Clinical trial NCT03022799
Conditions: Parkinson's Disease
Keywords: FAF1 Fas (TNFRSF6)-associated factor 1 FAF1 inhibitor KM-819
Sponsor: Kainos Medicine Inc.
Start date: 2016-11-01; Completion date: 2017-11-01
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This first in human, single-center, randomized, placebo-controlled, double blind, sequential group Phase 1 study in healthy subjects will be conducted to evaluate the safety, tolerability, PK, and PD following the escalation of single and multiple doses of KM-819.

The study will consist of 2 parts. In Part A, up to 5 cohorts of young adult male subjects, and 1 single dose cohort of elderly male or post menopausal female subjects will receive escalating single doses of KM-819. In Part B, up to 4 cohorts of healthy young adult male subjects and 1 multiple dose cohort of elderly male or post menopausal female subjects will receive escalating multiple doses of KM-819. Part B will be conducted after completion of all cohorts of young adult male subjects in Part A.

Dose escalation to the next level will be determined using safety, tolerability, and PK data of the previous cohort.

Part A, Single Ascending Dose (SAD) Up to 40 healthy young adult male subjects and 8 healthy elderly male or post menopausal female subjects will be enrolled and randomized to receive either KM-819 or placebo.

Each of the 5 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will receive 10, 30, 100, 200, or 400 mg of KM-819 and 2 subjects will receive placebo. In each single dose cohort, dosing of subjects will be sentinel, i.e., 2 subjects will be dosed on the first day (1 subject will receive active treatment and 1 subject will receive placebo) and the remaining 6 subjects will be dosed at least 24 hours after the first 2 subjects.

Cohorts will be dosed sequentially with escalating doses. Eight elderly male or post-menopausal female subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 and 2 subjects will receive placebo.

Part A consists of a Screening period of up to 28 days, and a 3 day Confinement period when subjects are hospitalized for study activities. Subjects are required to return for outpatient visits on Day 4, 7 and for the Follow up Visit on Day 14.

Part B, Multiple Ascending Dose (MAD) Up to 32 healthy young adult male subjects and 8 healthy elderly male or post menopausal female subjects will be enrolled and randomized to receive either KM-819 or placebo.

Each of the 4 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will receive 30, 100, 200, or 400 mg of KM-819 once a day (QD) for 7 days and 2 subjects will receive placebo. Cohorts will be dosed sequentially with escalating doses.

Eight elderly male or post-menopausal female subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 QD for 7 days and 2 subjects will receive placebo.

Detailed description:

Arms: arm 1: Each cohort consists of 8 subjects; 6 subjects will receive planned dose of KM-819 and 2 subjects will receive placebo. arm 2: Each cohort consists of 8 subjects; 6 subjects will receive planned dose of KM-819 and 2 subjects will receive placebo.
Interventions: intervention 1: KM-819 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
SAP_002.pdf: 
PAREXEL International 
Statistical Analysis Plan 
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14/Nov/2017 
TP-EP.BS-WW-001-05  
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Related to:  SOP-EP.BS-WW-002 
 
Page 1 of 61 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
KMCP-819-K101 
 
A First-in-Human, Randomized, Double-blind, Dose Escalation Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics Following Single and Multiple Oral 
Doses of KM-819 in Healthy Young Adult and Elderly Subjects 
 
 
 
 
 
Version:  Final 1.0 
Date: 14/Nov/2017 


PAREXEL International 
Statistical Analysis Plan 
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TP-EP.BS-WW-001-05  
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Related to:  SOP-EP.BS-WW-002 
 
Page 2 of 61 
 
 
REVISION HISTORY 
Version 
Version Date 
Author 
Summary of Changes Made 
Final 1.0 
14-Nov-2017 
Sampath Kalluri 
New Document 
 
 


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SIGNATURE PAGE - KAINOS MEDICINE, INC. 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this clinical study, as 
presented in this document. 
 
 
 
 
 
 
Jae Moon Lee 
 
Date (DD Mmm YY) 
VP 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SIGNATURE PAGE - PAREXEL 
Declaration 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
If this document has been signed electronically, signature(s) and date(s) are present at the end of the 
document: 
Document prepared and approved by: 
 
 
 
 
 
 
Sampath Kalluri 
 
Date (DD Mmm YY) 
Senior Biostatistician 
 
 
 
Document prepared and approved by: 
 
 
 
 
 
 
Joseph Kim  
 
Date (DD Mmm YY) 
QCD Senior Director 
 
 
 


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TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 2 
SIGNATURE PAGE - KAINOS MEDICINE, INC. ...................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF TABLES .......................................................................................................................... 7 
ABBREVIATION AND ACRONYM LIST .................................................................................. 8 
STATISTICAL ANALYSIS PLAN ............................................................................................. 10 
1. 
STUDY OBJECTIVES.................................................................................................... 11 
1.1 
Primary Objective ............................................................................................... 11 
1.2 
Secondary Objective ........................................................................................... 11 
2. 
STUDY DESIGN ............................................................................................................ 11 
3. 
STUDY POPULATION .................................................................................................. 17 
4. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 17 
5. 
RANDOMIZATION ....................................................................................................... 18 
6. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 18 
6.1 
Analysis Variables .............................................................................................. 18 
6.1.1 
Demographic and Background Variables ........................................................18 
6.1.2 
Safety Variables ..............................................................................................19 
6.1.2.1 
Adverse Events ................................................................................19 
6.1.2.2 
Clinical Laboratory Tests .................................................................19 
6.1.2.3 
Vital Signs ........................................................................................20 
6.1.2.4 
Electrocardiograms ..........................................................................20 
6.1.2.5 
Physical Examination .......................................................................21 
6.1.2.6 
Concomitant Medication ..................................................................22 
6.1.3 
Pharmacokinetic Variables ..............................................................................22 
6.1.3.1 
Pharmacokinetic Parameter Calculation Methods ...........................25 
6.1.4 
Pharmacodynamic Variables ...........................................................................27 
6.1.5 
Efficacy Variables ...........................................................................................28 
6.2 
Analysis Populations .......................................................................................... 28 
6.2.1 
Safety Population ............................................................................................28 
6.2.2 
Pharmacokinetic Population ............................................................................28 
6.2.3 
Pharmacodynamic Population .........................................................................29 
6.3 
Statistical Analysis Methods .............................................................................. 29 
6.3.1 
Listings and Descriptive Statistics ..................................................................29 
6.3.2 
Statistical Significance Level ..........................................................................30 
6.3.3 
Software ..........................................................................................................30 
6.3.4 
Missing Data ...................................................................................................30 
6.3.5 
Interim Analysis ..............................................................................................33 


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6.3.6 
Protocol Deviations .........................................................................................33 
6.3.7 
Demographic Data ...........................................................................................34 
6.3.8 
Subject Disposition .........................................................................................35 
6.3.9 
Medical History ...............................................................................................36 
6.3.10 
Concomitant Medication .................................................................................36 
6.3.11 
Exposure to the Investigational Medicinal Product .........................................37 
6.3.12 
Pharmacokinetic Concentrations and Variables ..............................................37 
6.3.12.1 Presentation of PK Data, Descriptive Statistics and PK Assessment38 
6.3.12.2 Handling of Values Below the Limit of Quantification (BLQ) in 
Concentration Summaries and Listings ...........................................39 
Handling of values below the limit of quantification (BLQ) in listings and for 
the calculation of descriptive statistics at each time point: ..............39 
6.3.12.3 Assessment of Dose Proportionality ................................................40 
6.3.12.4 Time Invariance (Part B Only).........................................................41 
6.3.12.5 Steady State Assessment (Part B Only) ...........................................41 
6.3.13 
Pharmacodynamic Variables ...........................................................................42 
6.3.13.1 Statistical Analysis (Pharmcodynamic Analysis) ............................43 
6.3.14 
Pharmacokinetic/Pharmacodynamic Analysis ................................................43 
6.3.15 
Safety Analysis ................................................................................................44 
6.3.15.1 Adverse Events ................................................................................44 
6.3.15.2 Clinical Safety Laboratory Tests (hematology, biochemistry and 
urinalysis) .........................................................................................45 
6.3.15.3 Vital Signs ........................................................................................46 
6.3.15.4 Twelve-Lead Electrocardiogram ......................................................46 
6.3.15.5 Physical Examination .......................................................................47 
7. 
REFERENCES ................................................................................................................ 48 
8. 
TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF THE CLINICAL 
STUDY REPORT ............................................................................................................ 49 
9. 
FIGURES ......................................................................................................................... 53 
10. 
LISTINGS TO BE INCLUDED IN SECTION 16 OF THE CLINICAL STUDY REPORT
 ......................................................................................................................................... 56 
11. 
DOCUMENTATION OF STATISTICAL METHODS.................................................. 61 
 
 
 


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LIST OF TABLES 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration .............................. 23 
Table 2 
Pharmacokinetic Parameters after Multiple Dose Administration ........................... 24 
 
 
 


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ABBREVIATION AND ACRONYM LIST  
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration-time curve 
AUC(0-inf)  
AUC from time zero extrapolated to infinity 
AUClast  
AUC from time zero to the last quantifiable concentration 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
Bpm 
Beats per minute 
CI 
Confidence interval 
CL/F 
Apparent clearance following oral administration 
CSF 
Cerebrospinal Fluid 
CSP 
Clinical Study Protocol 
CSSRS  
Columbia Suicide Severity Rating Scale 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration in the dosing interval 
CS 
Clinically significant 
Ctrough 
Concentration immediately prior to dosing 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IMP 
Investigational Medicinal Product 
K-WAIS-IV 
Korean Wechsler Adult Intelligence Scale-IV 
LLOQ 
Lower limit of quantification 


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Abbreviation / Acronym 
Definition / Expansion 
MAD 
Multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
NK 
Not known 
PD 
Pharmacodynamic 
PDAS 
Pharmacodynamic analysis set 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
POMS 
Profile of Mood States 
Rac 
Accumulation ratio 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation or single dose 
SE 
Standard error of the mean 
SOC 
System Organ Class 
t½ 
Apparent terminal elimination half-life  
tlast 
Time of last quantifiable concentration 
TEAE 
Treatment-emergent adverse event 
tmax 
Time corresponding to occurrence of Cmax 
VAS 
Visual Analogue Scale 
Vz/F 
Apparent volume of distribution during terminal phase 
WHO-DD 
World Health Organisation - Drug Dictionary 
λz 
Terminal elimination rate constant 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation 
 
 
 
 


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STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing study 
data and outlines the statistical programming specifications for the Tables, Listings and Figures (TLFs). 
It describes the variables and populations, anticipated data transformations and manipulations and other 
details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described are based on the final CSP 5.0, dated, 13/Feb/2017. The SAP will be finalized 
prior to database lock and describes the statistical analysis as it is foreseen when the study is being 
planned. If circumstances should arise during the study rendering this analysis inappropriate, or if 
improved methods of analysis should arise, updates to the analyses may be made. Any deviations from 
the SAP after database lock, reasons for such deviations and all alternative or additional statistical 
analyses that may be performed, will be described in a SAP Addendum. 
 
 


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1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
• To evaluate the safety and tolerability of single and multiple ascending oral doses of KM-819 in 
healthy young adult male subjects.  
1.2 
Secondary Objective 
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple 
ascending oral doses of KM-819 in healthy young adult male subjects. 
• To evaluate the safety and tolerability of single and multiple oral doses of KM-819 in elderly 
male or post-menopausal female subjects. 
• To evaluate the PK and PD of single and multiple oral doses of KM-819 in elderly male or post-
menopausal female subjects. 
2. STUDY DESIGN 
This is a first-in-human, single-center, randomized, placebo-controlled, double-blind, sequential group 
Phase 1 study in healthy subjects. The aim of this study is to evaluate the safety, tolerability, PK, and 
PD following the escalation of single and multiple doses of KM-819. The study will consist of 2 parts 
(Part A and Part B). 
 
Part A Single Ascending Dose (SAD): 
This part includes up to 5 cohorts of healthy young adult male subjects receiving single ascending 
doses (SAD)s of KM-819, and 1 additional single-dose cohort of elderly male or post-menopausal 
female subjects.  
Up to 40 healthy young adult male subjects and 8 healthy elderly male or post-menopausal female 
subjects will be enrolled and randomized to receive either KM-819 or placebo. 
 Each of the 5 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will 
receive single dose of 10 mg (1 x 10 mg tablet), 30 mg (2 x 10 mg tablet),, 100 mg (1 x 100 mg tablet),, 


PAREXEL International 
Statistical Analysis Plan 
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14/Nov/2017 
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Related to:  SOP-EP.BS-WW-002 
 
Page 12 of 61 
200 mg (2 x 100 mg tablet),, or 400 mg (4 x 100 mg tablet) KM-819 and 2 subjects will receive 
placebo. 
Cohorts will be dosed sequentially with escalating doses, escalation to the next dose level will take 
place only after the safety, tolerability data, and available PK data from the previously treated dose 
cohort has been reviewed; see Section 3.4 of CSP for dose escalation criteria. In each of the 5 single 
dose cohorts, dosing of subjects will be sentinel, i.e., 2 subjects will be dosed on the first day (1 subject 
will receive active treatment and 1 subject will receive placebo) and the remaining 6 subjects will be 
dosed at least 24 hours after the first 2 subjects 
After completion of the 5 dose escalation cohorts, 8 elderly male or post-menopausal female subjects 
will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 and 2 subjects will 
receive placebo. 
 
