential. Only female subjects of nonchildbearing 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 


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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 (subjects not receiving AChEI treatment), defined as: 
a) Treatment-naïve, OR 
b) Subjects who received an AChEI in the past and discontinued at least 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. Subject has atypical variant presentation of AD, if known from medical history, particularly 
non-amnestic AD. 
3. 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 


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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. 
4. Diagnosis with current symptoms of severe major depressive disorder even without 
psychotic features. Any subject with formalized delusions or hallucinations are excluded. 
5. 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. 
6. 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). 
7. History within 2 years of Screening, or current diagnosis of psychosis (American Psychiatric 
Association [APA], 2000) or moderate substance abuse disorder (according to the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) (APA, 2013). 
8. 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. 
9. Abnormal serum electrolytes (potassium, sodium, magnesium) of clinical significance. If 
treated, must be stably treated for at least 30 days before Screening. 
10. Active, acute, or chronic infectious disease of any type. 
11. Myocardial infarction or unstable angina within the last 6 months or history of more than 
one myocardial infarction within 5 years before Screening. 
12. Clinically significant (in the judgment of the investigator) cardiac arrhythmia (including 
atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: pacemaker is 
acceptable). 
13. Subject has either hypertension (supine diastolic blood pressure > 95 mmHg), or 
symptomatic hypotension in the judgment of the investigator. 
14. 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 


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subjects with a QRS value > 120 msec, those with a QTcF value < 500 msec may be eligible 
following discussion with the Medical Monitor. 
15. 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); subjects with a history of positive results for cured hepatitis 
B or hepatitis C may be eligible following discussion with the Medical Monitor and prior 
approval is required. 
16. Chronic kidney disease with estimated glomerular filtration rate (eGFR) < 45 mL/min using 
the Cockcroft and Gault formula with age, sex, and weight considered; subjects with 
moderate to severe impairment (eGFR between 44 and 30 mL/min inclusive) may be 
eligible following discussion with the Medical Monitor and prior approval is required. 
17. Hepatic impairment with alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 2 times the upper limit of normal, or Child-Pugh class B and C. 
18. 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; 
c) Fully-excised (biopsy-proven) melanoma in situ; prior Medical Monitor approval is 
required. 
19. Clinically significant (in the judgment of the investigator) unintentional weight loss within 
12 months of Screening. 
20. 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. 
21. Food supplements and nutraceuticals with potential effects on cognition, such as Axona and 
medium-chain triglyceride (MCT), are prohibited beginning 7 days prior to the first dose of 
study medication (Day 1) and for the duration of the study. 
22. 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.  
23. Prohibited prior and concomitant medications are excluded within 4 weeks prior to 
Screening. All allowed medications should remain stable throughout the study; for 
medications negatively 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 


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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) Acetylcholinesterase inhibitors in any dosage form 
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, ophthalmologics, skin creams, and intra-
articular injections are allowed) 
k) Antiepileptic medication if taken for control of seizures. Other uses, e.g., neuropathy and 
restless legs, are allowed 
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 (CYP3A4) inhibitors or inducers; 
topical applications are allowed 
24. 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. 


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25. 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. 
26. Subject has known allergy to any component of the investigational medicinal product (IMP). 
27. 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 
• The nature of expected AEs 
• How to report AEs 
• Scheduled weekly phone calls from site personnel 


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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 Investigational Medicinal Products 
The products that will be used in this study are outlined in Table 3. 
Table 3 
Identity of Investigational Medicinal Products 
Study Drug Name 
Formulation 
Strength 
Route 
Manufacturer 
ATH-1017 40 mg 
Injection 
40 mg/mL 
SC 
Patheon 
ATH-1017 70 mga 
Injection 
70 mg/mL 
SC 
Patheon 
Placebo  
Injection 
NA 
SC 
Patheon 
NA = not applicable; SC = subcutaneous 
a 
Subjects were only randomized to this dose prior to version 7 of the protocol. 
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. Placebo pre-filled syringes will be fully matching. 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 at the study site or as needed by direct-to-patient 
shipment. For visits greater than 2 weeks apart, additional study drug kits may be assigned. 
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 2) 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 


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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. 
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. 
An unblinded interim analysis was performed for this study by an independent DMC. Sponsor 
staff involved in the conduct of the trial remain blinded. Details of the interim analysis were 
pre-specified in the interim Statistical Analysis Plan (iSAP, dated September 2022). After 
database lock, the overall randomization code will be broken for final analysis and 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 in a satisfactory 
time frame per investigator judgment: 
• 
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: 


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− 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 
− A decrease from baseline in hemoglobin concentration > 2 g/dL 
− Absolute neutrophil count < 1,000/L 
− Platelets < 50,000/L 
• 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 
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There is no prior knowledge of clinical symptoms occurring with ATH-1017 overdose. In case of 
suspected or reported overdose, treatment of any clinical signs will be symptomatic. 
5.10 
Treatment after the End of the Study 
Access to study treatment will be limited to the period of study participation 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 upon discontinuation of 
randomized treatment may continue with their original treatment following consultation with 
their primary care physician; 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 
Baseline. 
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. 
6.2 
Efficacy 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. 
 
6.2.1 
Primary Efficacy Variable: Composite of Cognition and Function 
6.2.1.1 
Global Statistical Test (GST) Score 
A composite approach will be used to facilitate the assessment of an overall change in disease 
status/trajectory in the trial. The GST score will be defined as a single outcome variable based on 
standardizing and then combining individual patient-level change from baseline cognition 
(ADAS-Cog11; Section 6.2.2.1) and functional (ADCS-ADL23; Section 6.2.3.2) scores. The 
GST score will be determined for each patient at each time point and the resulting scores will 
define the efficacy outcome variable to be used in the primary efficacy analysis. Full details will 
be provided in the Study SAP. 


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6.2.2 
Cognitive Variables 
6.2.2.1 
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 at Screening and 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). 
 
 
 
 
 
 
 
 
 
 
 


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6.2.3 
Disease Condition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.3.2 
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 at any time during Visit 2 (Baseline/Day 1), post-dose at Visit 5 
(Week 12), Visit 7 (Week 20) and post-dose at Visit 8/ET (Week 26). 
 
 
 
 


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6.3 
Safety Variables 
6.3.1 
Adverse Events 
AE reporting will begin at Screening (Visit 1) and will continue until the end of the study 
(28 days from last dose of IMP, Visit 9 – Safety Follow-up). AEs will be reported by the subject 
(or, when appropriate, by a caregiver, support person, or the subject’s legally authorized 
representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AE 
(see Section 6.3.1.5). 
6.3.1.1 
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. 


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• Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AEs or SAEs if they fulfil the definition of an AE or SAE. 
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 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen (note: preexisting conditions will be 
recorded as part of the subject’s medical history) 
6.3.1.2 
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).  


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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 subject identifiers, with the exception of the subject 
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. 
In the event that a moderate or severe injection site reaction is reported, the site will take 
photographs of the affected area for subjects consenting to photographs. 
6.3.1.3 
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. 


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Causality 
The investigator will assess the causality/relationship between the AE and IMP/study procedure. 
One of the categories described in Table 4 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. 
Table 4 
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. 
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 


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the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements 
Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening; this means that the subject was at risk of death at the time of the event; 
it does not mean that the event hypothetically might have caused death if it were more 
severe. 
• Requires hospitalization or prolongation in existing hospitalization; in general, 
hospitalization signifies that the subject 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 


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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 
expedited reporting is appropriate. 
6.3.1.4 
Reporting of Serious Adverse Events 
Prompt (within 24 hours) notification by the investigator to the Sponsor’s designated Drug 
Safety and Pharmacovigilance vendor, i.e., MMS, of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects 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) a 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: 
 
 
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. 