 
All subjects will undergo a Screening period of up to 28 days and a 3-day Confinement period when 
they are hospitalized for study activities (Day -1 to Day 3). Subjects are required to return for 
outpatient visits on Day 4, Day 7, and for Follow-up Visit on Day 14.  
Table 1 
Dose Groups for Part A 
KM-819 
Dose (mg) 
Subjects on 
KM-819 (n) 
Subjects on 
Placebo (n) 
Total Subjects 
in Group (n) 
Age Group 
10†  
6 
2 
8 
Young adult male subjects  
30†  
6 
2 
8 
100†  
6 
2 
8 
200†  
6 
2 
8 
400†  
6 
2 
8 
200 
6 
2 
8 
Elderly male or post-menopausal female 
subjects  
† Doses between the current planned range may be assigned or a dose may be repeated depending on safety, tolerability, 
and pharmacokinetic data from previous subjects and cohorts.  


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Figure 1 
Part A SAD study design
 
Part B, Multiple Ascending Dose (MAD): 
This part includes up to 4 cohorts of healthy young adult male subjects receiving multiple ascending 
doses (MAD)s of KM-819, and 1 additional multiple-dose cohort of elderly male or post-menopausal 
female subjects.  
It includes Up to 32 healthy young adult male subjects and 8 healthy elderly male or post-menopausal 
female subjects will be enrolled and randomized to receive either KM-819 or placebo. Each of the 4 
dose escalation cohorts will consist of 8 healthy young adult male subjects; 6 subjects will receive 30 
mg (3 x 10 mg tablet), 100 mg (1 x 100 mg tablet), 200 mg (2 x 100 mg tablet), or 400 mg (4 x 100 mg 
tablet) of KM-819 once a day (QD) for 7 days and 2 subjects will receive placebo. Cohorts will be 
dosed sequentially with escalating doses.  
After completion of the 4 dose escalation cohorts, 8 elderly male or post-menopausal female subjects 
will be enrolled into an additional cohort; 6 subjects will receive KM-819 at a dose level not exceeding 
the highest dose tested in the young adult male cohorts and 2 subjects will receive placebo. The dose 
level will be decided by Investigator and Sponsor. 
 
 


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All subjects will undergo a Screening period of up to 28 days and an 8-day Confinement period when 
they are hospitalized for study activities (Day -1 to Day 8). Subjects are required to return for a Follow-
up Visit on Day 14. 
Figure 3 
Part B MAD study design 
 
 
 
Table 2 
Dose Groups for Part B 
KM-819 
Dose (mg) 
Subjects on 
KM-819 (n) 
Subjects on 
Placebo (n) 
Total Subjects 
in Group (n) 
Age Group 
30†  
6 
2 
8 
Young adult male subjects  
100†  
6 
2 
8 
200†  
6 
2 
8 
400†  
6 
2 
8 
200 
6 
2 
8 
Elderly male or post-menopausal female 
subjects  
† Doses between the current planned range may be assigned depending on safety, tolerability, and pharmacokinetic data 
from previous subjects and cohorts. 


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Criteria for Evaluation of the Study  
 
The study involves safety, PK, and PD assessments. The specific endpoints are listed below.  
 
• Safety Endpoints  
Parts A and B: 
1. Reporting AEs (nature, frequency, severity, time of onset/offset)  
2. Standard clinical laboratory evaluations  
3. Vital signs measurements (tympanic temperature, supine pulse, and supine BP)  
4. 12-lead ECGs  
 
• Pharmacokinetic Endpoints  
Plasma PK parameters for KM-819 include the following for single dose and/or multiple dose analysis 
as appropriate:  
Single Dose, Day 1 of multiple doses: 
1. AUC(0-24): area under the plasma concentration-time from predose (time 0) to 24hrs post dose 
2. AUClast: area under the plasma concentration-time from predose (time 0) to the last 
quantifiable concentration  
3. AUCinf: area under the plasma concentration-time curve from predose (time 0) extrapolated to 
infinity  
4. AUCinf (%extrap): Percentage of AUCinf that is due to extrapolation beyond tlast (%AUCex) 
5. CL/F: apparent oral clearance  
6. Cmax: maximum plasma concentration determined directly from the concentration-time profile  
7. λz: terminal elimination rate constant  
8. t1/2: apparent terminal elimination half-life  
9. tlag: lag time  
10. tmax: time to achieve maximum observed plasma concentration determined directly from the 
concentration-time profile  
11. Vz/F: volume of distribution  


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12. Other parameters, as appropriate, including dose-adjusted parameters (AUC_D_obs, 
AUClast_D, Cmax_D).  
Day 7 of multiple doses: 
 
1. AUCtau: area under the plasma concentration-time curve for a dosing interval  
2. AUClast: area under the plasma concentration-time from predose (time 0) to the last 
quantifiable concentration  
3. CL/F: apparent oral clearance  
4. Cmax: maximum plasma concentration determined directly from the concentration-time profile  
5. Cmin: minimum plasma concentration determined directly from the concentration-time profile  
6. Ctrough: observed plasma concentration before dosing  
7. Rac (AUC): observed accumulation by AUC  
8. Rac (Cmax): observed accumulation by Cmax  
9. tlag: lag time  
10. tmax: time to achieve maximum observed plasma concentration determined directly from the 
concentration-time profile  
11. Vz/F: volume of distribution  
12. Other parameters, as appropriate, including dose-adjusted parameters (AUCtau_D, AUClast_D, 
Cmax_D). 
Cerebrospinal fluid (CSF) PK parameter for KM-819 includes the following after multiple dose CSF 
sample collection:  
1. KM-819 concentration in CSF  
• Pharmacodynamic Endpoints  
In both Parts A and B, mean and absolute value change from baseline at each post-baseline 
measurements for:  
1. Bond and Lader Visual Analogue Scale (VAS)  


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2. Profile of Mood States (POMS)  
3. Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV)  
4. C-SSRS  
In Part B only, PD parameters in plasma and CSF including:  
1. alpha synuclein oligomer  
2. total Tau  
3. phospho-Tau 
4. Ratio of CSF concentration/Plasma Cmax  
3. STUDY POPULATION 
The study population will consist of for Parts A up to 40 and for Part B up to 32 healthy young adult 
male (19 to 45 years old) or healthy elderly male or post-menopausal female (over 60 years old). 
subjects. 
For further details of inclusion and exclusion criteria please refer to the sections 4.1 and 4.2 of the CSP. 
4. STATISTICAL BASIS FOR SAMPLE SIZE 
It is planned to recruit in total 72 healthy young adult subjects and 16 healthy elderly subjects at one 
center in this study.  
Part A: up to 40 healthy young adult male and 8 healthy elderly male or post-menopausal female 
subjects will be enrolled. 
Part B: up to 32 healthy young adult male and 8 healthy elderly male or post-menopausal female 
subjects will be enrolled. 
The sample size of 8 subjects each cohort in both parts is standard in first-in-human study for dose 
escalation. The number of subjects planned for both parts of this study is considered sufficient to 
achieve the study objectives (safety, tolerability, PK, and PD). 


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5. RANDOMIZATION 
In each dose cohort, 8 subjects will be randomized to have 6 subjects receiving KM-819 and 2 subjects 
receiving placebo in both Part A and Part B. 
For further details of randomization scheme please refer the section 4.5.2 and 4.5.3 of the CSP. 
6. STATISTICAL ANALYSIS CONVENTIONS 
6.1 
Analysis Variables 
6.1.1 
Demographic and Background Variables 
The following demography information will be collected at Visit 1:  
• Date of informed consent 
• 
Medical history (including previous and current medical conditions and medications) 
• 
Age  
• 
Sex 
• 
Race 
• 
Ethnicity 
The following body measurements will be performed at Visit 1: 
• 
Height (cm) 
• 
Body weight (kg) 
• 
Body mass index (BMI)  
All medical history will be coded using Version 19.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA). 


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6.1.2 
Safety Variables  
6.1.2.1 
Adverse Events 
An adverse event is any untoward medical occurrence that occurs in a subject or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the product.  
All AEs will be coded using the latest available version 19.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in severity 
after at least one dose of the study drug has been administered. 
Any AEs with incomplete start and end dates/times will be treated as follows: 
• 
Adverse events with unknown start and/or end times (but where the date is known) will be imputed 
with a time of 00:00 h for the tabulations but will be shown as NK:NK in the listings (where NK = 
Not Known). 
• 
Adverse events with completely unknown start dates will be considered as treatment-emergent for 
the tabulations and will be shown as NK in the listings. 
6.1.2.2 
Clinical Laboratory Tests 
The following safety laboratory parameters will be measured at the time points mentioned in the table 
of assessments in the CSP section 7. 
• 
Clinical chemistry: albumin, creatinine, glucose, urea, uric acid, TBIL, total protein, triglycerides 
(TG), total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein 
(HDL) cholesterol. 
• 
Hematology: erythrocytes, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, 
hemoglobin, and hematocrit.  
• 
Urinalysis: pH, protein, glucose, ketone, bilirubin, blood, and nitrite.  


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• 
Serological marker: Hepatitis B surface antigen (HbsAg), Anti-Hepatitis A Virus Immunoglobulin 
M (HAV IgM), Anti-Hepatitis C Virus (HCV Ab) and Anti-Human immunodeficiency virus (HIV 
Ab). 
• 
Urine Drug and cotinine screening, alcohol breath test: Amphetamines, Barbiturates, 
Benzodiazepines, Cannabinoids, Cocaine, Opiates, Cotinine, and Alcohol. 
• 
Electrolytes: sodium, potassium, calcium, and chloride.  
• 
Liver enzymes: alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT).  
Clinical significance of out-of-range laboratory findings is to be determined and documented by the 
Investigator/sub-Investigator who is a qualified physician. Clinically relevant changes will be recorded 
as AEs in the eCRF (see Section 6.4.1.2 of CSP).  
For safety laboratory tests, the total volume of blood drawn will be approximately 51 mL for subject in 
Part A SAD, and approximately 51 mL for subject in Part B MAD. Additional safety samples may be 
collected if clinically indicated at the discretion of the investigator. 
6.1.2.3 
Vital Signs 
The following vital signs measurements will be obtained at the time points mentioned in the table of 
assessments in the CSP section 7 (Table 7-1 and Table 7-3). 
• 
Blood Pressure (BP), supine (systolic and diastolic; mmHg)  
• 
Pulse, supine (beats per minute)  
• 
Body temperature (°C) (tympanic)  
BP and pulse will be measured using the normal practice at study center; after the subject has been in a 
supine position for at least 5 minutes.  
6.1.2.4 
Electrocardiograms  
The following electrocardiogram (ECG) parameters will be recorded at the time points mentioned in 
the table of assessments in the CSP section 7 (Table 7-1 to Table 7-3). 
ECG will be performed using an internationally recognized 12-lead cardiograph (10 sec. rhythm strip) 
after the subject has been resting in a supine position for 5 minutes. All records will be done in 


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triplicate within 5 minutes, with at least a 1-minute interval. ECG printouts will include: date, time, at 
least 2-3 complexes for 12 leads data,  
• Heart rate (HR) (beats per minute [bpm]) 
• 
QRS-duration (msec) 
• 
PR (PQ)-interval (msec) 
• 
RR-interval (msec) 
• 
QT-interval (msec) 
• 
QTcF (QT interval corrected for HR according to Fridericia) (msec)  
Where QTcF is calculated using QTcF=QT x R-R1/3  
The review of the ECG must be done by the Investigator or delegate. The interpretation of the ECG 
result must follow the categories: “normal”, “abnormal, not clinically significant”, or “abnormal, 
clinically significant”. Clinically significant findings must be recorded as AEs, or if present at 
Screening, it should be documented as concomitant illness (see Section 6.4.1 of CSP).  
6.1.2.5 
Physical Examination 
The following physical examination parameters will be recorded at the time points mentioned in the 
table of assessments in the CSP section 7. 
The examinations will include:  
• 
General appearance  
• 
Head, ears, eyes, nose, throat, neck   
• 
Lymph node palpation  
• 
Abdomen  
• 
Skin  
• 
Extremities  
• 
Respiratory system  
• 
Cardiovascular system  
• 
Gastrointestinal system  


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• 
Musculoskeletal system  
• 
Central and peripheral nervous system  
If the subject experiences any changes during the visits which fulfill the criteria of an AE it must be 
recorded as such (see Section 6.4.1 of CSP). 
6.1.2.6 
Concomitant Medication 
Concomitant medication will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) (Version WHO-DD March 2016) and will be classified by Anatomical Therapeutic Chemical 
(ATC) categories. 
Any medication that the subject takes other than the study drug, including herbal and other non-
traditional remedies, is considered a concomitant medication. Prior concomitant medications are 
defined as those taken from Screening until the time of the first study drug administration. Concomitant 
medications are defined as those taken at the time of or after the first study drug administration.  
Concomitant medication will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) (Version WHO-DD March 2016) and will be classified by Anatomical Therapeutic Chemical 
(ATC) categories. 
6.1.3 
Pharmacokinetic Variables 
Unless otherwise stated, derivation of pharmacokinetic (PK) parameters will be the responsibility of 
Quantitative Clinical Development (QCD), PAREXEL International.  The following PK parameters 
will be determined for KM-819 in plasma following single dose administration: 


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Table 1 
Pharmacokinetic Parameters after Single Dose Administration (Part A) 
Parameter 
Definition 
Cmax 
Maximum plasma concentration determined directly from the concentration-time 
profile 
tmax 
Time to achieve maximum observed plasma concentration determined directly 
from the concentration-time profile 
t½ 
Apparent terminal elimination half life 
Tlag 
Lag time 
λz 
Terminal elimination rate constant 
AUClast 
Area under the plasma concentration-time from predose (time 0) to the last 
quantifiable concentration 
AUCinf 
Area under the plasma concentration-time curve from predose (time 0) 
extrapolated to infinity 
AUC(0-24) 
Area under the plasma concentration-time from predose (time 0) to 24hrs postdose 
%AUCex 
Percentage of AUCinf that is due to extrapolation beyond tlast 
CL/F* 
Apparent oral clearance 
Vz/F* 
Apparent volume of distribution 
AUCINF_D_obs 
AUCinf divided by dose 
AUClast_D 
AUClast divided by dose 
Cmax_D 
Maximum observed concentration divided by dose 
*Parent drug only 
This Table is applicable for Single ascending dose (Part A) and Day1 of Multiple ascending dose (Part 
B). 


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Table 2 
Pharmacokinetic Parameters after Multiple Dose Administration 
Parameter 
Definition 
Ctrough 
Observed concentration before dosing 
Cmaxs 
Maximum plasma concentration determined directly from the concentration-
time profile 
Cmin 
Minimum plasma concentration determined directly from the concentration-
time profile 
tmax 
Time to achieve maximum observed plasma concentration determined directly 
from the concentration-time profile 
Tlag 
Lag time 
AUCtau 
Area under the plasma concentration-time curve for a dosing interval 
AUClast 
Area under the plasma concentration-time from predose (time 0) to the last 
quantifiable concentration 
CL/F* 
Apparent oral clearance 
Vz /F* 
Apparent volume of distribution 
Cav,ss 
Average concentration at steady-state 
Rac(AUC) 
Observed accumulation by AUC 
Rac (Cmax)  
Observed accumulation by Cmax 
AUCtau_D 
AUCtau divided by dose,  
AUClast_D  
AUClast divided by dose 
Cmax_D 
Maximum observed concentration divided by dose 
 
 
*Parent drug only 
This Table is applicable for Day7 of Multiple ascending dose (Part B). 
 
All urine voided will be collected in the following intervals: pre-dose and 0-24 hours post-dose.  Urine 
samples will be used for qualitative analysis of KM-819 and possible metabolic profiling, if 
appropriate, and will be reported separately. For cerebrospinal fluid (CSF) PK, the concentration of 
KM-819 will be listed and no other PK parameters will be calculated as there will be only one sample 
from each subject. 


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6.1.3.1 
Pharmacokinetic Parameter Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the concentration-time 
data using WinNonlin (WNL) Professional (Version 6.3 or higher) following these guidelines: 
• Actual sampling times relative to dosing rather than nominal times will be used in the 
calculation of all derived PK parameters. 
• There will be no imputation of missing data.  
• Any subjects with more than one observed concentration data will be included in the PK 
analysis set provided that at least Cmax and AUC(0-t) can be reliably calculated . 
• If one or more non-quantifiable (NQ) values occur in a profile before the first measurable 
concentration, they will be assigned a value of zero concentration. If a single NQ value occurs 
between measurable concentrations in a profile, the NQ should generally be omitted (set to 
missing) in the derivation of pharmacokinetic parameters, statistical analysis, and the 
individual subject plots. If two or more NQ values occur in succession between measurable 
concentrations, the profile will be deemed to have terminated at the last measurable 
concentration prior to these NQs. For the purpose of individual subject plots, these NQs will be 
set to 0, and the subsequent measurable concentrations will be retained. For the derivation of 
pharmacokinetic parameters, these NQs and any subsequent measurable concentrations will be 
omitted (set to missing). 
• PK parameters following single and repeat dose will be estimated according to the following 
guidelines: 
 
• 
Cmax will be obtained directly from the concentration-time data. 
• 
tmax is the time at which Cmax is observed. 
• 
λZ will be estimated at terminal phase by linear regression after log-transformation of the 
concentrations: 
− Only those data points that are judged to describe the terminal log-linear decline will be used in 
the regression.  


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− A minimum number of three data points in the terminal phase will be used in calculating λz with 
the line of regression starting at any post-Cmax data point (Cmax should not be part of the 
regression slope) and including Clast. 
− The duration of time over which λz is estimated should generally be at least twice the 
subsequently estimated terminal phase half-life (t ½); exceptions to this duration made at the 
discretions of the PK scientist 
− The adjusted correlation coefficient (R2 adjusted) in general should be greater than 0.90. Any 
value less than 0.90 may be used at the PK Scientist’s best knowledge and judgment. 
− An appropriate number of decimal places should be used for λz to enable the reported value of 
t½ to be calculated. 
• 
t1/2 will be calculated as ln2/λZ. 
• 
AUC is calculated as follows: 
− The linear trapezoidal method will be employed for all incremental trapezoids arising from 
increasing concentrations and the logarithmic trapezoidal method will be used for those arising 
from decreasing concentrations. 
− AUC(0-t)=∫
 t
0
dt
t
C
)
(
. (AUCtau for repeat dose) 
− AUC(0-inf) =∫
 t
0
dt
t
C
)
(
＋∫
∞
t
dt
t
C
)
(
= AUC(0-t)＋Ct/λz. (single dose only) 
− Ct is last observed quantifiable concentration. 
• 
%AUCex will be calculated as (1－[AUC(0-t)/AUC(0-inf)] )×100. 
• 
CL/F will be calculated as dose/AUC(0-inf), parent drug only. 
• 
Vz/F will be calculated as CL/F/λZ, parent drug only. 
The following PK parameters will also be derived using SAS 
 (version 9.2) or WinNonlin (WNL) Professional (Version 6.3 or higher) as deemed appropriate. 
• 
Rac 
 
Accumulation ratio calculated as: 
Cmax (last dose interval)/ Cmax (first dose interval). 
AUC(0-τ) (last dose interval)/ AUC(0-τ) (first dose interval). 


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6.1.4 
Pharmacodynamic Variables 
The pharmacodynamic parameters will be recorded at the time points mentioned in the table of 
assessments in the CSP section 7. 
In both Parts A and B, mean and absolute value change from baseline at each post-baseline 
measurements for 
Bond and Lader Visual Analogue Scale (VAS)  
The Bond-Lader VAS will be used to rate subjects’ feelings in terms of 16 dimensions. The dimensions 
will be presented as 100 mm lines, the 2 extremes of the emotion (i.e., 'alert' and 'drowsy') written at 
each end, and subjects will be asked to record their current state on each line.  
The Bond-Lader VAS will be analyzed using 3 factor scores: alertness, contentedness, and calmness. 
Calculation of these 3 scores is based on the main factors resulting from statistical factor analysis. A 
high score indicates impairment.  
1. Alertness (9 subscales): [Q1 + Q3 + (100 – Q4) + Q5 + (100 – Q6) + (100 – Q9) + Q11 + (100 
– Q12) + Q15] / 9  
2. Contentedness (5 subscales): [Q7 + (100 – Q8) + Q13 + (100 – Q14) + (100 – Q16)] / 5  
3. Calmness (2 subscales): [Q2 + (100 – Q10)] / 2  
Profile of Mood States (POMS): 
POMS will be used to describe subjects’ feelings with a questionnaire containing 65 words/statements. 
Feelings will be scored using different statement: "Not at All", "A Little", "Moderately", "Quite a lot", 
and "Extremely". 
Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV): 
The K-WAIS-IV consists of an assessment of the cognitive ability using a core battery of 10 unique 
subtests (Block Design, Similarities, Digit Span, Matrix Reasoning, Vocabulary, Arithmetic, Symbol 
Search, Visual Puzzles, Information, and Coding) that focus on four specific domains of intelligence: 
verbal comprehension, perceptual reasoning, working memory, and processing speed. 
 
 


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Columbia Suicide Severity Rating Scale (C-SSRS):  
The C-SSRS is a scale that captures the occurrence, severity and frequency of suicide-related thoughts 
and behaviors during the assessment period. The scale includes suggested questions to solicit the type 
of information needed to determine if a suicide-related thought or behavior occurred. The C-SSRS 
must be administered by appropriately trained site personnel. The C-SSRS will be administered at the 
times specified in Schedule of Procedures 
In Part B only, PD parameters in plasma and CSF including:  
• 
alpha synuclein oligomer  
• 
total Tau  
• 
phospho-Tau  and   
• 
ratio of CSF concentration/Plasma Cmax  
6.1.5 
Efficacy Variables 
Efficacy will not be tested in this study. 
6.2 
Analysis Populations 
6.2.1 
Safety Population 
The safety analysis set (SAF) will be the primary analysis set for all safety displays and consists of all 
subjects who received at least one dose. 
6.2.2 
Pharmacokinetic Population 
The pharmacokinetic analysis set (PKAS) will be the primary analysis set for all PK displays and 
analyses, consists of all subjects from the SAF for whom sufficient plasma concentration data are 
available to facilitate the calculation of at least one PK parameter, had no important protocol deviations 
affecting the PK variables, as confirmed during a pre-analysis review of the data prior to database lock. 
Data may/will be excluded (depending on the protocol and compound under study) from PK analysis 
(concentrations listed only) if any of the following criteria are fulfilled: 
− Concomitant medication, which could render the plasma concentration-time profile unreliable  


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− The pre-dose concentration is greater than 5% of the corresponding Cmax in any given treatment 
period (single dose cohort only). 
− Subject vomits within 2 x the reported median Tmax for the analyte (oral studies only). 
− Subject has moderate or severe diarrhea within 2 x the reported median tmax for the analyte (oral 
studies only). 
Any data excluded will be discussed in the CSR. Subjects who receive placebo will not be part of the 
PK analysis set. 
6.2.3 
Pharmacodynamic Population 
The PD analysis set (PDAS) consists of all subjects from the SAF for whom sufficient data for 
neuropsychologic testing (Parts A and B) or plasma and CSF concentration data are available (Part B) 
to facilitate the calculation of at least one PD parameter and had no important protocol deviations 
affecting the PD analysis, as confirmed during a pre-analysis review of the data prior to database lock.  
6.3 
Statistical Analysis Methods 
6.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed and described 
using summary statistics. Frequency counts (number of subjects [n] and percentages) will be made for 
each qualitative variable. Descriptive statistics (n, mean, standard deviation [SD], median, minimum 
and maximum) will be calculated for each quantitative variable (unless otherwise stated). All listings 
will include repeated and unscheduled measurements. 
Study Part A and Part B will be analyzed separately. For each part Tables, listings and figures will be 
generated separately. 
The following rules will apply to any repeated measurements: 
• 
If the repeated measurement occurs prior to study drug administration (in each treatment period if 
applicable) then the last obtained value (or last obtained set of triplicate measurements) prior to 
dosing will be used in the descriptive statistics and in the calculation of changes from baseline (for 
results measured in triplicate the mean of the triplicates will be used in the calculation of changes 
from baseline).  


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• 
If the repeated measurement occurs after study drug administration (in each treatment period if 
applicable) then the first (non-missing) value of any repeated measurements (or first set of triplicate 
measurements) will be used in the descriptive statistics and in the calculation of changes from 
baseline (for results measured in triplicate the mean of the triplicates will be used in the calculation 
of changes from baseline).  
• 
If not otherwise specified, baseline refers to the last scheduled measurement (or mean of the set of 
triplicate measurements) before study drug administration (using the rules described above for 
repeated measurements).  
All descriptive statistics will be presented by cohorts (dose). Subjects receiving placebo within each 
cohort will be presented as pooled treatment group.  
All descriptive statistics will be presented by cohorts for measurements obtained during each treatment 
period. Descriptive statistics for all data obtained at Screening and follow-up will be presented. 
6.3.2 
Statistical Significance Level 
All statistical tests will be two-sided and will be performed at the 5% level of significance, unless 
otherwise stated. 
6.3.3 
Software 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9.2 or 
later. The PK analysis will be performed using WinNonlin Professional Software Version 6.3. 
6.3.4 
Missing Data 
Any AEs with unknown severity or causality will be considered as ‘severe’ and ‘related’ respectively, 
for the tabulations. The unknown severity or causality without imputation will be presented in listings. 
AEs with missing dates/times will be handled as described below. The incomplete dates/times without 
imputation will be presented in listings. 
Concomitant medications (CMs) with missing times will be handled as described below. The 
incomplete times without imputation will be presented in listings. 
All other data will be analyzed and reported as observed. No imputation schemes for other missing 
values will be applied. 


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Handling of AEs with Missing Dates/Times 
 
Any AEs with incomplete start and or end dates/times will be handled as described below for the 
classification as treatment-emergent, assignment to treatment periods and calculation of duration. 
• Adverse events with unknown start times, but with start date known, will be imputed with a 
time of 00:00 hours, unless the start date corresponds to any given dosing date, in this case the 
start time will be imputed with the time of dosing. If this results in a start date/time after end 
date/time of the AE then the start time will also be imputed with 00:00 hours. 
• Adverse events with completely unknown start dates will be imputed with the date and time of 
first IMP administration, unless the end date is known and prior to first administration of IMP, 
then the start date will be imputed as the date of screening and a time of 00:00 hours. 
• Adverse events with completely unknown end times, will be imputed with an end time of 23:59 
hours; 
• Adverse events with completely unknown end dates will be imputed with the date of final FU 
(or date of discontinuation in the case of withdrawals).  
Adverse events with partially known start dates will be treated as follows: 
• If only the day is missing, then the day will be imputed with the first day of the month, unless 
the month and year in which the AE started is a month and year in which IMP was 
administered, then the day will be imputed with the first day on which IMP was administered in 
that month. If this results in a start date after end date then the day will be imputed with the first 
day of the month. 
• If both the day and month is missing and the year is a year in which IMP was administered then 
the day and month will be imputed with the day and month of first IMP administration. If this 
results in a start date after end date then the day and month will be imputed with 01JAN. If the 
year is not a year in which IMP was administered then the day and month will also be imputed 
with 01JAN. 
• If only the year is missing then the year will be imputed with the year of first IMP 
administration. 