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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. 
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. In rare circumstances, and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE Report Form sent by email 
 or Fax 
. Initial notification via telephone does not 
replace the need for the investigator to complete and sign the SAE Report Form within the 
designated reporting time frames. Contacts for SAE reporting can be found on the protocol title 
page. 
All SAE reports submitted by the investigator will be reviewed by the study Sponsor and 
assessed for meeting criteria of Suspected Unexpected Serious Adverse Reactions (SUSARs). 
All SUSARs will be reported by the Sponsor to Competent National Authorities and 
investigators according to local regulatory requirements and Sponsor policy. 
An investigator who receives an Individual Case Safety Report (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. 
6.3.1.5 
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 


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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 7.7). 
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. 
6.3.2 
Pregnancy 
The investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject 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 
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 (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
6.3.3 
Clinical Laboratory Assessments 
The following laboratory variables will be determined as outlined in Table 5 below: 
Table 5 
Clinical Laboratory Assessments 
Test 
Parameters 
Hematology 
CBC 
HbA1c 
Hemoglobin 
Hematocrit 
Erythrocytes (RBC) 
Leukocytes (WBC)  
Differential WBC 
Platelets 
Biochemistry 
Sodium 
Potassium 
Magnesium 
FSH (post-menopausal females only) 
Calcium 
Chloride 
Glucose 
Creatinine 
ALP 
AST 
GGT 
CPK 
Total bilirubin 
Total protein 
Albumin 
Total Cholesterol 
Low-density lipoprotein  
High-density lipoprotein 
Triglycerides 
Vitamin B12 a 


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ALT 
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; fT4 = 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 
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 per stopping criteria 
described in Section 5.8. 
A medical alert for potential Hy’s law 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
) 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). 


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Any clinically significant abnormalities from Screening labs must be discussed with the Medical 
Monitor to confirm eligibility of the subject. Additional testing during the study may be done if 
medically indicated. If a clinically significant abnormality is found in the samples taken after 
dosing, during the study, and/or at the safety follow-up visit, it should be recorded as an AE and 
the subject will be followed until the test(s) has (have) normalized or stabilized. 
6.3.4 
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) 
• 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 systolic 
blood pressure of ≥ 20 mmHg, or in diastolic blood pressure of ≥ 10 mmHg will be considered 
abnormal. 
6.3.5 
Weight 
Weight will be measured at Screening (for calculation of BMI as part of the eligibility criteria), 
at Baseline/Day 1 (Visit 2), Visit 5 (Week 12), Visit 8 (Week 26), and Visit 9 (Safety follow-up). 
6.3.6 
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 sequentially, as detailed in the Schedule of Assessments (Table 1). 
The 12-lead ECGs will be performed after the subject has been resting supine for ≥ 5 minutes. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing. The following ECG parameters will be collected: PR interval, QRS interval, RR interval, 
QT interval, and QTcF. 


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All ECGs must be evaluated by the investigator or qualified designee for the presence of 
abnormalities. Collection and analysis of ECG data will be performed by a central ECG vendor. 
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.  
6.3.7 
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, and neurological 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 (m2). 
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. 
6.3.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be performed at Screening, Baseline/Day 1, 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. 
6.3.9 
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 5 (Week 12), Visit 8/ET 
(Week 26), and Visit 9 (Safety follow-up). 


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6.4 
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. 
6.5 
Genotyping 
Blood sample(s) will be collected at Screening for analysis of ApoE genotype.  
6.6 
Plasma Sample Collection (Biomarker Analyses) 
Collection of samples for blood-based biomarkers is also part of this study, with sample results 
analyzed as described in Sections 8.3.2 and 8.3.3 (further biomarkers may be analyzed in 
addition to those specified). Plasma samples for biomarkers will be collected pre-dose at 
Baseline (Day 1), Week 12 (Visit 5), and at the last scheduled visit (Week 26) from all subjects 
in this study (Table 1). 
analysis will be performed to determine impact of 
ATH-1017 treatment on biomarkers thought to relate to AD progression and/or pathology, as 
well as to evaluate their association with observed clinical responses. 


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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. 
7.1 
Schedule and Order of Assessments 
The study will consist of up to 28 days of Screening (Day -28 through Day -1) followed by 
26 weeks of randomized treatment and a 4-week safety follow-up. Note: if 28 days is not 
sufficient to complete the screening period, the possibility of an extension can be discussed with 
the Medical Monitor. 
All assessments to be performed during the study are detailed by visit/timepoint in Table 1. 
For clinical outcome assessments evaluating subject’s cognitive condition, the general order 
should be followed: 
 
(2) ADAS-Cog11 
 
 
At Baseline/Day 1 (Visit 2), MMSE should be done first before all other assessments pre-dose.  


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MMSE assessments will be performed first before all other clinical outcome assessments post-
dose at approximately 30 minutes (± 15 minutes) at Week 20 (Visit 7) and Week 26 (Visit 8).  
ADAS-Cog11 
 assessments should occur at clinic visits in the morning at 
approximately the same time they were performed during the initial Baseline/Day 1 assessment. 
ADAS-Cog11 
 assessments will be performed pre-dose at Baseline/Day 1 (Visit 2), 
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). 
 
PK plasma samples will be collected at pre-dose and 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 any time 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): 
• Visits 1 (Screening), 2 (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 subjects 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) 


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• Visits 3 (Week 2), 4 (Week 6), 6 (Week 16), and 7 (Week 20) should be conducted onsite 
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 
Supportive Care Measures for Potential Adverse Events 
If a subject experiences an AE relating to eosinophilia or an ISR, the investigator will take the 
appropriate follow-up action to manage clinical symptoms and monitor subject safety (Table 6). 
Table 6 
Supportive Care Measures and Follow-up of Potential Adverse Events 
Adverse Event 
Action Required 
Eosinophilia 
AEC < 3000/µL 
Continue IP as per protocol. 
AEC > 3000/µL 
Arrange repeat measurement within 2 weeks and continue IP. 
• 
If further increase of AEC on 2 repeat tests, consult with 
Medical Monitor and Sponsor. 
o 
Consider hold of IP for 2 weeks. 
• 
If trend is stable or downward on 2 repeat tests, continue IP and 
standard testing schedule as per protocol. 
AEC increase associated with other 
hematologic signs or symptoms 
Consult with Medical Monitor and Sponsor promptly and follow local 
SOP for SAE/Emergency as appropriate. 
• 
Consider hold of IP for 2 weeks. 


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Injection Site Reaction 
Mild ISR 
Consider treatment with topical hydrocortisone 1% and/or non-sedating 
antihistamines up to twice daily, as needed. 
Moderate ISR 
Immediately apply prescription strength ointment/cream (e.g., 
Triamcinolone, 0.1% Betamethasone, 0.05% Clobetasol, and/or 
non-sedating antihistamines) up to twice daily, as needed. 
AEC = absolute eosinophil count; IP = investigational product; SAE = serious adverse event; SOP = standard operating procedure. 
7.5 
Concomitant Medications and Treatments 
7.5.1 
Prohibited Treatments During the Study 
All allowed medications should remain stable throughout the study; for medications affecting 
cognition, the doses should be stable for at least 4 weeks before Screening and throughout the 
study, unless otherwise noted.  
Use of the following drugs is excluded within 4 weeks prior to Screening: 
• Memantine in any form, combination, or dosage 
• Any AChEI in any dosage form 
The following drugs are prohibited during the study: 
• Memantine in any form, combination, or dosage 
• Any AChEI in any dosage form 
• 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 7.5.2). 
• 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 7.5.2) 
• Antiepileptic medication if taken for control of seizures. Other uses e.g., neuropathy and 
restless legs, are allowed 


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• 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 randomized treatment period of 
the study may be discontinued from study drug. 
Note: The discontinuation of a subject due to use of a prohibited medication shall be discussed 
between the investigator, Medical Monitor, and Sponsor. The investigator should contact the 
Medical Monitor prior to discontinuing a subject for disallowed medications. 
See Appendix 1: List of Prohibited Medications for a non-exhaustive list of prohibited 
medications. 
7.5.2 
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 
The dosage(s) of 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 negatively 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 7.5.1, and below, concomitant medications will be allowed at the investigator’s 
discretion. When in doubt, the Medical Monitor should be contacted. 


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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, 
ophthalmologics, skin creams, and intra-articular injections are allowed. 
If the permissibility of a specific medication/treatment is in question, please contact the Medical 
Monitor. 
7.5.3 
Other Restrictions 
7.5.3.1 
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. 
7.5.3.2 
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. 
7.6 
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 


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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. 
7.6.1 
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 may continue with their 
original treatment following consultation with their primary care physician; 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). 
7.6.2 
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: 
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 


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• 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 ET 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 an ET visit for final assessments. 
Upon discontinuation of study drug, subjects may continue with their original treatment 
following consultation with their primary care physician; tapering off study medication is not 
required. 
7.7 
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. 