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Adverse events with partially known end dates will be treated as follows: 
• If only the day is missing, then the day will be imputed with the last day of the month, or date 
of final FU/early discontinuation if this is earlier.  
• If the day and month is missing then the end date will be imputed as 31 December, or date of 
final FU/early discontinuation if this is earlier. 
Handling of CMs with Missing Dates/Times 
Any CMs with incomplete start and or end dates/times will be handled as described below for the 
classification as concomitant medication, assignment to treatment periods and calculation of duration. 
• Concomitant medications with unknown start times, but with start date known, will be imputed 
with a time of 00:00 hours, unless the start date corresponds to any given dosing date, in this 
case the start time will be imputed with the time of dosing. If this results in a start date/time 
after end date/time of the CM then the start time will also be imputed with 00:00 hours. 
• Concomitant medications with completely unknown start dates will be imputed with the date 
and time of first IMP administration, unless the end date is known and prior to first 
administration of IMP, then the start date will be imputed as the date of screening and a time of 
00:00 hours. 
• Concomitant medications with completely unknown end times will be imputed with an end time 
of 23:59 hours. 
• Concomitant medications with completely unknown end dates will be imputed with the date of 
final FU (or date of discontinuation in the case of withdrawals). 
Concomitant medications with partially known start dates will be treated as follows: 
• If only the day is missing, then the day will be imputed with the first day of the month, unless 
the month and year in which the CM started is a month and year in which IMP was 
administered, then the day will be imputed with the first day on which IMP was administered in 
that month. If this results in a start date after end date then the day will be imputed with the first 
day of the month. 


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•  If both the day and month is missing and the year is a year in which IMP was administered then 
the day and month will be imputed with the day and month of first IMP administration. If this 
results in a start date after end date then the day and month will be imputed with 01JAN. If the 
year is not a year in which IMP was administered then the day and month will also be imputed 
with 01JAN. 
• If only the year is missing then the year will be imputed with the year of first IMP 
administration. 
Concomitant medications with partially known end dates will be treated as follows: 
• If only the day is missing, then the day will be imputed with the last day of the month, or date 
of final FU/early discontinuation if this is earlier. 
• If the day and month is missing then the end date will be imputed as 31 December, or date of 
final FU/early discontinuation if this is earlier. 
6.3.5 
Interim Analysis 
No formal interim analysis is planned.  
6.3.6 
Protocol Deviations 
Major protocol deviations will be defined at the data review meeting (DRM). Subjects with major 
protocol deviations might be excluded from the Pharmacokinetic population.  
All protocol deviations will be recorded by the Investigator and will be listed by subject with each 
study part, by cohort. All protocol deviations will be discussed between PAREXEL and the Sponsor 
during the data review meeting before database lock in order to determine whether these may warrant 
exclusion of a subject from the statistical analyses. 
Protocol deviations will be presented using the safety population.  
All protocol deviations will be listed [Listing 16.2.2.1 (Part A) and Listing 16.2.2.2 (Part B)] by study 
part and cohort will include, the subject number, actual study day (if applicable), visit, time point, 
date/time, and a description of the deviation and classification (major or minor).  


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Protocol deviations will be summarized [Table 14.1.3.1 (Part A) and Table 14.1.3.2 (Part B)] by 
treatment period for each study part for the subjects in the safety population. 
Major protocol deviations will include the following: 
• Deviation from the inclusion and exclusion criteria 
• Deviation from study medication compliance in terms of medical conditions and/or AEs that 
may have interfered with drug absorption or with respect to factors likely to affect the primary 
endpoints 
• Deviation from study procedure compliance; Non-compliance to study procedures or deviations 
from study procedures likely to affect the primary endpoints. 
Time window deviations for PK blood sampling and safety or exploratory assessments will also be 
listed as protocol deviations. Tolerance windows for safety, PK blood sampling and exploratory 
assessments (when applicable) are provided in the final Windows Allowance Agreement (WAA). 
6.3.7 
Demographic Data 
All demographic data will be listed and summarized using the safety population. 
Demographic characteristics will be tabulated [Table 14.1.2.1 (Part A) and Table 14.1.2.2 (Part B)] 
within each study part, and by cohort (n, mean, standard deviation, minimum and maximum for age, 
height, weight and BMI; and frequency counts and percentages for sex, race and ethnicity). 
Demographic characteristics will be listed [Listing 16.2.4.1.1 (Part A) and Listing 16.2.4.1.2 (Part B)] 
by subject within each study part, and by cohort and will include subject number, age (years), gender, 
race, ethnicity, height (cm), weight (kg) and BMI (kg/m2). 
Informed consent [Listing 16.2.1.2.1 (Part A) and Listing 16.2.1.2.2 (Part B)], study visits [Listing 
16.2.1.3.1 (Part A) and Listing 16.2.1.3.1 (Part B)], Failed Inclusion and exclusion criteria will be listed 
[Listing 16.2.1.4.1 (Part A) Listing 16.2.1.4.2 (Part B)] and Assignment to Analysis Populations 
[Listing 16.2.3.1 (Part A) and Listing 16.2.3.2 (Part A)]. 


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6.3.8 
Subject Disposition 
Subject disposition will be tabulated [Table 14.1.1.1 (Part A) and Table 14.1.1.2 (Part B)] within each 
study part, and by cohort including number and percentage of dosed, withdrawn and completed 
subjects and primary reason for discontinuation. 
Subject disposition will be listed [16.2.1.1.1 (Part A) and Listing 16.2.1.1.2 (Part B)] within each study 
part, and by cohort and will include the following information:  Subject Number,  
Primary 
Reason for Withdrawal, AE number,  
Date of Last Drug Administration,  Date 
of 
Completion/Early termination,  
Date of Final Contact with subject, Subject status at the time of 
completion, Blind Broken (Yes/No), Date/Time of Blind and Reason Broken Blind. 
Subject disposition will be summarized for each treatment and overall including the number of subjects 
randomised, number and percentage of subjects dosed, number and percentage of discontinued subjects 
and primary reason for discontinuation* [Table 14.1.1.1 (Part A) and Table 14.1.1.2 (Part B)]. This will 
be done for subjects in the safety population. 
*The primary reason for discontinuation will be documented as one of the following: 
• ECG abnormalities (any increases in QTcF > 500 msec or increase > 60 msec from baseline as 
confirmed with 3 consecutive ECGs taken within 5 minutes, with at least a 1-minute interval) 
• Suicidality (any suicide attempt or any recent suicidal ideation (a level of 4 or 5) since the last 
assessment, or a significant risk to commit suicide, as judged by the PI using the CSSRS) 
• Liver Safety monitoring 
• After enrollment, the subject is found to violate the inclusion/or exclusion criteria 
• Adverse event 
• Subject lost to follow-up 
• Major protocol violation 
• Use of prohibited medications 
• Any serious safety concern 
• Premature termination of the study 


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• Death 
• Other 
6.3.9 
Medical History 
Medical history will be coded using Version 19.1 of the Medical Dictionary for Regulatory Activities 
(MedDRA).   
Medical history will be summarized [Table 14.1.4.1 (Part A) and Table 14.1.4.2 (Part B)] by overall 
within study part by cohort using safety population. 
Medical history will be listed [Listing 16.2.4.2.1 (Part A) and Listing 16.2.4.2.2 (Part B)] by study part, 
and will include subject Number, Medical History Number, Description of Disease/Procedure, 
MedDRA Preferred Term, MedDRA System Organ Class, Start Date/Study day, Stop Date, Status, 
Medication Taken, and Concomitant medication number. 
6.3.10 
Concomitant Medication 
Prior and concomitant medication will be coded according to the latest available version of the World 
Health Organization’s Drug Dictionary (WHO-DD) and the Anatomical Therapeutic Chemical (ATC) 
classification system.  
Summary tables will be provided for prior medications and significant nondrug therapies significant 
nondrug therapies within each study part, and by cohort [Table 14.1.5.1 (Part A) and Table 14.1.5.2 
(Part B)] for the safety population. Summary tables will be provided for concomitant medications and 
significant nondrug therapies within each study part, and by cohort [Table 14.1.6.1 (Part A) and Table 
14.1.6.2 (Part B)] for the safety population. 
Prior and concomitant medication will be listed [Listing 16.2.4.3.1 (Part A) and Listing 16.2.4.3.2 (Part 
B)  ] by subject within each study part, by cohort, and will include, at least, the following information: 
Product/s (study drug), medication/generic name (trade name), dose (and dose units), frequency, route 
of administration, start date/study day, end date/end date, duration, indication and origin (medical 
history or AE). Duration of concomitant medication will be calculated and included in the listing. The 
duration of prior or concomitant medications will be calculated based on the start and end dates. 
Duration of medication administration will not be calculated for concomitant medications with start 
date and/ or end date missed. 


PAREXEL International 
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6.3.11 
Exposure to the Investigational Medicinal Product 
Exposure to study drug will be listed [Listing 16.2.5.1.1 (Part A) and Listing 16.2.5.1.2 (Part B)] by 
subject within each study part and will include: Subject Number, Time Point, Treatment Received, 
Date/Time of Administration, Dose (unit), Partial Dose Taken and Comments.  
6.3.12 
Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the Pharmacokinetic Population (see section 6.2.3). 
Concentrations below the (LLOQ) will be indicated by BLQ in the listings.  
Pharmacokinetic concentration data will be listed [Listing 16.2.6.1.1 (Part A) and Listing 16.2.6.1.2 
(Part B) ] by subject including actual sampling times relative to dosing. Plasma concentrations will be 
summarized [Table 14.2.1.1 (Part A) and Table 14.2.1.2 (Part B)] within each part, by cohorts and 
nominal time point  The following descriptive statistics will be presented for plasma concentrations 
obtained at each nominal time point: n, arithmetic mean, SD, 95% CI of Arithmetic mean, coefficient 
of variation (CV%), geometric mean, 95% CI of Geometric mean, geometric SD, SD on log scale 
(SD(log)), geometric CV% (calculated as:  gCV% =SQRT(es²-1)*100; where s is the standard deviation 
of the log-transformed values), median, minimum and maximum values. 
Pharmacokinetic parameters will be listed [Listing 16.2.6.2.1 (Part A) and Listing 16.2.6.2.2 (Part B)]  
by subject and summarized [Table 14.2.2.1 (Part A) and Table 14.2.2.2 (Part B)] within each study 
part, and by cohorts,  nominal timepoint. Descriptive statistics for calculated PK parameters will 
include: n, arithmetic mean, SD, 95% CI of Arithmetic mean, coefficient of variation (CV%), 
geometric mean, 95% CI of Geometric mean geometric SD, SD on log scale (SD (log)), geometric 
CV%. No descriptive statistics will be determined when fewer than three individual PK parameters are 
available. 
Individual plasma concentration versus actual times will be plotted by cohorts of SAD [Figure 
14.2.1.1.1 (Part A) and Figure 14.2.1.2.1 (Part A)] and MAD [Figure 14.2.1.1.2 (Part B) and Figure 
14.2.1.2.2 (Part B)]  parts including elderly male or post-menopausal females cohort for KM-819 in 
linear and semi-logarithmic scale.  
Arithmetic (+/-SD)  mean and geometric mean plasma concentrations versus nominal times will also be 
presented in linear-linear scale of SAD [Figure 14.2.2.1.1 (Part A) and Figure 14.2.3.1.1 (Part A)], 
MAD [Figure 14.2.2.1.2 (Part B) and Figure 14.2.3.1.2 (Part B)] and young vs. elderly male or post-


PAREXEL International 
Statistical Analysis Plan 
Kainos Medicine, Inc. 
 
Final 1.0 
KMCP-819-K101 
 
14/Nov/2017 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 38 of 61 
menopausal females cohorts [Figure 14.2.2.2.1(Part A), Figure 14.2.2.2.2 (Part B) and Figure 
14.2.3.2.1 (Part A), Figure 14.2.3.2.2 (Part B) ]). 
 Median plasma concentrations versus nominal times will also be presented in linear-linear scale (single 
ascending dose [Figure 14.2.4.1.1 (Part A)], multiple ascending dose [Figure 14.2.4.1.2 (Part B)] and 
young vs. elderly male or post-menopausal females cohorts [Figure 14.2.4.2.1 (Part A) , Figure 
14.2.4.2.2  (Part B)].  
All Single dose cohorts will be overlaid on the same plot. Similar plots will be generated for multiple 
dosing and young vs. elderly male or and post-menopausal females cohorts. 
Individual urine concentration for SAD will be presented by cohort and subject [Listing 16.2.6.4 (Part 
A)]. 
 