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7.8 
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 subjects 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 
ITT Population 
The intent-to-treat (ITT) population will consist of all randomized subjects regardless of whether 
or not the subject received test article. A subject is considered randomized when the test article 
assignment (i.e., completes a randomization transaction) is provided. Analyses will be based on 
the randomized treatment assignment. 
8.1.2 
MITT Population 
The modified intent-to-treat (mITT) population is a subset of the ITT population, which will 
include all randomized subjects who took at least one dose of the study medication and who, 
during at least one post-baseline visit, completed both an ADAS-Cog11 and ADCS-ADL23 
assessment, as well as at baseline. Analyses will be based on the randomized treatment 
assignment. 
8.1.3 
Primary Analysis Population 
The primary analysis population is comprised of all members of the mITT population who were 
not taking AChEIs during the trial, and were randomized to either ATH-1017 40 mg/qd or 
placebo. Analyses will be based on the randomized treatment assignment.  
8.1.4 
Per Protocol Population 
The per protocol population will include all primary analysis subjects who took the assigned 
medication, completed both an ADAS-Cog11 and ADCS-ADL-23 assessment during at least one 
post-baseline visit as well as at baseline, and did not have any major protocol deviations that are 
deemed to potentially interfere with efficacy as evaluated at a classification meeting prior to 
unblinding. Analyses will be based on the actual treatment received. 
8.1.5 
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. 


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Change from baseline is calculated by subtracting the baseline score from the observed value at 
any subsequent visit. For safety summaries, the last measurement prior to first dose is defined as 
the baseline value. For efficacy measures, baseline is defined as either the measurement on 
Day 1, or else the last measurement before Day 1 if there is no Day 1 measurement. If no test 
article is received, baseline is defined as the value closest to but prior to randomization. 
Statistical tests for the primary and secondary efficacy endpoints will use a hierarchical 
gatekeeping procedure to account for multiplicity, with two-sided tests at 0.05 
(Dmitrienko, 2013). 
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. 
8.3 
Statistical Analyses 
8.3.1 
Primary Efficacy Analysis - GST Score 
The primary efficacy hypothesis is that treatment with ATH-1017 40 mg/qd will result in a 
statistically significant reduction in the Global Statistical Test score (GST; O’Brien, 1984) 
compared to the placebo group at Week 26 in the primary analysis population (Section 8.1.3). 
The primary analysis will test the statistical null hypothesis of no difference between ATH-1017 
40 mg/qd and placebo. 
The primary analysis will use a mixed model for repeated measures (MMRM) to compare 
treatment and placebo in the GST score, which is a composite of cognition and function, 
calculated as the average of two change from baseline z-scores; the z-scores are calculated for 
the change from baseline scores for cognition (ADAS-Cog11) and function (ADCS-ADL23). 
This analysis will assess whether there is a difference in mean GST scores between treatment 
and placebo at 26 weeks using least squares means estimates from the MMRM model, which 
will include terms for baseline value, visit, treatment, visit by treatment interaction, ApoE4 
carrier status, pooled site as a factor (with geographically similar sites grouped and a group of 
sites using Spanish for clinical assessments), baseline age (continuous), and the baseline MMSE 
stratification factor. Least squares means and standard errors will be estimated from the MMRM 
model at Week 26. Further details relating to the primary analysis will be described in the SAP. 
Statistical testing to the key secondary efficacy endpoints only continues if the null hypothesis 
for the primary endpoint is rejected. 
8.3.2 
Key Secondary Efficacy Analysis – ADAS-Cog11, ADCS-ADL23, and Biomarkers 
(NfL) 
If the null hypothesis for GST score is rejected, then the key secondary endpoints of change from 
baseline in ADAS-Cog11 and ADCS-ADL23 will be analyzed (Refer to the SAP for details), 


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using an MMRM as described for the primary analysis. These individual endpoints will be tested 
using the Hochberg procedure. If both of these null hypotheses are also rejected after the 
Hochberg-based multiplicity adjustment, then the key secondary efficacy endpoint of change 
from baseline in NfL concentration will also be analyzed using an MMRM as described for the 
primary analysis.  
The statistical testing hierarchy for the study is presented in Figure 3. This strategy controls the 
overall Type I error rate for the primary and key secondary efficacy endpoints. 
Figure 3 
Hierarchical Statistical Gatekeeping Strategy 
 
ADAS-Cog11 = Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS-ADL23 = Alzheimer’s Disease 
Cooperative Study-Activities of Daily Living, 23-Item Version; GST = Global statistical test score; 
NfL = Neurofilament light chain. 
The null hypothesis of no effect is presented for each comparison of ATH-1017 40 mg/qd versus placebo as follows: 
H1 = GST score; H2 = ADAS-Cog11 score; H3 = ADCS-ADL23 score; H4 = NfL. 
 
 
 
 
 
 


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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 


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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 
• 
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 
12-Lead Electrocardiogram 
12-lead ECG data (observed and change from baseline) will be listed for each subject by visit. 
Observed values and change from baseline will be summarized descriptively.  
8.4.4 
Columbia-Suicide Severity Rating Scale 
Results from the C-SSRS questionnaire will be listed and summarized using descriptive statistics 
by treatment group and visit. 
8.4.5 
Geriatric Depression Scale 
Results from the GDS questionnaire will be listed and summarized using descriptive statistics by 
treatment group and visit. 
8.5 
Pharmacokinetic Analyses 
PK and pharmacogenetics analyses will be described in a separate document.  


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8.6 
Determination of Sample Size 
The sample size for the trial was chosen to provide 85% power for the primary endpoint. The 
following 40 mg/qd treatment effect premises were made to support sample size calculations: 
• 
Change from Baseline to Week 26 in ADAS-Cog11: Mean treatment difference (standard 
deviation): 1.8 (6). 
• 
Change from Baseline to Week 26 in ADCS-ADL23: Mean treatment difference 
(standard deviation): 2.7 (9). 
The sample size of 149 evaluable subjects (subjects in the primary analysis population) per trial 
arm would yield at least 85% power with a two-sided 0.05 level. The power calculations were 
performed using a simulation-based approach with 10,000 simulation runs based on the 
parameters listed above (in addition, it was assumed that the endpoint-specific statistics follow a 
multivariate normal distribution with a correlation coefficient of 0.5). Power was estimated as 
the fraction of the simulation runs where the primary endpoint was significant at a two-sided 
0.05 level. 
In view of the overall number of subjects already enrolled prior to version 7 of this protocol, 
including those receiving background AChEI therapy (200 subjects), and those already 
randomized to the 70 mg treatment group not receiving AChEI therapy (60 subjects), the 
maximum number of subjects to be enrolled would be approximately 558. 
8.7 
Interim Analysis 
An interim analysis was planned for this study to allow the possibility of stopping for futility, or 
to potentially increase sample size to achieve a target study power. The SSR procedure was 
based on the Promising Zone Design (Mehta and Pocock, 2011). The interim analysis included 
approximately the first 100 subjects not on background AChEIs who had completed the trial 
(either completion of Week 26 assessments or else terminated early). This corresponded to 
approximately a 45% information fraction, based on a planned final sample size of 
approximately 175 subjects not on background AChEIs. The futility stopping and SSR rules 
were based on the CP calculated for the primary efficacy endpoint (GST score), using a pooled 
analysis of the ATH-1017 cohorts versus the placebo cohort, at a one-sided 0.05 level. Subject 
enrollment proceeded without interruption while the interim analysis was ongoing.  
Detailed definitions of the zones, sample size increase rule within the promising zone and 
statistical methods used for the interim analysis were pre-specified in a separate iSAP prior to the 
actual interim analysis. An Independent Data Monitoring Committee (IDMC) reviewed the SSR 
report and provided an appropriate recommendation for a sample size increase from among 
several pre-specified options, which were each keyed to various potential CP results. The written 
recommendation was provided to the Sponsor for implementation of the new recommended 
sample size as described in the iSAP. The final analysis will apply the combination function 


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method (Cui-Hung-Wang method; Cui, 1999) to account for the sample size increase resulting 
from the interim, refer to the study SAP for details. 
The specific required sample size post-interim analysis recommended by IDMC was not 
communicated to staff involved in the day-to-day conduct of this clinical trial. 


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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, 
 
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 study site and the CRO/Sponsor is essential to ensure that 
the safety of the study is monitored adequately. The investigator will make all appropriate safety 
assessments on an ongoing basis. The Medical Monitor may review safety information as it 
becomes available throughout the study. 
All aspects of the study will be carefully monitored with respect to GCP and SOPs for 
compliance with applicable government regulations. The Study Monitor will be an authorized 
individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study 
with the Principal Investigator. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator at least 2 years after the last approval of a marketing application in 
an International Council for Harmonisation (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. No records 
may be destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 


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9.2 
Access to Source Data/Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
The investigator will ensure the accuracy, completeness and timeliness of the data reported to the 
Sponsor. Data reported or entered in the eCRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records. Also, current medical records 
must be available. 
Data collection processes and procedures will be reviewed and validated to ensure completeness, 
accuracy, reliability, and consistency. A complete audit trail will be maintained of all data 
changes. The investigator or designee will cooperate with the Sponsor’s representative(s) for the 
periodic review of study documents to ensure the accuracy and completeness of the data capture 
system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE, and concomitant medication reporting, raw data collection forms, 
as well as the results of diagnostic tests such as 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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McKhann, G.M., et al. (2011). The diagnosis of dementia due to Alzheimer’s disease: 
Recommendations from the National Institute on Aging – Alzheimer's Association workgroups 
on diagnostic guidelines for Alzheimer's disease. Alzheimer’s & Dementia: The Journal of the 
Alzheimer’s Association 7, 263 – 269. 
Mehta, C.R., and Pocock, S.J. (2011). Adaptive Increase in Sample Size when Interim Results 
are Promising: A Practical Guide with Examples. Statistics in Medicine 30(28): 3267-3284. 
Molnarfi, N., Benkhoucha, M., Funakoshi, H., Nakamura, T., and Lalive, P.H. (2015). 
Hepatocyte growth factor: A regulator of inflammation and autoimmunity. Autoimmun Rev 14, 
293–303. 
O’Brien, P.C. (1984). Procedures for comparing samples with multiple endpoints. Biometrics 40, 
1079-1087. 
Organ, S.L, Tsao, M-S. (2011). An overview of the c-MET signaling pathway. Ther Adv Med 
Oncol 3(1):S7-S19. 
Piguet et al. (2017) Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and 
Future. Human Gene Therapy 28(11):988-1003. 
Rosen WG, Mohs RC, Davis KL (1984). A new rating Scale for Alzheimer’s disease. Am J 
Psychiatry 141:1356–1364. 


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Clinical Study Protocol 
CONFIDENTIAL 
 
Version 8 
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21-MAR-2024 
 
Sano, M., et al. (1997). A controlled trial of selegiline, alpha-tocopherol, or both as treatment for 
Alzheimer's disease. New England Journal of Medicine 336(17), 1216-1222. 
 
 
 
Shang, J., et al. (2011). Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of 
hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. J. 
Neurosci. Res. 89, 86–95. 
Sheikh JI, Yesavage JA. (1986). Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontologist: The Journal of Aging and Mental 
Health, 5(1-2), 165–173. 
 
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. 
 
 
. 
 
 


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Version 8 
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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 (Namenda) in any form, combination 
or dosage 
Acetylcholinesterase inhibitors 
• Donepezil (Aricept) 
• Galantamine (Rasadyne) 
• Rivastigmine (Alzest, Exelon, Kerstipon, 
Nimvastid, Prometax) 
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 23c 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)  


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Category of Prohibited Medications 
Examples: General Name (Trade Name) 
• 
Risperidone (Risperdal)  
• 
Trimipramine (Surmontil) 
• 
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 
• Verapamil 


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

SAP_001.pdf: 
Statistical Analysis Plan: ATH-1017-AD-0201 
Study Title: 
A Randomized, Placebo-Controlled, Double-Blind Study of ATH-
Disease 
Study Number: 
ATH-1017-AD-0201 
Study Phase: 
Phase 2/3 
Sponsor: 
Athira Pharma, Inc. 
18706 North Creek Parkway 
Suite 104 
Bothell, WA 98011 
USA 
NCT #: 
NCT04488419 
Version: 
Final 1.1 
Date: 
13 August 2024 
 
Confidentiality Statement 
This document contains confidential and proprietary information, and is not to be distributed 
to any third party. 
 
 




 
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7.1.4 
Per Protocol Population ...............................................................................................19 
7.1.5 
Safety Population .........................................................................................................19 
 
 
8 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL .........20 
9 
OVERALL STATISTICAL CONSIDERATIONS ................................................................22 
9.1 
General Conventions ..........................................................................................................22 
9.2 
Baseline Definition ............................................................................................................22 
9.3 
Handling of Partial Dates ...................................................................................................22 
9.4 
Interim Analysis .................................................................................................................23 
9.5 
Pooling Strategy for Study Sites ........................................................................................23 
9.6 
Visit Windows/Unscheduled Visits ...................................................................................23 
9.7 
Determination of Participants on AChEIs .........................................................................25 
10 STATISTICAL ANALYSIS METHODS ..............................................................................26 
10.1 
Subject Disposition ............................................................................................................26 
10.2 
Demographics and Baseline Characteristics ......................................................................26 
10.3 
Medical History .................................................................................................................26 
10.4 
Prior and Concomitant Medications and Procedures .........................................................26 
10.5 
Treatment Compliance and Exposure ................................................................................27 
10.6 
Efficacy 
27 
10.6.1 
Primary Analysis ..........................................................................................................27 
10.6.1.1 
Primary Estimand...................................................................................................28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.6.6 
Pharmacokinetic Analyses ...........................................................................................36 
10.6.7 
Interim Analysis ...........................................................................................................36 
10.6.7.1 
Interim Analysis Rules ...........................................................................................36 
10.6.7.2 
Updated Primary Analysis Population ...................................................................36 
10.6.8 
Final Analysis Rules ....................................................................................................36 
10.7 
Safety and Tolerability .......................................................................................................37 
10.7.1 
Adverse Events ............................................................................................................37 


 
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10.7.2 
Clinical Laboratory ......................................................................................................38 
10.7.3 
Electrocardiograms ......................................................................................................39 
10.7.4 
Vital Signs ....................................................................................................................39 
10.7.5 
Physical and Neurological Examinations ....................................................................39 
10.7.6 
Columbia-Suicide Severity Rating Scale (C-SSRS). ...................................................39 
10.7.7 
Geriatric Depression Scale (GDS) ...............................................................................40 
10.8 
Pharmacokinetics/Pharmacodynamics ...............................................................................40 
10.9 
Other Relevant Data Analyses/Summaries ........................................................................40 
11 REFERENCES .......................................................................................................................41 
12 APPENDICES ........................................................................................................................43 
LIST OF TABLES 
Table 1 
Study Objectives and Associated Endpoints..........................................................11 
Table 2 
Futility and SSR rules at the interim analysis ........................................................36 
Table 3 
Imputation Rules for Partial Dates  AEs and Prior/Concomitant Medications ...50 
LIST OF FIGURES 
Figure 1 
Statistical Gatekeeping Strategy ............................................................................32 


 
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LIST OF APPENDICES 
APPENDIX 1 
DERIVATION OF GST SCORES. .................................................................44 
APPENDIX 2 
STATISTICAL METHODOLOGY AT THE FINAL ANALYSIS ...............46 
APPENDIX 3 
SCHEDULE OF ASSESSMENTS AND PROCEDURES .............................47 
APPENDIX 4 
IMPUTATION OF PARTIAL DATES ...........................................................50 
 
 
 
 
 
 
 
 
 


 
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2 SIGNATURE PAGE 
Study Title: 
A Randomized, Placebo-Controlled, Double-Blind Study of 
ATH-1017 Treatment in Subjects with Mild to Moderate 
 
Study Number: 
ATH-1017-AD-0201 
 
 
Prepared by:
Date: 
 
 
VP, Biometrics & Data Management 
Athira Pharma, Inc. 
 
 
Reviewed by:
Date: 
 
 
Associate Manager, Biostatistics 
MMS Holdings, Inc. 
 