6.3.12.1 
Presentation of PK Data, Descriptive Statistics and PK Assessment 
The following rules will be followed with regards to the number of decimal places and presentation of 
data in the tables and listings of concentration data: 
• The individual concentrations will be reported to the same precision as the source data (for 
example, if the source data is presented to five significant digits, the individual values will be 
presented to five significant digits). 
• The arithmetic mean, median, standard deviation (SD), geometric mean, geometric SD will be 
tabulated to one more significant digit compared to the source data, but with a maximum of four 
significant digits.  
• Minimum and maximum values will be tabulated to the same precision as the source data, but 
with a maximum of four significant digits. 
• 95% CI of Arithmetic mean and 95% CI of Geometric mean will be presented to two decimal 
places. 
• Coefficient of variation (CV%) and geometric CV% will be presented to one decimal place. 
The following rules will be followed with regards to the number of decimal places and presentation of 
data in the tables and listings of PK parameters: 


PAREXEL International 
Statistical Analysis Plan 
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• Individual PK parameters will be presented to four significant digits, with the exception of 
tmax, which will be presented to two decimal places.  In addition, parameters directly derived 
from source data (e.g. Cmax,) shall be reported with the same precision as the source data (if 
this is not four significant digits). 
• The arithmetic mean, median, standard deviation (SD), geometric mean, geometric SD will be 
reported to four significant digits, all other descriptive statistics will be reported to three 
significant digits except, coefficient of variation (CV%) and geometric CV% which will be 
presented to one decimal place. 
• For tmax the minimum and maximum will be presented to two decimals places and the rest of 
the descriptive statistics to three decimal places. 
• P-values will be presented to four decimal places. 
• Estimates and confidence intervals (95% CI of Arithmetic mean and 95% CI of Geometric 
mean) in the form of percentages will be presented to two decimal places.  
• Source data shall be used in all derived PK parameter calculations without prior rounding. 
6.3.12.2 
Handling of Values Below the Limit of Quantification (BLQ) in Concentration Summaries 
and Listings 
Graphical presentation: 
For graphs of arithmetic means all BLQ mean concentrations will be substituted by zeros.  Graphs of 
geometric means include only time points with minimum concentration greater than zero. Any 
arithmetic mean that is BLQ will be excluded from log/linear presentation of arithmetic means. Any 
BLQ values prior to the last quantifiable concentration will be plotted at zero for individual 
linear/linear graphs and excluded from log/linear graphs. All BLQ values after the last quantifiable 
concentration will be excluded from individual linear/linear and log/linear graphs.  
Handling of values below the limit of quantification (BLQ) in listings and for the calculation of descriptive 
statistics at each time point: 
All concentrations below the limit of quantification (BLQ) or missing data will be labeled as such in 
the concentration data listings. Missing samples will be reported as no sample ("NS") and excluded 
from analysis. Values that are BLQ will be substituted with zero for the calculation of descriptive 


PAREXEL International 
Statistical Analysis Plan 
Kainos Medicine, Inc. 
 
Final 1.0 
KMCP-819-K101 
 
14/Nov/2017 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
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statistics of concentration by time point and will be displayed as “not calculable” or NC for the 
calculation of statistical summaries.   
6.3.12.3 
Assessment of Dose Proportionality 
For Part A, dose proportionality [Table 14.2.3.1 (Part A)] will be assessed for parameters Cmax, AUC(0-t) 
and AUC(0-inf) and for Part B [Table 14.2.3.2 (Part B)] for paramters AUCtau and Cmax on Day 1 and Day 
7 using the pharmacokinetic population via the power model. 
Individual concentration values will be used to perform a least-squares linear regression analysis, using 
the formula log_pkvar = β0 × log_dose + β1, where ‘log_pkvar’ represents the natural log transformed 
Cmax, AUClast or AUC(0-inf) and ‘log_dose’ represents the natural log transformed dose. An estimate of 
the slope of the regression line and corresponding 95% confidence interval (CI) will be obtained. 
The following SAS code will be used: 
PROC REG DATA=pkparam alpha=0.05; 
MODEL log_pkvar = log_dose / CLB; 
RUN; 
For each of the parameters Cmax, AUClast, AUC(0-inf) of part A and Cmax, AUCtau of part B a plot of the 
log-transformed concentration against the log-transformed dose will be constructed including the fitted 
line from the linear regression and the line of unity. 
Dose proportionality plots of individual primary PK parameters will be displayed versus dose (log-log 
scale) along with the regression line and the 95% CI [Figure 14.3.1.1 (Part A) and Figure 14.3.1.2 (Part 
B) ]. Plots of dose-normalized parameters versus dose [Figure 14.3.2.1 (Part A) and Figure 14.3.2.2 
(Part B)] will also be provided.  
Additionally, an analysis of variance (ANOVA) [Table 14.2.4] of the natural log-transformed dose-
normalized PK parameters AUCinf/dose and Cmax/dose with log-transformed KM-819 dose as a 
covariate and subject as random effect, will be performed to estimate the slope of the effect of dose 
level on the PK parameter and its 95% CI. 
Proc Mixed Data = data; 
By parameter; 


PAREXEL International 
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Class Subject; 
 
Model log (pk Parameter) = log (dose)/ ddfm = kr outp=pred; 
 
Random subject; 
 
Estimate 'Mean Log Slope' lgdose 1 /cl alpha=0.05; 
Run; 
 
6.3.12.4 
Time Invariance (Part B Only) 
If data permits, the time invariance ratio will be calculated as the ratio of AUC(0-τ) on Day 7 to 
AUC(0-∞) on Day 1 (If have reliable AUC(0-∞) on Day 1) for each subject in each cohort. An 
ANOVA with terms for subject as a random effect and day as a fixed effect will be performed by dose 
on the loge-transformed AUC.  Day will be treated as a class variable in the model.  The time 
invariance of KM-819 will be assessed by calculating the ratio of the geometric least square means of 
AUC(0-τ) to AUC(0-∞) and the corresponding 90% CI for each dose.  AUC(0-∞) on Day 1 will be 
considered as the reference phase in the analysis [Table 14.2.5].  
An example of SAS code is included here. 
ODS output solutionf=stat; 
Proc Mixed; 
    by dose;    
    class subject day; 
    model logAUC = day / ddfm=kr; 
    random subject; 
    lsmeans day; 
    estimate 'test vs ref' day -1 1/cl alpha=0.1; 
run; 
 
The time invariance ratio will also be listed and summarized along with other PK parameters.  
 
6.3.12.5 
 Steady State Assessment (Part B Only) 
To evaluate whether steady state was achieved, statistical analysis of Cτ levels will be performed 
before Day 7, after a log-e transformation of the data from all active treatment doses. Only pre-dose 
concentration on days 1-7 for the 7 day analysis will be included in the analysis. A mixed effect model 


PAREXEL International 
Statistical Analysis Plan 
Kainos Medicine, Inc. 
 
Final 1.0 
KMCP-819-K101 
 
14/Nov/2017 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 42 of 61 
will be fitted separately with day as a continuous covariate and subject as a random effect. The 
coefficient of the slope of the day effect on the log-e scale for each treatment dose will be used to 
assess whether steady state was achieved on Day 7. Using the estimate of variance, the 90% confidence 
intervals for the slopes will be calculated. If the 90% limits for the slope is including one then steady-
state is statistically confirmed.[Table 14.2.6].   
An example of SAS code to assess achievement of steady-state is included here. 
ODS output solutionf=stat; 
Proc Mixed; 
    by dose;  
    where (Day in (1,2,3,4,5,6,7)); 
    class subject; 
    model logCtau = Day/cl alpha=0.1 solution;     
    random intercept/subject=subject type=un; 
run; 
6.3.13 
Pharmacodynamic Variables 
The analysis of the pharmacodynamic (PD) data will be based on the pharmacodynamic population. 
In both Parts A and B, mean and absolute value change from baseline at each post-baseline 
measurements for:  
• Bond and Lader Visual Analogue Scale (VAS) [Table 14.2.8.1 (Part A) and Table 14.2.8.2 (Part 
B)] 
• Profile of Mood States (POMS) [Table 14.2.9.1 (Part A) and Table 14.2.9.2 (Part B)] 
• Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) [Table 14.2.10.1 (Part A) and 
Table 14.2.10.2 (Part B)] 
• C-SSRS  
In Part B only, PD parameters in plasma and CSF including:  
• alpha synuclein oligomer [Table 14.2.11] 
• total Tau [Table 14.2.12] 


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• phospho-Tau [Table 14.2.13] 
• Ratio of CSF concentration/Plasma Cmax. [Table 14.2.14] 
For Part A and Part B, the PD parameters (Bond and Lader Visual Analogue Scale (VAS) [Listing 
16.2.9.4.1 (Part A) and Listing 16.2.9.4.2 (Part B)], Profile of Mood States (POMS) [Listing 16.2.9.5.1 
(Part A)  and Listing 16.2.9.5.2 (Part B) ], Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) 
[Listing 16.2.9.6.1 (Part A) and Listing 16.2.9.6.2 (Part B)], C-SSRS [Listing 16.2.9.7.1 (Part A) and 
Listing 16.2.9.7.2 (Part B)],   
In Part B only, PD parameters in plasma and CSF including: alpha synuclein oligomer [Listing 
16.2.9.8], total Tau [Listing 16.2.9.9], phospho-Tau [Listing 16.2.9.10], Ratio of CSF 
concentration/Plasma Cmax. [Listing 16.2.9.11]) will be listed within each study part and by cohort and 
time point and will include both absolute values and changes from baseline. Listing of CSF 
Concentration of KM-819 will be presented [Listing 16.2.6.3 (Part B)].  
The baseline for each of Bond and Lader Visual Analogue Scale (VAS), Profile of Mood States 
(POMS), Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV), alpha synuclein oligomer, total 
Tau and phospho-Tau parameters will be the Day 1. 
Pharmacodynamic data will be summarized using descriptive statistics (n, mean, SD, minimum, 
median and maximum).  
6.3.13.1 
Statistical Analysis (Pharmcodynamic Analysis) 
No formal statistical analysis is planned for the study. 
6.3.14 
Pharmacokinetic/Pharmacodynamic Analysis 
No formal PK/PD statistical analysis will be performed for the study. Relationship between 
Pharmacokinetics and Pharmacodynamics parameters are assessed graphically.  
PD parameters (Part A and Part B): Bond and Lader Visual Analogue Scale (VAS), Profile of Mood 
States (POMS) Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV); Part B only: alpha 
synuclein oligomer, total Tau phospho-Tau) will be plotted vs PK parameters (AUCinf, AUClast and 
Cmax) [Figure 14.4.1.1 (Part A), Figure 14.4.1.2(Part B) , Figure 14.4.2.1 (Part A), Figure 
14.4.2.2(Part B), Figure 14.4.3.1 (Part A), Figure 14.4.3.2(Part B), Figure 14.4.4 (Part B), Figure 14.4.5 
(Part B), 14.4.6 (Part B)] with in each study part, by cohorts and nominal time point.  


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6.3.15 
Safety Analysis 
The analysis of the safety variables will be based on the safety population. 
Safety will be assessed based on reported AEs, clinical laboratory assessments, vital signs 
measurements, 12-lead ECGs, and abnormal findings from physical examination. 
Safety data will be summarized using descriptive statistics (n, mean, SD, minimum, median and 
maximum) will be reported within each study part and by cohort and time point and will include both 
absolute values and changes from baseline. 
Categorical data will be summarized using frequencies and percentages will be reported within each 
study part, and by cohort. 
6.3.15.1 
Adverse Events 
The following listings will be produced: 
• 
All AEs. [Listing 16.2.7.1 (Part A) and Listing 16.2.7.2 (Part B)]: 
• 
Withdrawals due to AEs [Listing 14.3.2.2.1 (Part A) and Listing 14.3.2.2.2 (Part B)] 
• 
SAEs. [Listing 14.3.2.3.1 (Part A) and Listing 14.3.2.3.2 (Part B)] 
A treatment-emergent AE (TEAE) will be defined as an AE that begins or that worsens in severity after 
at least one dose of study drug has been administered. 
The following information will be included in the AE listing [Listing 16.2.7.1 (Part A) and Listing 
16.2.7.2 (Part B)]: Verbatim, MedDRA lower level term (LLT), preferred term (PT), system organ 
class (SOC), AE onset date (and time) and study day, AE end date (and time) and duration (days), 
Concomitant Medication Administered, Related to Medical history condition, relationship to IMP, AE 
outcome, severity, AE ongoing and SAE indicator flag. 
A table of summary of Treatment Emergent Adverse Events [Table 14.3.1.1.1 (Part A) and Table 
14.3.1.1.2 (Part B)]; A table of number and percentage of subjects with AEs summarized by SOC, PT 
[Table 14.3.1.2.1 (Part A) and Table 14.3.1.2.2 (Part B)]; SOC, PT and severity [Table 14.3.1.4.1 (Part 
A) and Table 14.3.1.4.2 (Part B)]; SOC, PT and maximum severity [Table 14.3.1.5.1 (Part A) and 
Table 14.3.1.5.2 (Part B)] will be presented for each study part and also the number (percentage) of 
subjects with AEs summarized by SOC, PT, and relationship [Table 14.3.1.3.1 (Part A) and Table 


PAREXEL International 
Statistical Analysis Plan 
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14.3.1.3.2 (Part B)] to IMP.  In the case of multiple occurrences of the same AEs (at the same preferred 
term level) in an individual patient, the AE with the greatest severity will be reported. 
Serious AE, if any occur, will be summarized. 
6.3.15.2 
Clinical Safety Laboratory Tests (hematology, biochemistry and urinalysis) 
Laboratory values (hematology [Listing 16.2.8.2.1 (Part A) and Listing 16.2.8.2.2 (Part B)], 
biochemistry [Listing 16.2.8.1.1 (Part A) and Listing 16.2.8.1.2 (Part B)] and urinalysis [Listing 
16.2.8.3.1 (Part A) and Listing 16.2.8.3.2 (Part B)]) will be listed for each study part by subject and 
study time point including changes from baseline (with the exception of urinalysis). The baseline for 
the laboratory values will be the results obtained on Day -1. 
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal values 
will be flagged with ‘L’ for values below the lower limit of the clinical reference range and ‘H’ for 
values above the upper limit of the clinical reference range and included in the listings. The 
Investigator will assess whether the values outside the clinical reference range are clinically significant 
and these will be reported as abnormal not clinically significant (NCS) or abnormal clinically 
significant (CS). Clinically significant laboratory values will be recorded by the Investigator as AEs. 
Shift from baseline of laboratory finding for hematology and clinical chemistry (Normal, Low NCS, 
Low CS, High NCS and High CS) will be summarized, using frequencies and percentages, for each 
laboratory test by cohort group and nominal time point within each study. 
Screening serology [Listing 16.2.8.4.1 (Part A) and Listing 16.2.8.4.2 (Part B)], drug screen test 
[Listing 16.2.8.5.1 (Part A) and Listing 16.2.8.5.2 (Part B)], pregnancy test [Listing 16.2.8.6.1 (Part A) 
and Listing 16.2.8.6.2 (Part B)] , Alcohol breath test [Listing 16.2.8.7.1 (Part A) and Listing 16.2.8.7.2 
(Part B)]results will be listed. 
Any laboratory parameters that are given as '<xx' or '>xx' in the database will be imputed with the 
absolute value of the number without the sign (e.g., <2.2 will be imputed as 2.2) for the calculation of 
the changes from baseline and for the descriptive statistics. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for non-categorical data including 
hematology [Table 14.3.5.2.1 (Part A) Table 14.3.5.2.2 (Part B)]  and biochemistry [Table 14.3.5.1.1 
(Part A) and Table 14.3.5.1.2 (Part B)] and any quantitative urinalysis [Table 14.3.5.3.1 (Part A) and 
Table 14.3.5.3.2 (Part B)]   will be presented for each study part, by cohort and time point for both 


PAREXEL International 
Statistical Analysis Plan 
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observed values and changes from baseline. Urinalysis results (normal or abnormal) will also be 
tabulated. 
Abnormal laboratory values will be listed using conventional and standard units [Listing 14.3.4.1.1 
(Part A), Listing 14.3.4.1.2 (Part B), Listing 14.3.4.2.1 (Part A), Listing 14.3.4.2.2 (Part B), Listing 
14.3.4.3.1 (Part A) and Listing 14.3.4.3.2 (Part B) ]. Shift tables for hematology [Table 14.3.5.5.1 (Part 
A), Table 14.3.5.5.2 (Part B)] and biochemistry [Table 14.3.5.4.1 (Part A) and Table 14.3.5.4.2 (Part 
B)] will be constructed that show the change in quantitative laboratory values from baseline with each 
study part, and by cohort and nominal time point. 
No change from baseline will be calculated for screening visits. 
6.3.15.3 
Vital Signs 
Vital signs data will be listed [Listing 16.2.9.1.1 (Part A) , Listing 16.2.9.1.2 (Part B)] by subject for 
each study part by subject including subject number, time point, changes from baseline for supine 
measurements, flags for measurements outside the reference ranges and the corresponding Investigator 
assessment (CS or NCS)and repeat/unscheduled measurements. The mean of any triplicate assessments 
performed at a given time point will be used in all calculations of changes from baseline and in all 
tabulations. The baseline for each measurement will be the mean of the triplicate assessments obtained 
on Day -1. 
Vital signs data will be summarized [Table 14.3.6.1.1 (Part A)  and Table 14.3.6.1.2 (Part B)], 
descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes from 
baseline will be presented by for each study part, by cohort and time point for both observed values and 
changes from baseline. 
No change from baseline will be calculated for screening visits. 
6.3.15.4 
Twelve-Lead Electrocardiogram 
All ECG parameters obtained from the ECG measurement will be listed [Listing 16.2.9.2.1 (Part A) 
and Listing 16.2.9.2.2 (Part B)] by subject for each study part by subject and time point including 
changes from baseline and repeat/unscheduled measurements. The mean of any triplicate assessments 
performed at a given time point will be used in all calculations of changes from baseline and in all 
tabulations. The baseline for each measurement will be the mean of the triplicate assessments obtained 
on Day -1. 


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All ECG parameters will be summarized [Table 14.3.6.2.1 (Part A) and Table 14.3.6.2.2 (Part B)], 
descriptive statistics (n, mean, SD, median, minimum, maximum) will be presented within each study 
part, and by cohort and time point for both observed values and changes from baseline. 
No change from baseline will be calculated for screening visits. 
6.3.15.5 
Physical Examination 
Abnormal physical examination results will be listed [Listing 16.2.9.3.1 (Part A) and Listing 16.2.9.3.2 
(Part B)] by subject within each study part, by cohort and time point. Listing of spinal X-ray will be 
provided (if appropriate).  
 


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7. REFERENCES 
1. SAS® Version 9.2 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
2. WinNonlin Professional Software Version 6.3. http://www.pharsight.com 
3. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000 Oct; 17(10): 
1278-83. 
4. CPMP/EWP/QWP/1401/98 Rev. 1/ Corr, Guideline on the investigation of 
bioequivalence, London, 20 January 2010.  
 
 


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8. TABLES AND LISTINGS TO BE INCLUDED IN SECTION 14 OF 
THE CLINICAL STUDY REPORT 
Subject Disposition 
Table 14.1.1.1 
Summary of Subject Disposition (Safety Population) (Part A)  
Table 14.1.1.2 
Summary of Subject Disposition (Safety Population) (Part B) 
 
Baseline and Demographic Data 
 
Table 14.1.2.1 
Summary of Subject Demographics (Safety Population) (Part A) 
Table 14.1.2.2 
Summary of Subject Demographics (Safety Population) (Part B) 
Table 14.1.3.1 
Summary of Protocol Deviations (Safety Population) (Part A) 
Table 14.1.3.2 
Summary of Protocol Deviations (Safety Population) (Part B) 
Table 14.1.4.1 
Summary of Medical History (Safety Population) (Part A) 
Table 14.1.4.2 
Summary of Medical History (Safety Population) (Part B) 
Table 14.1.5.1 
Summary of Prior Medications and Significant Non-Drug Therapies (Safety 
Population) (Part A) 
 
Table 14.1.5.2 
Summary of Prior Medications and Significant Non-Drug Therapies (Safety 
Population) (Part B) 
 
Table 14.1.6.1 
Summary of Concomitant Medications and Significant Non-Drug Therapies 
(Safety Population) (Part A) 
Table 14.1.6.2 
Summary of Concomitant Medications and Significant Non-Drug Therapies 
(Safety Population) (Part B) 
 
Pharmacokinetic Data 
 
Table 14.2.1.1 
Summary of Plasma Concentrations of KM-819 Versus Nominal Sampling 


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Times (Pharmacokinetic Population) (Part A) 
Table 14.2.1.2 
Summary of Plasma Concentrations of KM-819 Versus Nominal Sampling 
Times (Pharmacokinetic Population) (Part B) 
Table 14.2.2.1 
Summary of Pharmacokinetic Parameters of KM-819 (Pharmacokinetic 
Population) (Part A) 
Table 14.2.2.2 
Summary of Pharmacokinetic Parameters of KM-819 (Pharmacokinetic 
Population) (Part B) 
Table 14.2.3.1 
Statistical Analysis To Assess Dose Proportionality of KM-819 Pharmacokinetic 
Parameters (Power Model) (Pharmacokinetic Population) (Part A) 
Table 14.2.3.2 
Statistical Analysis To Assess Dose Proportionality of KM-819 Pharmacokinetic 
Parameters (Power Model) (Pharmacokinetic Population) (Part B) 
Table 14.2.4 
Statistical Analysis To Assess Dose Proportionality of KM-819 Pharmacokinetic 
Parameters (ANOVA Model) (Pharmacokinetic Population) (Part A) 
Table 14.2.5 
Statistical Analysis of Time Invariance of KM-819 Pharmacokinetic Parameters 
(ANOVA Model) (Pharmacokinetic Population) (Part B) 
Table 14.2.6 
Statistical Analysis To Steady State of KM-819 Pharmacokinetic Parameters 
(Pharmacokinetic Population) (Part B) 
Pharmacodynamic Data 
 
Table 14.2.8.1 
Summary of Observed and Change From Baseline of Bond and Lader VAS 
(Pharmacodynamic Population) (Part A) 
Table 14.2.8.2 
Summary of Observed and Change From Baseline of Bond and Lader VAS 
(Pharmacodynamic Population) (Part B) 
Table 14.2.9.1 
Summary of Profile of Mood States (Pharmacodynamic Population) (Part A) 
Table 14.2.9.2 
Summary of Profile of Mood States (Pharmacodynamic Population) (Part B) 
Table 14.2.10.1 
Summary of Observed and Change From Baseline of Korean Wechsler Adult 


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Intelligence Scale-IV (Pharmacodynamic Population) (Part A) 
Table 14.2.10.2 
Summary of Observed and Change From Baseline of Korean Wechsler Adult 
Intelligence Scale-IV (Pharmacodynamic Population) (Part B) 
Table 14.2.11 
Summary of Observed and Change From Baseline of Alpha Synuclein Oligomer 
(Pharmacodynamic Population)  (Part B) 
Table 14.2.12 
Summary of Observed and Change From Baseline of Alpha Total Tau 
(Pharmacodynamic Population)  (Part B) 
Table 14.2.13 
Summary of Observed and Change From Baseline of 
Phospho-Tau 
(Pharmacodynamic Population)  (Part B) 
Table 14.2.14 
Summary of Observed and Change From Baseline of Ratio of CSF 
Concentration/Plasma Cmax (Pharmacodynamic Population)  (Part B) 
Safety Data 
 
 
Table 14.3.1.1.1 
Summary of Treatment Emergent Adverse Events (Safety Population) (Part A) 
Table 14.3.1.1.2 
Summary of Treatment Emergent Adverse Events (Safety Population) (Part B) 
Table 14.3.1.2.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) (Part A) 
Table 14.3.1.2.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) (Part B) 
Table 14.3.1.3.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Relationship (Safety Population) (Part A) 
Table 14.3.1.3.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Relationship (Safety Population) (Part B) 
Table 14.3.1.4.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Severity (Safety Population) (Part A) 


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Table 14.3.1.4.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Severity (Safety Population) (Part B) 
Table 14.3.1.5.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity (Safety Population) (Part A) 
Table 14.3.1.5.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity (Safety Population) (Part B) 
Listing 14.3.2.1.1 
Serious Adverse Events Leading To Death (Safety Population) (Part A) 
Listing 14.3.2.1.2 
Serious Adverse Events Leading To Death (Safety Population) (Part B) 
Listing 14.3.2.2.1 
Serious Adverse Events (Safety Population) (Part B) 
Listing 14.3.2.2.2 
Serious Adverse Events (Safety Population) (Part B) 
Listing 14.3.2.3.1 
Adverse Events Leading To Discontinuation (Safety Population) (Part A) 
Listing 14.3.2.3.2 
Adverse Events Leading To Discontinuation (Safety Population) (Part B) 
Listing 14.3.4.1.1 
Abnormal Biochemistry Values (Safety Population) (Part A) 
Listing 14.3.4.1.2 
Abnormal Biochemistry Values (Safety Population) (Part B) 
Listing 14.3.4.2.1 
Abnormal Hematology Values (Safety Population) (Part A) 
Listing 14.3.4.2.2 
Abnormal Hematology Values (Safety Population) (Part B) 
Listing 14.3.4.3.1 
Abnormal Urinalysis Values (Safety Population) (Part A) 
Listing 14.3.4.3.2 
Abnormal Urinalysis Values (Safety Population) (Part B) 
Table 14.3.5.1.1 
Summary of Biochemistry (Safety Population) (Part A) 
Table 14.3.5.1.2 
Summary of Biochemistry (Safety Population) (Part B) 
Table 14.3.5.2.1 
Summary of Hematology (Safety Population) (Part A) 
Table 14.3.5.2.2 
Summary of Hematology (Safety Population) (Part B) 
Table 14.3.5.3.1 
Summary of Urinalysis (Safety Population) (Part A) 