 
 


 
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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
amyloid-  
AChEI 
acetylcholinesterase inhibitor 
AD 
 
AE 
adverse event 
AEC 
absolute eosinophil counts 
ADAS-Cog11 
-Cognitive Subscale 
ADCS-ADL23 
 Activities of Daily Living, 
23-item version 
ADCS-CGIC 
Alzheimer's Disease Cooperative Study  Clinical Global Impression of 
Change 
AIC 
Information Criteria 
ANOVA 
analysis of variance 
ApoE 
apolipoprotein E 
ATC 
anatomical therapeutic class 
BIC 
Bayesian Information Criteria 
BMI 
body mass index 
BP 
Blood pressure 
BPSD 
Behavioral and Psychological Signs of Dementia 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CDR 
Clinical Dementia Rating Scale 
CFB 
change from baseline 
CI 
confidence interval 
COWAT 
Controlled Oral Word Association Test 
CP 
conditional power 
CRF 
case report form 
CT 
Computed tomography 
DSMB 
Data Safety Monitoring Board 
ECG 
12-lead electrocardiogram 
EQ-5D-5L 
EuroQol Group 5-Dimension 5 Level Questionnaire 
FSH 
Follicle-Stimulating Hormone 
fT3 
Free Triiodothyronine 


 
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fT4 
Free Thyroxine 
GDS 
Geriatric Depression Scale 
GFAP 
glial fibrillary acidic protein 
GST 
Global Statistical Test 
HR 
Heart rate 
ICE 
intercurrent event 
ICF 
informed consent form 
IDMC 
Independent Data Monitoring Committee 
ISR 
injection site reaction 
ITT 
intent-to-treat 
LFT 
liver function test 
LLN 
lower limit of normal 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
Mixed Models for Repeated Measures 
MMSE 
Mini-Mental State Examination 
N/A 
Not Applicable 
NfL 
neurofilament light chain 
NIA-AA 
National Institute on Ageing  
 
NPI 
Neuropsychiatric Inventory 
p-tau 
phosphorylated tau 
OD 
once daily 
PK 
pharmacokinetic(s) 
PR 
interval from the P wave (atrial contraction or depolarization) to the onset 
of the Q wave in the measurement of electrical activity of the myocardium
PT 
preferred term 
QD 
once a day 
QRS 
Q wave, R wave, and S wave 
QTcB 
 
QTcF 
 


 
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RR interval 
the time elapsed between two successive R-waves of the QRS signal on 
the electrocardiogram 
RUD-Lite® 
Resource Utilization in Dementia lite version 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
SSR 
sample size re-estimation 
TEAE 
treatment-emergent adverse event 
TSH 
Thyroid-Stimulating Hormone 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
WHO 
World Health Organization 
ZBI 
Zarit Burden Interview 
 


 
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4 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the framework for the reporting, 
summarization and statistical analysis methodology of the safety and efficacy parameters 
measured throughout the study. It is based on Protocol v8.0 dated 21 Mar 2024. 






 
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Safety Objectives 
Safety Endpoints 
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) 
* The comparison between ATH-1017 40 mg and placebo in participants not on background AChEIs will serve 
as the primary efficacy comparison for the primary and key secondary endpoints. 
 
 
 
 
 


 
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6 STUDY DESIGN CONSIDERATIONS 
The study (ATH-1017-AD-0201) underwent several changes during conduct. The original high 
level study design is provided in Section 6.1 with key changes summarized in Section 6.1.1.  
Additional protocol changes are described in Section 8.  
6.1 
Original Study Design 
This study (ATH-1017-AD-0201) is designed to demonstrate efficacy in mild to moderate 
AD) participants and establish long-term safety information. Eligible 
participants will receive once daily (OD) subcutaneous (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. 
Participants who complete the double-blind study will have the option to roll over into a long-term 
(26-week) open-label extension study. 
This is a Phase 2/3 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 
participants 
 
according to National Institute on Ageing 
 
Association (NIA-AA) criteria 
(McKhann, 2011). The study will be conducted at a total of approximately 70 centers in the United 
States (US). Participants 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. 
Those who meet all inclusion/exclusion criteria will be randomized in a ratio of 1:1:1 to 3 parallel 
arms, either the active treatment (ATH-1017 40 mg/day or ATH-1017 70 mg/day) or to the placebo 
group. During randomization, participants will be stratified by screening Mini-Mental State 
Examination (MMSE) severity: mild (MMSE: 20-24) versus moderate (MMSE: 14-19). All 
eligible participants will be tested for apolipoprotein E (ApoE) genotype. 
6.1.1 
Changes to Original Study Design Important for this SAP 
Patients receiving background acetylcholinesterase inhibitors (AChEIs) were no longer enrolled 
following implementation of the protocol v5 amendment (13 September 2022). This amendment 
also enabled an interim analysis, as described in Section 9.4. The protocol was further amended 
(03 May 2023) to discontinue enrollment at 70 mg/day, and patients enrolling after implementation 
of this amendment will be randomized in a 1:1 ratio to the two remaining parallel arms, i.e., 
ATH-1017 40 mg/day or placebo. The open label extension study was lengthened to 30 months. 
Further information on protocol amendments relevant to this SAP are provided in Section 8. All 
of these changes, except for the sample size increase defined in the Interim Analysis SAP, were 
based on data external to the LIFT trial or blinded data. 
 
 
6.1.2 
Safety Review Committee/Data Monitoring Committee 
An independent Data Safety Monitoring Board (DSMB) is planned to conduct periodic review and 
assessments of unblinded safety data (adverse events [AEs], labs, 12-lead electrocardiogram 






 
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6.3.2.2 
 Activities of Daily Living, 23-item 
Version  
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 participant
 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 0-78, 
with lower scores indicating greater functional impairment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
 
  
  
 
 




 
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7 STUDY POPULATIONS 
7.1 
Analysis Populations 
7.1.1 
Intent-to-Treat (ITT) Population
The ITT population will consist of all randomized participants regardless of whether or not the 
participant received test article. A participant is considered randomized when the test article 
assignment (ie, completes a randomization transaction) is provided. No analyses are planned for 
the ITT population.  
7.1.2 
Modified Intent-to-Treat (mITT) Population 
The mITT population is a subset of the ITT population, which includes all randomized participants 
who took at least one dose of the study medication and who, during at least one post-baseline visit, 
completed both an ADAS-Cog11 and ADCS-ADL23 assessment, as well as at baseline. Analyses 
will be based on the randomized treatment assignment. 
7.1.3 
Primary Analysis Population  
The primary analysis population is comprised of all members of the mITT population who were 
not taking AChEIs < 28 days before the first dose of study drug and were randomized to either 
ATH-1017 40 mg or placebo. Primary analyses will be based on the randomized treatment 
assignment.  
7.1.4 
Per Protocol Population  
The per protocol population will include all randomized participants who took the assigned 
medication, completed both an ADAS-Cog11 and ADCS-ADL23 assessment during at least one 
post-baseline visit as well as at baseline, and did not have any major protocol deviations that are 
deemed to potentially interfere with efficacy as evaluated at a classification meeting prior to 
unblinding. Analyses will be based on the actual treatment received. 
7.1.5 
Safety Population  
The Safety population will include all randomized participants who received at least one dose of 
the study medication. Participants will be analyzed based on actual treatment received. 
 
 
 
 
  
 
 


 
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8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
The following 
 
ADCS-CGIC, as a component of the GST score, was replaced by ADCS-ADL23 
Patients receiving background AChEIs were no longer enrolled following implementation 
of the protocol v5 amendment (13 September 2022).  
Patient randomization in the ATH-1017 70 mg/day arm discontinued (amendment v7, 03 
May 2023). Moving forward, patients are randomized in a 1:1 ratio to the two remaining 
parallel arms, i.e., ATH-1017 40 mg/day or placebo, maintaining the same ratio between 
those two arms. The comparison between ATH-1017 40 mg and placebo in participants 
not on background AChEIs will serve as the primary efficacy comparison. The comparison 
between ATH-1017 70 mg and ATH-1017 40 mg, between ATH-1017 70 mg and placebo, 
and between pooled ATH-1017 and placebo will be treated as an exploratory comparison. 
The ADCS-ADL23 evaluation at Week 20 was added with protocol amendment v5 
(13 September 2022); this results in some designed missingness for the exploratory 
endpoints GST and ADCS-ADL23 at Week 20 
Samples for biomarker analysis at Week 12 were added with protocol v6 
(07 December 2022); this results in some designed missingness for the exploratory 
biomarker endpoints at Week 12. 
Samples for plasma biomarker analysis became mandatory with protocol amendment v7 
(May 2023). 
The efficacy evaluations will be performed at a two-sided 0.05 level at the final analysis, 
e.g., the overall Type I error rate for the analysis of the primary and key secondary 
endpoints will be controlled at a two-sided 0.05 level. 
NfL CFB to Week 26 has been included as a key secondary endpoint. 
The testing strategy for the primary and key secondary endpoints has been revised to 
include all primary and key secondary endpoints. The updated strategy is defined in 
Section 10.6. 
The final analysis methodology has been modified to apply the combination function 
approach at the final analysis regardless of the value of conditional power (CP) at the 
interim analysis. The updated methodology is defined in Section 10.6.  
Provided additional details and clarify on the following: 


 
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Visit windowing for GST score: Components will be visit windowed first and GST 
will be calculated only where ADAS-Cog11 and ADCS-ADL are available at the 
same visit window. 
ICE definition: Clarification with regards to how ICE-1 for lack of efficacy will be 
defined. 
GST score and ADCS-ADL analysis: Clarification that the analysis will not include 
Week 20 for those included in the interim analysis, since Week 20 was not collected 
prior to the interim analysis. 
Subgroup analysis: Cleaned up language to maintain consistency within the 
document about how to handle subgroup analysis (using the BY approach without 
subgroup by treatment interaction terms). 
Multiple imputations: Clarification of how the multiple imputations analysis for 
sensitivity analysis will be performed. 
Additional baseline characteristic for Years since diagnosis and calculation details 
Laboratory measurements (safety labs): The data handling for values above or 
below the limit of quantification was clarified. 
 


 
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9 OVERALL STATISTICAL CONSIDERATIONS 
9.1
General Conventions 
Efficacy and safety data may be summarized and presented by treatment group and time point 
(Visit) in summary tables. Continuous variables will be presented by descriptive statistics: n, mean, 
SD, median, minimum, and maximum. Categorical variables will be tabulated by frequency count 
and percentage. Unless otherwise stated, all statistical tests will be two-sided hypothesis tests 
performed at the 5% level of significance and all confidence intervals (CIs) will be two-sided 
95%CIs. The efficacy and baseline summary statistics tables, as described in Section 10.2, will 
include statistics for the difference vs placebo. 
Means, medians and percentiles will usually be displayed to one more decimal place than the 
reported data, dispersion statistics (e.g., SD) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. P-values will be quoted to 4 decimal places 
consistent with statistical analysis system (SAS) PVALUEw.d format set to PVALUE6.4. P-values 
< 0.0001 will be presented as p<0.0001. 
All data will be listed and patients who were not randomized will be displayed after the randomized 
treatment. 
All data will be analyzed using the SAS® Version 9.4 or later.   
9.2 
Baseline Definition 
For safety summaries, the last measurement prior to first dose is defined as the baseline value. 
GST score is a change score, and Appendix 1 describes calculation of a baseline GST value for 
the purpose of use as a covariate variable. 
 
 For all other efficacy measures, baseline is defined as either the 
measurement on Day 1, or else the last measurement before Day 1 if there is no Day 1 measurement. 
If no test article is received, baseline is defined as the value closest to but prior to randomization.  
In all cases, to capture necessary data for split visits, the baseline window will include the first 3 
days after randomization. Meaning, if there is missing data at the date of randomization but data 
captured one to 3 days after, those are to be considered the baseline values. Otherwise, missing 
baseline values will not be imputed. 
9.3 
Handling of Partial Dates 
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 


 
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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. Details on imputation of partial dates 
for AEs and prior/concomitant medications are available in Appendix 4. 
9.4 
Interim Analysis 
An adaptive design with a single interim analysis was employed in this trial. The interim analysis 
was performed after approximately 100 patients (about 45% of the enrollment which was planned 
at the time of the interim) completed the trial. 
participation in the trial, either due to early termination or completion of the Week 26 visit. The 
unblinded interim data were examined by an Independent Data Monitoring Committee (IDMC) to 
determine if the sample size in the trial needed to be increased if the original treatment effect 
assumptions were not aligned with the interim data. The IDMC recommended sample size was 
later superseded by a small additional sample size increase based on simulations, in view of both 
a revised statistical testing hierarchy (moving CFB NfL to last in the hierarchy), and no longer 
randomizing participants to 70 mg ATH-1017, as described in Section 6.2. 
9.5 
Pooling Strategy for Study Sites 
This schema is based on pooling geographically similar sites. The pooled site term (Region) shall 
be included as a fixed effect variable in the Mixed Models for Repeated Measures (MMRM) model.  
All sites who use Spanish data collection forms for assessments for any participants will comprise 
their own Region pool and not be included in the other Regions. 
 
 Analyses based on this SAP will comprise of all sites per 
pooled site. Post-hoc analyses may be produced excluding Spanish assessment sites.  
Sites in States (USA) 
Pooled Site (Region) 
FL, GA, NC, TN, AL, LA, MS 
SE 
OH, NM, CO, IL, IN, TX, MO 
MW 
NJ, NY, MA, ME, PA, RI, MD 
NE 
WA, CA, NV, OR, AZ, HI, UT 
W 
Spanish Assessment Site 
SP 
MW, Midwest; NE, Northeast; SE, Southeast; SP, Spanish Assessment Site; W, West 
9.6 
Visit Windows/Unscheduled Visits 
For listings, all timepoint (including unscheduled and early termination visits) will be included. 
For analyses that use visit categories (summary tables, figures, and statistical analysis), visit 
windowing will be applied. All visits (including early termination assessments and unscheduled 
visits) will be put in a visit window based on the number of days since Day 1 and will be used to 
identify visit categories. If there are multiple assessments that fall within the same visit window, 


 
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the scheduled visit will supersede other visits (that is, only the scheduled visit will be considered 
for analysis if assessed within the window). Otherwise, the visit closest to the scheduled post-
baseline visit will be used.  
The analysis visit windows for ADAS-Cog11
 will be followed as: 
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 
 
The analysis visit windows for C-SSRS, Physical and Neurological exams, ECG, Vital Signs, and 
safety labs will be followed as: 
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 
 
The analysis windows for GDS, Height, Weight will be followed as: 
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 
 
The analysis visit windows for ADCS-ADL23 will be followed as: 
Analysis Visit 
Protocol-Specified Day 
Analysis-Specified Interval 
Week 12 
Day 84 
Day 2-112 
Week 20 
Day 140 
Day 113-161 
Week 26 
Day 182 
Day 162-217 






 
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(therapeutic main group) and preferred term (PT). Listings of Prior and Concomitant Medications 
and Procedures will also be created. 
10.5 Treatment Compliance and Exposure 
A summary table will be provided for the Safety Population grouped by treatment group to 
summarize the duration of treatment, total injections received, average number of injections per 
week and compliance as reported on case report form (CRF). The count and percentage of 
participants with compliance below 80% and above 110% will be provided as an assessment of 
under/overdosing.  
10.6 Efficacy 
All statistical tests will be carried out using a two-sided 5% significance level and all comparisons 
between ATH-1017 and placebo will be reported with 95% CIs, unless otherwise stated. The 
comparison between ATH-1017 40 mg and placebo among participants not receiving AChEIs will 
serve as the primary efficacy comparison. The comparisons between ATH-1017 70 mg and 
placebo, between ATH-1017 70 mg and ATH-1017 40 mg, between ATH-1017 and placebo, and 
between pooled ATH-1017 and placebo will be treated as exploratory comparisons.  
 
 
. Due to the designed missingness of ADCS-ADL23 at Week 20, that visit may not be 
included in the MMRM primary analysis of GST score and ADCS-ADL23. 
 
 
10.6.1 
Primary Analysis 
The primary efficacy endpoint will be analyzed using a MMRM with the GST score (a composite 
of the CFB z-scores for the variables ADAS-Cog11 and ADCS-ADL23) as the outcome variable 
and the following fixed terms: baseline GST score, treatment arm, visit, treatment by visit 
interaction, ApoE4 carrier status, baseline age (continuous) and the baseline MMSE stratification 
factor. Study site pool (with sites grouped as described in Section 9.5) will also be included as a 
fixed effect factor. This will be performed for the primary analysis population. 
The correlations among repeated observations within a patient will be accounted for by specifying 
an unstructured covariance matrix. If this model fails to converge, the following covariance 
matrices may be evaluated in the following order to achieve model convergence: Heterogeneous 
Toeplitz, Toeplitz, first-order autoregressive, and compound symmetry. The objective is to achieve 
a covariance model with reasonable parsimony and without noteworthy model failure (this 
.  
The Kenward-Roger adjustment for the degrees of freedom will be applied. The least squares 
means and treatment differences will be estimated from the MMRM model. Appendix 2 describes 
how the p-value for evaluation of primary endpoint success will be derived. This involves the 
weighting of Wald statistics from two analyses performed on subsets of the primary analysis 
population: participants who were included in the interim analysis and those who were not. The 


 
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MMRM model used for those two subsets will use the same structure using the order as defined 
above for which both subsets converge. Further information on this may also be found in Section 
10.6.8. 
As noted in Section 10.6, the analysis for GST score for those included in the interim analysis will 
not include Week 20 (but will only include Weeks 12 and 26), since at the time of the interim 
analysis ADCS-ADL23 was not collected at Week 20. The analysis for GST for those not in the 
interim analysis will include Weeks 12, 20 and 26. 
As such, the p-value for GST score based on the weighted test statistics will also not be reported 
for Week 20, since the Week 20 results will not be available for those included in the interim 
analysis. 
 