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Table 14.3.5.3.2 
Summary of Urinalysis (Safety Population) (Part B) 
Table 14.3.5.4.1 
Summary of Biochemistry Shift Table (Safety Population) (Part A) 
Table 14.3.5.4.2 
Summary of Biochemistry Shift Table (Safety Population) (Part B) 
Table 14.3.5.5.1 
Summary of Hematology Shift Table (Safety Population) (Part A) 
Table 14.3.5.5.2 
Summary of Hematology Shift Table (Safety Population) (Part B) 
Table 14.3.6.1.1 
Summary of Vital Signs (Safety Population)  (Part A) 
Table 14.3.6.1.2 
Summary of Vital Signs (Safety Population)  (Part B) 
Table 14.3.6.2.1 
Summary of Electrocardiograms (Safety Population) (Part A) 
Table 14.3.6.2.2 
Summary of Electrocardiograms (Safety Population)  (Part B) 
9. FIGURES 
Figure 14.2.1.1.1 
Individual Plasma KM-819  Concentrations (Unit) (Linear-Linear Scale) 
(Pharmacokinetic Population)  (Part A) 
Figure 14.2.1.1.2 
Individual Plasma KM-819  Concentrations (Unit) (Linear-Linear Scale) 
(Pharmacokinetic Population)  (Part B) 
Figure 14.2.1.2.1 
Individual Plasma KM-819  Concentrations (Unit) (Semi Logarithmic Scale) 
(Pharmacokinetic Population)  (Part A) 
Figure 14.2.1.2.2 
Individual Plasma KM-819  Concentrations (Unit) (Semi Logarithmic Scale) 
(Pharmacokinetic Population)  (Part B) 
Figure 14.2.2.1.1 
Plasma KM-819  Arithmetic Mean(+/- SD) Concentrations (Unit) 
(Pharmacokinetic Population) (Part A) 
Figure 14.2.2.1.2 
Plasma KM-819  Arithmetic Mean(+/- SD) Concentrations (Unit) 
(Pharmacokinetic Population) (Part B) 
Figure 14.2.2.2.1 
Plasma KM-819  Arithmetic Mean(+/- SD) Concentrations (Unit) (Young Vs. 
Elderly Male Or Post-Menopausal Females)  (Pharmacokinetic Population) (Part 
A) 


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Figure 14.2.2.2.2 
Plasma KM-819  Arithmetic Mean(+/- SD) Concentrations (Unit) (Young Vs. 
Elderly Male Or Post-Menopausal Females)  (Pharmacokinetic Population) (Part 
Part B) 
Figure 14.2.3.1.1 
Plasma KM-819  Geometric Mean (+/- SD)  Concentrations (Unit) 
(Pharmacokinetic Population) (Part A) 
Figure 14.2.3.1.2 
Plasma KM-819  Geometric Mean (+/- SD)  Concentrations (Unit) 
(Pharmacokinetic Population) (Part B) 
Figure 14.2.3.2.1 
Plasma Blood KM-819  Geometric Mean(+/- SD) Concentrations (Unit) (Young 
Vs. Elderly Male Or Post-Menopausal Females) (Pharmacokinetic Population) 
(Part A) 
Figure 14.2.3.2.2 
Plasma Blood KM-819  Geometric Mean(+/- SD) Concentrations (Unit) (Young 
Vs. Elderly Male Or Post-Menopausal Females) (Pharmacokinetic Population) 
(Part B) 
Figure 14.2.4.1.1 
Plasma KM-819  Median  Concentrations (Unit) (Pharmacokinetic Population) 
(Part A) 
Figure 14.2.4.1.2 
Plasma KM-819  Median  Concentrations (Unit) (Pharmacokinetic Population) 
(Part B) 
Figure 14.2.4.2.1 
Plasma KM-819  Median  Concentrations (Unit) (Young Vs. Elderly Male Or 
Post-Menopausal Females) (Pharmacokinetic Population) (Part A) 
Figure 14.2.4.2.2 
Plasma KM-819  Median  Concentrations (Unit) (Young Vs. Elderly Male Or 
Post-Menopausal Females) (Pharmacokinetic Population) (Part B) 
Figure 14.3.1.1 
Plasma KM-819 PK Parameters Versus Dose (Log-Log) (Unit) Along With The 
Regression Line and The 95% CI (Pharmacokinetic Population)  (Part A) 
Figure 14.3.1.2 
Plasma KM-819 PK Parameters Versus Dose (Log-Log) (Unit) Along With The 
Regression Line and The 95% CI (Pharmacokinetic Population)  (Part B) 
Figure 14.3.2.1 
Plasma KM-819 Dose-normalized PK parameters versus dose (unit) 
Subject Profiles for KM-819 Plasma Concentration Time Data (Linear Scale) 
(Part A) 
Figure 14.3.2.2 
Plasma KM-819 Dose-normalized PK parameters versus dose (unit) 
Subject Profiles for KM-819 Plasma Concentration Time Data (Linear Scale) 
(Part B) 


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Figure 14.4.1.1 
Scatter plot of Bond and Lader Visual Analogue Scale (VAS) vs. pharmacokinetic 
parameters (Pharmacodynamic Population) (Part A) 
Figure 14.4.1.2 
Scatter plot of Bond and Lader Visual Analogue Scale (VAS) vs. pharmacokinetic 
parameters (Pharmacodynamic Population) (Part B) 
Figure 14.4.2.1 
Scatter plot of Profile of Mood States (POMS)  vs. pharmacokinetic parameters 
(Pharmacodynamic Population) (Part A) 
 
Figure 14.4.2.2 
Scatter plot of Profile of Mood States (POMS)  vs. pharmacokinetic parameters 
(Pharmacodynamic Population) (Part B) 
 
Figure 14.4.3.1 
Scatter plot of Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) vs. 
pharmacokinetic parameters (Pharmacodynamic Population) (Part A) 
 
Figure 14.4.3.2 
Scatter plot of Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) vs. 
pharmacokinetic parameters (Pharmacodynamic Population) (Part B) 
 
Figure 14.4.4 
Scatter plot of alpha synuclein oligomer vs. pharmacokinetic parameters 
(Pharmacodynamic Population) (Part B) 
 
Figure 14.4.5 
Scatter plot of total Tau vs. pharmacokinetic parameters (Pharmacodynamic 
Population) (Part B) 
 
Figure 14.4.6 
Scatter plot of phospho-Tau vs. pharmacokinetic parameters (Pharmacodynamic 
Population) (Part B) 
 
 


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10. LISTINGS TO BE INCLUDED IN SECTION 16 OF THE 
CLINICAL STUDY REPORT 
Subject Disposition 
 
Listing 16.2.1.1.1 
Subject Disposition  (Part A) 
Listing 16.2.1.1.2 
Subject Disposition  (Part B) 
Listing 16.2.1.2.1 
Informed Consent (Part A) 
Listing 16.2.1.2.2 
Informed Consent (Part B) 
Listing 16.2.1.3.1 
Study Visits (Part A) 
Listing 16.2.1.3.2 
Study Visits (Part B) 
Listing 16.2.1.4.1 
Failed Inclusion and Exclusion Criteria (Part A) 
Listing 16.2.1.4.2 
Failed Inclusion and Exclusion Criteria (Part B) 
Listing 16.2.2.1 
Protocol Deviations (Part A) 
Listing 16.2.2.2 
Protocol Deviations (Part B) 
Listing 16.2.3.1 
Assignment To Analysis Populations (Part A) 
Listing 16.2.3.2 
Assignment To Analysis Populations (Part B) 
 
 
Baseline and Demographic Data 
Listing 16.2.4.1.1 
Subject Demographics (Part A) 
Listing 16.2.4.1.2 
Subject Demographics (Part B) 
Listing 16.2.4.2.1 
Medical History (Part A) 
Listing 16.2.4.2.2 
Medical History (Part B) 


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Concomitant Medication 
Listing 16.2.4.3.1 
Prior and Concomitant Medication (Safety Population) (Part A ) 
Listing 16.2.4.3.2 
Prior and Concomitant Medication (Safety Population) ( Part B) 
Exposure 
Listing 16.2.5.1.1 
Exposure To Study Drug (Part A) 
Listing 16.2.5.1.2 
Exposure To Study Drug (Part B) 
Pharmacokinetic Data 
Listing 16.2.6.1.1 
Pharmacokinetic Plasma Concentration of KM-819 (Pharmacokinetic Population) 
(Part A) 
Listing 16.2.6.1.2 
Pharmacokinetic Plasma Concentration of KM-819 (Pharmacokinetic Population) 
(Part B) 
Listing 16.2.6.2.1 
Pharmacokinetic Parameters of KM-819 (Pharmacokinetic Population) (Part A) 
Listing 16.2.6.2.2 
Pharmacokinetic Parameters of KM-819 (Pharmacokinetic Population) (Part B) 
Listing 16.2.6.3 
CSF Concentration of KM-819 (Pharmacokinetic Population) (Part B) 
Listing 16.2.6.4 
Urine Concentration - Part A 
Pharmacodynamic Data 
Listing 16.2.9.4.1 
Bond and Lader VAS (Pharmacodynamic Population) (Part A) 
Listing 16.2.9.4.2 
Bond and Lader VAS (Pharmacodynamic Population) (Part B) 
Listing 16.2.9.5.1 
Profile of Mood States (Pharmacodynamic Population) (Part A) 
Listing 16.2.9.5.2 
Profile of Mood States (Pharmacodynamic Population) (Part B) 
Listing 16.2.9.6.1 
Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) (Pharmacodynamic 
Population) (Part A) 


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Listing 16.2.9.6.2 
Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) (Pharmacodynamic 
Population) (Part B) 
Listing 16.2.9.7.1 
Columbia Suicidal Severity Rating Scale (C-SSRS) (Pharmacodynamic Population) 
(Part A) 
Listing 16.2.9.7.2 
Columbia Suicidal Severity Rating Scale (C-SSRS) (Pharmacodynamic Population) 
(Part B) 
Listing 16.2.9.8 
Alpha Synuclein Oligomer (Pharmacodynamic Population) (Part B) 
Listing 16.2.9.9 
Alpha Total Tau (Pharmacodynamic Population) (Part B) 
Listing 16.2.9.10 
Phospho-Tau (Pharmacodynamic Population) (Part B) 
Listing 16.2.9.11 
Ratio of CSF Concentration/Plasma Cmax (Pharmacodynamic Population) (Part B) 
 
 


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Safety Variables 
 
Listing 16.2.7.1 
Adverse Events (Safety Population) (Part A) 
Listing 16.2.7.2 
Adverse Events (Safety Population) (Part B) 
Listing 16.2.8.1.1 
Biochemistry (Safety Population) (Part A) 
Listing 16.2.8.1.2 
Biochemistry (Safety Population) (Part B) 
Listing 16.2.8.2.1 
Hematology (Safety Population) (Part A) 
Listing 16.2.8.2.2 
Hematology (Safety Population) (Part B) 
Listing 16.2.8.3.1 
Urinalysis (Safety Population) (Part A ) 
Listing 16.2.8.3.2 
Urinalysis (Safety Population) (Part B) 
Listing 16.2.8.4.1 
Serology (Safety Population) (Part A) 
Listing 16.2.8.4.2 
Serology (Safety Population) (Part B) 
Listing 16.2.8.5.1 
Drugs of Abuse (Safety Population) (Part A) 
Listing 16.2.8.5.2 
Drugs of Abuse (Safety Population) (Part B) 
Listing 16.2.8.6.1 
Pregnancy Test (Safety Population) (Part A) 
Listing 16.2.8.6.2 
Pregnancy Test (Safety Population) (Part B) 
Listing 16.2.8.7.1 
Alcohol breath Test (Safety Population) (Part A) 
Listing 16.2.8.7.2 
Alcohol breath Test (Safety Population) (Part B) 
Listing 16.2.9.1.1 
Vital Signs (Safety Population) (Part A) 
Listing 16.2.9.1.2 
Vital Signs (Safety Population) (Part B) 
Listing 16.2.9.2.1 
Electrocardiogram Parameters (Safety Population) (Part A) 
Listing 16.2.9.2.2 
Electrocardiogram Parameters (Safety Population) (Part B) 


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Listing 16.2.9.3.1 
Physical Examination (Safety Population) (Part A) 
Listing 16.2.9.3.2 
Physical Examination (Safety Population) (Part B) 


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11. DOCUMENTATION OF STATISTICAL METHODS 
• Appendix 16.1.9.1.1: Raw SAS Output of Table 14.2.3.1 Statistical Analysis To Assess Dose 
Proportionality Analysis of KM-819  Pharmacokinetic Parameters (Power Model) 
(Pharmacokinetic Population) (Part A)  
• Appendix 16.1.9.1.2: Raw SAS Output of Table 14.2.3.2 Statistical Analysis To Assess Dose 
Proportionality Analysis of KM-819  Pharmacokinetic Parameters (Power Model) 
(Pharmacokinetic Population) (Part B)  
• Appendix 16.1.9.2: Raw SAS Output of Table 14.2.4 Statistical Analysis To Assess dose-
normalized 
parameters 
KM-819 
 
Pharmacokinetic 
Parameters 
(ANOVA 
Model) 
(Pharmacokinetic Population) (Part A) 
• Appendix 16.1.9.3: Raw SAS Output of Table 14.2.5 Statistical Analysis of Time Invariance of 
KM-819 Pharmacokinetic Parameters (ANOVA Model) (Pharmacokinetic Population) (Part B) 
• Appendix 16.1.9.4: Raw SAS Output of Table 14.2.6 Statistical Analysis To Steady State of 
KM-819 Pharmacokinetic Parameters (Pharmacokinetic Population) (Part B) 
 

ICF_001.pdf: 
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Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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MODEL INFORMED CONSENT FORM 
VERSION LOG 
Version 
Date 
Reason for Change 
1.0 
01 Jun 2016 
Not applicable 
2.0 
23 Jun 2016 
Addition of side effects from pre-clinical tests 
3.0 
07 Oct 2016 
Addition of information on restrictions during the 
study and on adverse effects observed in a non-
clinical study. 
4.0 
29 Dec 2016 
Addition of information selected dose for food 
effect study and elderly cohorts 
5.0 
15 Feb 2017 
Removing of food effect sections according to 
protocol update 
This page should be deleted in all country/site-specific ICFs. 
 