10.6.1.1 Primary Estimand 
The primary estimand will be defined as follows: 
Treatment: Randomization to ATH-1017 or placebo. 
Population: Patients in the primary analysis population with mild to moderate AD defined 
by the protocol  inclusion/exclusion criteria.  
Patient-level outcome variable: The GST score, which is a composite of CFB 
components.  
Intercurrent events (ICEs): Two types of ICEs are defined below. 
Population-level summary measure: Between treatment group difference expressed in 
terms of the mean CFB at Week 26.  
 
The following ICEs will be defined for the primary estimand and analysis: 
ICE-1: Discontinuation of treatment due to (1) an AE or (2) lack of efficacy. This event (1) 
discontinuation/withdrawal, even if other reasons are selected. The (2) lack of efficacy will 
be determined via the 
discontinuation/withdrawal, even if other reasons are selected. 
ICE-2: Discontinuations due to other reasons other than (1) an AE or (2) lack of efficacy.  
A treatment policy strategy will be applied to both types of ICEs, i.e., all data observed up until 
the last day of Week 26 analysis window (Day 196) will be included in the analysis irrespective 


 
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of whether or not the ICE occurred without imputing missing outcomes, and the treatment effect 
will be evaluated using the model defined in Section 10.6.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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. 
 
 
 
 
 
 
 
 
 


 
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Figure 1 
Statistical Gatekeeping Strategy 
 
ADAS-Cog11, 
-Cognitive Subscale; ADCS-ADL23, 
Cooperative Study  Activities of Daily Living, 23-item version; GST, Global Statistical Test; NfL, 
neurofilament light chain 
The null hypothesis of no effect is presented for each comparison of ATH-1017 40 mg/qd versus placebo as follows: 
H1 = GST score; H2 = ADAS-Cog11 score; H3 = ADCS-ADL23 score; H4 = NfL 
 
Four null hypotheses of interest will be defined for the comparison of ATH-1017 40 mg versus 
placebo based on the key secondary endpoints and selected exploratory endpoints: 
: Null hypothesis of no difference between ATH-1017 40 mg vs placebo with respect to the 
GST score. 
: Null hypothesis of no difference between ATH-1017 40 mg vs placebo with respect to ADAS-
Cog11.  
: Null hypothesis of no difference between ATH-1017 40 mg vs placebo with respect to ADCS-
ADL23. 
: Null hypothesis of no difference between ATH-1017 40 mg vs placebo with respect to NfL. 
 


 
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The hypotheses will be grouped into three families: 
Family 1: Hypothesis 
. 
Family 2: Hypothesis 
 and 
. 
Family 3: Hypotheses 
. 
The families will be tested using a sequentially rejective approach starting with Family 1. The null 
hypotheses in Family 2 will be tested using the standard Hochberg test and the null hypothesis in 
Family 3 will be tested only if both null hypotheses are rejected in Family 2.   
As an illustration, consider the gatekeeping procedure that would have been applied to test the four 
hypotheses of interest if only the first source of multiplicity had been present in the trial.  Let 
 
through 
 denote the two-sided p-values for the four null hypotheses, respectively, let the two-
sided Type I error rate be denoted by 
  
The following testing algorithm would have been used in this case:  
Step 1. Let 
 and reject the hypothesis 
 if 
.  Proceed to Step 2 if the 
hypothesis is rejected. 
Step 2. Let 
 and apply the Hochberg test to the hypotheses 
 and 
, i.e., reject 
both hypotheses if the larger p-value is 
; otherwise reject the associated hypothesis if 
the smaller p-value is 
.  Proceed to Step 3 if 
 and 
 are both rejected. 
Step 3. Let 
 and reject the hypothesis 
 if 
. 
Since there are two sources of multiplicity in the trial, the gatekeeping procedure will be applied 
in conjunction with the combination function approach, see Section 10.6.8. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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The combination function approach will be applied in conjunction with the gatekeeping procedure 
defined in Section 10.6.3 to ensure that the overall Type I error rate is preserved at a two-sided 
0.05 level with respect to the two sources of multiplicity in the trial.  The two sources of 
multiplicity will be accounted for analogous to the method developed in Kordzakhia, 2018. The 
details of this method are presented in Appendix 2. This approach requires that the primary and 
key secondary endpoint analyses will be conducted for two sets of participants: participants in the 
primary analysis set who 1) were included in the interim analysis, and 2) were not included in the 
interim analysis. The Wald statistic from the first will receive weight square root of 0.45, and the 
Wald statistic from the second will receive weight square root of 0.55. The resulting test statistic 
will be evaluated as per asymptotic normality. 
10.7 Safety and Tolerability 
10.7.1 
Adverse Events 
AEs reported on CRFs will be coded into system organ classes and PTs using MedDRA v23.1 or 
later. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset date on or 
after the start of dosing. Any AEs that are not considered treatment-emergent will be provided in 
data listings only.  
All safety summaries will be based on the safety set. In addition, for selected safety summaries, 
the primary analysis set will be used, as specified in the Table of Contents for the Tables, Listings, 
and Figures. For each treatment group, AE incidence rates will be summarized with frequency and 
percentage by MedDRA system organ class (SOC) and PT, with all participants treated in that 
treatment group as the denominator, unless otherwise specified. In addition, TEAE incidence rates 
will also be summarized by severity grade and relationship to study drug. Treatment-related AEs 
are those judged by the Investigator to be at least related to the blinded study treatment. Participants 
with multiple occurrences of events will only be counted once at the maximum severity to study 
drug for each PT, SOC, and overall. The number and percentage of participants with the following 
TEAEs will be summarized: 
Overall summary of TEAEs:  participants experiencing at least one AE, any serious adverse event 
(SAE), any treatment-related AE, any treatment-related SAE, any discontinuations due to an AE, 
and any deaths 
TEAEs by SOC and PT  
TEAEs by SOC, PT, and maximum severity 
Drug-related TEAEs by SOC and PT  
Drug-related TEAEs by SOC, PT, and maximum severity   
TEAEs that led to study drug interruption by SOC and PT  
TEAEs that led to study drug discontinuation by SOC and PT  


 
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TEAEs that led to study drug discontinuation by SOC, PT, and maximum severity. 
Treatment-emergent SAEs by SOC and PT  
Treatment-emergent SAEs by SOC, PT, and maximum severity  
Drug-related Treatment-emergent SAEs by SOC and PT  
TEAEs that led to study discontinuation 
TEAEs leading to death 
Deaths and cause of death will be summarized. 
Most commonly reported TEAEs or treatment-emergent SAEs will be defined as an event of 
interest reported with a frequency of > 5% and >2% respectively per treatment group.   
Also, data listings by participant, treatment group, verbatim term, and PT for all these AEs will be 
created as appropriate. 
10.7.2 
Clinical Laboratory 
Continuous blood clinical laboratory analytes absolute values and CFB values will be summarized 
by analyte and visit using descriptive statistics (mean, median, SD, minimum, maximum, and 
number of participants). Categorical laboratory analytes, classified as normal or abnormal, will be 
summarized by analyte and visit using the number and percentage of participants in each category 
and in each treatment group. The denominators for calculating the percentages will be based on 
the number of participants 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 participants 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 participants with non-missing 
assessments for a particular analyte.   
Clinical laboratory results will be provided in data listings by participant, visit and analyte. 
Abnormal lab results (either below lower limit of normal [LLN] or above upper limit of normal 
[ULN]) will be provided in a separate listing by participant, center, analyte, treatment group and 
visit.  
Listings will be provided for clinical laboratory results for hematology, blood chemistry and 
urinalysis, and abnormal laboratory results. 


 
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Laboratory values that are below or above the limit of quantification will be handled as follows: 
Limit of quantification 
Values to use 
Below the limit of quantification 
Use the lower limit of quantification 
Above the limit of quantification 
Use the upper limit of quantification 
 
10.7.3 
Electrocardiograms 
ECG values and CFB values will be summarized by visit using descriptive statistics for (interval 
from the P wave [atrial contraction or depolarization] to the onset of the Q wave in the 
measurement of electrical activity of the myocardium [PR]) interval, QT interval, QT interval 
QTcB) interval, 
(QTcF) interval, 
the time elapsed between two successive R-waves of the QRS signal on the electrocardiogram (RR 
interval), mean heart rate, and Q wave, R wave, and S wave (QRS) duration. ECG abnormalities 
will be summarized as the count and percentage of participants 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 participants 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.  
10.7.4 
Vital Signs 
Each vital sign will be summarized by treatment and by visit, using descriptive statistics (mean, 
median, SD, minimum, maximum, and number of participants) 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 participant, treatment group, visit, and parameter.  
10.7.5 
Physical and Neurological Examinations 
Physical and neurological examination findings will be listed, and also summarized as the count 
and percentage of participants in each treatment group.  
10.7.6 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
Results from the C-SSRS questionnaire will be listed and summarized using descriptive statistics 
by treatment group and visit. Additionally, descriptive summaries will be provided for CFB values 
for each treatment by visit. 


 
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10.7.7 
Geriatric Depression Scale (GDS) 
Results from the GDS questionnaire total score will be listed and summarized using descriptive 
statistics by treatment group and visit. Additionally, descriptive summaries will be provided for 
CFB values for each treatment by visit. 
10.8 
 Pharmacokinetics/Pharmacodynamics 
These will be addressed in a SAP specific for PK analyses. 
10.9 
Other Relevant Data Analyses/Summaries 
N/A 


 
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11  REFERENCES 
  
 
 
Cui, L., Hung, H.M., Wang, S.J. (1999).  
Modification of sample size in group sequential clinical trials. Biometrics. 55, 853-857. 
Folstein M.F., Folstein S.E., McHugh P.R. (1975).  
-
clinician. J Psychiatric Research 12(3), 189-198. 
 
Galasko D., Bennett D., Sano M., Ernesto C., Thomas R., Grundman M., et al. (1997).  
Disorders, 11(S2), S33-S39. 
 
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. (1982). 
A new clinical scale for the staging of dementia. Br J Psychiatry 140, 566-572. 
 
Kordzakhia, G., Dmitrienko, A., Ishida, E. (2018).  
Mixture-based gatekeeping procedures in adaptive clinical trials. Journal of 
Biopharmaceutical Statistics. 28, 129-145. 
 
Lipkovich, I. and A. Dmitrienko (2014).  
            
 
             
-153. 
 
McKhann, G.M., et al. (2011).  
National Institute on Aging  Alzheimer's Association workgroups on diagnostic 
tion 7, 263-269. 
 
 
Procedures for comparing samples with multiple endpoints. Biometrics. 40, 1079-1087.  
 
Rosen WG, Mohs RC, Davis KL (1984).  
-1364. 
 
 


 
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S.P. Dickson, B. Haaland, C.H. Mallinckrodt, et al.  
            
-Making in Progressive Disease Studies,     
             J Prev Alz Dis 2024;3(11):529-536; http://dx.doi.org/10.14283/jpad.2024.64 
Wassmer, G., Brannath, W. (2016).  
Group Sequential and Confirmatory Adaptive Designs in Clinical Trials. New York: 
Springer. 
 
 
 
 
 


 
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12 APPENDICES 
 


 
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Appendix 1 Derivation of GST scores. 
A composite approach will be utilized to derive the GST score for each patient at each visit in 
order to support an overall assessment of disease based on the combination of the cognition and 
functional scores (z-score of CFB ADAS-Cog11 and z-score of CFB ADCS-ADL23 scores). 
The GST score follows the principles articulated in 
, using z-scores to achieve 
comparable scales for effect sizes (relative to the variation among participants for that measure) in 
the components of this composite score. For this trial, we will use the principle that for pooling 
used to estimate SD, one does not include participants in a pool if they have different values of a 
variable being tested; in this case we will not put participants in the same pool if they differ for 1) 
treatment arm, 2) AChEI usage, or 3) before protocol amendment v5 vs after protocol amendment 
v5. This results in 9 pools (each treatment arm +/-AChEI before/after protocol amendment v5, 
noting that there were no +AChEI participants after protocol amendment v5). This approach leads 
to the calculation of ADAS-Cog11 and ADCS-ADL23 z-scores and the resulting GST scores once, 
for all analyses of GST score, for each participant-visit combination
will use the overall visit mean (without regard to treatment arm, +/-AChEI usage, or before/after 
protocol amendment v5), and the nine pools just described for estimation of a pooled SD. 
In the development below, the notation includes a subscript for VISIT, and the algorithm is applied 
at each VISIT without consideration of the other VISITs. This means that each VISIT, an overall 
mean and pooled SD are calculated for both CFB ADAS-Cog11 and CFB ADCS-ADL23 for 
creating the z-scores. 
Note that a participant is only included in the overall mean and pooled SD at a particular VISIT if 
that participant has reported values for both CFB ADAS-Cog11 and CFB ADCS-ADL23 at that 
particular VISIT. 
In brief, for each VISIT, we calculate an overall mean and a pooled SD, where we include each 
participant who has values for both CFB ADAS-Cog11 and CFB ADCS-ADL23 at that VISIT; z-
scores are calculated for each participant at that VISIT for both CFB ADAS-Cog11 and CFB 
ADCS-ADL23 by subtracting the respective overall mean and then dividing by the respective 
overall pooled SD. 
The remainder of this Appendix is an exposition which details how this is done for the case of only 
two pools, noting that our specific use case does involve nine pools, and so for this study the 
natural extension of this example is required.  
The following notation will be used to compute the GST score. Let 
 and 
 denote the 
changes from baseline to the th visit for the th patient in the th trial arm (
 corresponds to 
placebo and 
 corresponds to the selected ATH-1017 arm, i.e., ATH-1017 40 mg or 
ATH-1017 70 mg) for CFB ADAS-Cog11 and CFB ADCS-ADL23, respectively. To simplify 
notation, it will be assumed that the number of patients in a trial arm does not depend on the visit, 
i.e., 
 patients in the placebo arm and 
 patients in the selected ATH-1017 arm at each visit.    




 
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Appendix 2 Statistical Methodology at the Final Analysis 
The following notation will be used to set up the decision rules for the final analysis. First, two 
trial stages are defined: 
Stage 1 is comprised of all patients included in the interim analysis database. 
Stage 2 is comprised of the remaining patients. 
Let 
 through 
 denote the two-sided p-values for the hypotheses of interest computed from the 
Stage 1 data and, similarly, let 
 through 
 denote the two-sided p-values for the hypotheses 
computed from the Stage 2 data. 
The final decision rules for the four null hypotheses will be defined in terms of the combination p-
values denoted by 
.  The combination p-value for the intersection hypothesis 
 is derived 
using CHW method, i.e., 
 
where 
 is the pre-specified weight, Z1 is the t test statistic using the pre-IA patients, Z2 is 
the t test statistic using the post-IA patients, and ZCHW is the weighted Z-score for the CHW method.  
A p-value is calculated from ZCHW based on a standard normal distribution. 
The resulting set of decision rules protects the overall Type I error rate at a two-sided 0.05 level 
with respect to both sources of multiplicity in the trial.  
 
 
 
 
 
 








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Appendix 4 Imputation of Partial Dates 
Table 3 
Imputation Rules for Partial Dates  AEs and Prior/Concomitant Medications 
Parameter 
Missing 
Additional Condition 
Imputation 
Start Date 
D only 
M and Y same as M and Y of first study 
drug dosing 
Date of first study drug dose 
 
M and/or Y not the same as M and Y of 
first study drug dosing 
First day of indicated month 
M and D 
Y same as Y of first study drug dosing 
Date of first study drug dose 
 
Y not the same as Y of first study drug 
dosing 
01 Jan of indicated year 
M, D, and Y 
none  date completely missing 
Date of first study drug dose 
End Date 
D only 
M and Y same as M and Y of last study 
date 
Date of last study date 
 
M and/or Y not the same as M and Y of 
last study drug dosing 
Last day of indicated month 
M and D 
Y same as Y of last study date 
Date of last study date 
 
Y not the same as Y of last study drug 
dosing 
31 Dec of indicated year 
M, D, and Y 
none  date completely missing 
AE or medication is ongoing 
D, day; AE, adverse event; M, month; Y, year 
Note: If the end date is complete and the imputed start date is after the end date, then the start data will be 
imputed using the end date. If the imputed end date is before the start date, then the imputed end date will 
be equal to the start date.