 


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CONSENT TO PARTICIPATE IN A CLINICAL STUDY 
 
Title of Study: 
A First-in-Human, Randomized, Double-blind, Dose 
Escalation Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Following Single 
and Multiple Oral Doses of KM-819 in Healthy Young Adult 
and Elderly Subjects 
Protocol Number: 
KMCP-819-K101 
Sponsor: 
Kainos Medicine, Inc. 
Investigator: 
Kyoung Soo Lim, MD, PhD 
Study Center: 
 
 
1. WHY HAVE I BEEN GIVEN THIS FORM? 
You are being invited to take part in this clinical study because you are a healthy 
volunteer. This study involves the use of an investigational drug called KM-819. 
“Investigational new drug” means a drug that has not been approved as a marketed 
product (i.e., available to be prescribed or sold) by any regulatory authorities. This is the 
first time KM-819 will be given to humans. This clinical study is being sponsored by 
Kainos Medicine, Inc. (hereafter referred to as the Sponsor), and the investigational new 
drug KM-819 is called the study medication. 
Before you decide if you want to participate in this study, it is important for you to 
understand why the study is being done, how your information will be used, what the 
study will involve, and the possible benefits, risks and discomforts. Please take time to 
read the following information carefully. Some terms may be unfamiliar to you. If there is 
anything you do not understand or if you would like more information, please ask the 
study doctor or study staff. You may also discuss the study with family members and 
friends, if you wish. If you decide that you want to take part in this study, you will be 
asked to sign the consent statement at the end of this informed consent form (you will be 
given a copy of this to take home with you). No study procedures will be done until you 
have read and signed this form. You will be free to withdraw from the study at any time 
without having to give any reason. A decision not to take part in this study, or to 
withdraw at any time, will not affect your health care. 
 
2. WHAT IS THE BACKGROUND AND PURPOSE OF THE STUDY? 
Before a new medicine can be approved for use in humans, it is necessary to confirm that 
it is safe and effective. This is done by carrying out clinical studies such as this one. 
KM-819 is being developed for the possible treatment of Parkinson’s disease (PD). PD is 
a degenerative disorder of the central nervous system mainly affecting the motor system. 
KM-819 is an innovative new drug that protects neuron cells from death.  
The purpose of this study is to look at the safety, tolerability, pharmacokinetics and 
pharmacodynamics of KM-819 in healthy volunteers. This safety and tolerability means 
that we are looking for the effects of the study medication (if it causes changes to your 
body and to look at side effects of the study medication). This study will investigate how 


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your body takes the medication into the blood, delivers the medication throughout the 
body, breaks down or processes the medication, and removes the medication, which is 
called pharmacokinetics. The study will also measure how the medication takes effect on 
your body, which is called pharmacodynamics. 
In this study, you will receive KM-819 or placebo. A placebo is a “dummy treatment” 
that looks like the study medication but contains no active ingredients. 
This study is divided into 2 parts, Part A and Part B. You will only be enrolled into 
one part of the study; for example, if you are enrolled in Part A of this study, you 
will not be able to take part in Part B. 
2.1. Part A 
The purpose of this part of the study is to look at the safety, tolerability, pharmacokinetics 
and pharmacodynamics of KM-819 when single dose given to healthy volunteers. 
2.2. Part B 
The purpose of this part of the study is to look at the safety and tolerability of multiple 
doses KM-819 when given to healthy male and female volunteers. 
 
3. WHAT IS THE STUDY ABOUT? 
3.1. Part A 
Part A will involve 40 healthy young adult male volunteers and 8 healthy elderly male or 
post-menopausal female volunteers. If you are a healthy young adult male volunteer, you 
will be recruited to participate in one of following dose cohorts of the study depending on 
the progression of the study: 
• Single dose of 10 mg KM-819 
• Single dose of 30 mg KM-819 
• Single dose of 100 mg KM-819 
• Single dose of 200 mg KM-819 
• Single dose of 400 mg KM-819 
If you are a healthy elderly male or post-menopausal female volunteer, you will have an 
opportunity to take part in one separate dose cohort special for elderly subjects, the 
dosage level will be 200 mg. 
Part A is expected to last up to 6 weeks (the possible amount of time from the Screening 
Visit through to the Follow-up Visit [last visit]). 
You will be randomized (this means purely by chance, like tossing a coin) in the morning 
of Day 1 to receive either KM-819 or placebo. 
You will receive study medication on Day 1 and remain at the study site for a minimum 
3-day/2-night in-house stay. 
You will be allowed to leave the site on Day 3 if the study doctor considers that you are 
in good health. You will then return on Day 4, Day 7, and Day 14 for further assessments. 


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3.2. Part B 
Part B will involve 32 healthy young adult male volunteers and 8 healthy elderly male or 
post-menopausal female volunteers. 
If you are a healthy young adult male volunteer, you will be recruited to participate in one 
of following dose cohorts of the study depending on the progression of the study: 
• Multiple doses of 30 mg KM-819 
• Multiple doses of 100 mg KM-819 
• Multiple doses of 200 mg KM-819 
• Multiple doses of 400 mg KM-819 
Please note that Part B will not start until completion of all cohorts of young adult male 
volunteers in Part A. 
If you are a healthy elderly male or post-menopausal female volunteer, you will have an 
opportunity to take part in one separate dose cohort special for elderly subjects, the dose 
level will be 200 mg. 
Part B is expected to last up to 6 weeks (the possible amount of time from the Screening 
Visit through to the Follow-up Visit [last visit]). 
You will be randomized (this means purely by chance, like tossing a coin) in the morning 
of Day 1 to receive either KM-819 or placebo. 
You will be given study medications once daily for 7 days, and you will remain at the 
study site for a minimum 8-day/7-night in-house stay. 
You will be allowed to leave the site on Day 8 if the study doctor considers that you are 
in good health. You will then return on Day 14 for Follow-up Visit. 
3.3. For Both Parts 
You will only be able to take part in one of the above cohorts, which means you will not 
be allowed to enter other cohorts if you have already taken part in one cohort. 
If you decide to participate, you will have a Screening Visit to see if you qualify. If you 
qualify and wish to continue with the study, you will be asked to return to the study site 
within 27 days. You will need to return to the study site on Study Day -1 (1 day before 
receiving study medication) and stay overnight at the study site. 
In the morning of Day 1, you will be randomized to receive either KM-819 or placebo. 
The process of deciding who gets KM-819 and who gets placebo is called randomization, 
which will be performed by a computer. You, the study doctor, and the clinical staff will 
not know what treatment you are receiving because the study is double-blinded. However, 
the study doctor will be able to find out this information, if needed for a valid reason. 
The study doctor may decide not to admit you into the study or may discontinue your 
participation in the study at any time (for example, if the study doctor feels your health 
may be at risk, if the Sponsor decides to discontinue the study for any reason, or if you do 
not follow the instructions given by the study doctor). 
 


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4. DO I HAVE TO TAKE PART? 
It is up to you to decide whether or not to take part. You are free to refuse to participate. 
Even if you refuse to participate in this study, you will not be disadvantaged in any way, 
including medical treatment and care you are entitled to receive. If you decide to 
participate, you may change your mind and decide to withdraw from the study at any time 
and for any reason. You are not required to explain your reasons for withdrawing. If you 
withdraw, you will not suffer any penalty or loss of benefits regarding your future care. 
The study doctor can withdraw you from the study at any time if he or she feels it is in 
your best interest or if you cannot comply with study requirements. 
In addition, your participation in the study may be stopped by the Sponsor or by the 
regulatory authorities or by an independent ethics committee (e.g., Institutional Review 
Board [IRB]/Institutional Ethics Committee [IEC]; these committees review study safety 
and ethics to ensure that subjects’ rights are not violated) at any time without your 
consent, after the reason(s) for doing so (e.g., your own safety, study medication safety, 
Sponsor decision) have been explained to you, and after you have been given advice 
about continued care for your condition, if this is appropriate. Also, the Sponsor has the 
right to stop the study for medical or business reasons. If this happens, all subjects 
participating in the study will be withdrawn. 
If you withdraw (or are withdrawn) from the study, you will be asked to go through study 
withdrawal procedures detailed in Section 5.3 and information about you will be collected 
as detailed in Section 12. 
 
5. WHAT WILL HAPPEN TO ME DURING THE STUDY?  
5.1. Study Medication 
You will be given tablets containing study medication. The tablets will be either KM-819 
or placebo. The KM-819 tablets and placebo tablets look the same. 
You will take the tablets by mouth at the study site only. 
5.2. Study Visits 
5.2.1. Part A 
If you qualify for the study, you will be randomized to receive KM-819 or placebo. 
After an 8-hour overnight fast (no food or drink except water), you will be given KM-819 
or placebo on Day 1 with approximately 240 mL (around 16 tablespoons) of water. Your 
mouth and hands will be checked to make sure you have taken KM-819 or placebo as 
instructed. You will keep fasting for 4 hours after receiving study medication. In addition, 
you will not be allowed to take water or any liquid 1 hour before and after the study 
medication administration. 
The doses are planned to range from 10 mg to 400 mg KM-819. 
Each cohort will start with dosing of 2 subjects; one will receive KM-819 and one will 
receive placebo. If after 24 hours, these subjects have shown no significant side effects, 
the remaining 6 subjects will be dosed with KM-819 or placebo. The remaining 6 subjects 
will have a 5 out of 6 chance of receiving KM-819 and a 1 out of 6 chance of receiving 
placebo. 


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Each dose cohort will be conducted in sequence, starting from 10 mg cohort. After all the 
8 subjects in a dose cohort have been given study medication and observed to Day 4, their 
study results will be reviewed and a decision will be made whether or not to proceed with 
dose escalation and if enrollment of the next dose cohort should occur. 
Within the planned dose range, a dose lower than the next planned dose level may be 
tested in a future cohort, based on the data from previous cohort(s). 
If you are over 60 years old, you will be enrolled when the previous 5 cohorts have been 
finalized. The dose level in your cohort will be 200 mg. 
If you agree to take part in this study, you will have the tests and procedures described 
below. 
The study doctor will talk to you about the things you must do and things you must not do 
during participation. 
5.2.1.1. Screening (Visit 1) 
To determine if you meet the conditions for participation in the study, the study doctor 
will perform a screening evaluation. Before you start the screening evaluation, an 8-hour 
overnight fast is required. Then the following study procedures will be performed: 
• Informed Consent: You will read and review this Informed Consent Form, and 
the study doctor will also explain the study to you, and if you agree to take part in 
the study, you will be asked to sign the form. 
• Medical History: You will be asked about your medical history, including all 
medications, over-the-counter and herbal medications that you have and are 
currently taking. You will also be asked about your alcohol and smoking history. 
• Adverse events: You will be asked about how you are feeling (whether you feel 
okay, different from normal or unwell). 
• Physical Examination: You will have a physical examination, and your general 
health condition will be measured. 
• Height and Weight: Your height and weight will be measured. 
• Vital Signs: Your vital signs including blood pressure, pulse rate, and body 
temperature will be measured. Your blood pressure and pulse rate will be 
measured 3 times, after you have been resting for at least 5 minutes. 
• Electrocardiograms (ECG): You will have an ECG (recording of your heart’s 
electrical activity) which will be performed 3 times after you have been resting for 
at least 5 minutes. 
• Columbia-Suicide Severity Rating Scale (C-SSRS): You will be asked 
questions on whether you ever have considered committing suicide or whether 
you have ever tried to harm yourself or if you have ever attempted suicide. 
• Blood and urine samples for routine lab tests: Blood and urine samples for 
routine lab tests will be collected from you; the main aim of these tests is examine 
your health status. 
o Some of your blood will be tested for human immunodeficiency virus 
(HIV) and hepatitis A, B and C. If any of these test results are positive, 
you will be informed of this. The results from these tests are confidential 
and results will not be shared outside of this study except as required by 
national law. 


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o Your urine will also be tested for drugs of abuse (including amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates). 
• Alcohol breath test: The amount of alcohol in your breath will be tested by 
blowing into a device. 
When all results are available the study doctor will review the entry criteria to find out 
whether or not you qualify to be in this study. 
Even if you meet all qualifications for participation in the study, you may be excluded if 
the study doctor determines that you have any condition that might make the study 
harmful to you or may interfere with the study results. 
A known intolerance, allergic reaction, sensitivity, etc., to any components of the 
medication formulations used in this study will also exclude you from the study. You will 
not be allowed to enter the study if you must take medications not allowed by the study, if 
you have taken alcohol, drugs of abuse or certain medications in a time period considered 
unacceptable by the study doctor or if you have a history of alcohol or drug abuse within 
a certain time period. 
If you qualify and wish to continue with the study, the following study procedures will 
take place. 
5.2.1.2. Confinement Visit (Visit 2) 
The start day of Visit 2 (Day -1) will take place within 28 days after Visit 1, and you will 
be required to attend in the study site after an 8-hour overnight fast on Day -1. 
On Day -1, the procedures: adverse events, physical exam, vital signs, ECG, alcohol 
breath test, blood and urine samples for routine lab tests (except the blood tests for HIV 
and hepatitis A, B and C) will be done the same as you have on Visit 1. You will also 
have the following tests: 
• Concomitant medications: You will be asked about what medications you are 
currently taking. 
• Scales: The following 3 tests will take you around 20 to 30 minutes to complete. 
o Bond and Lader Visual Analogue Scale (VAS): You will be asked to rate 
your feelings and your emotions in a 10 cm line in the scale. 
o Profile of Mood States (POMS): A questionnaire containing 
65 words/statements will be provided to you, and you will need to record 
your feelings. 
o Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV): This test 
contains 10 unique subtests; and you will be asked to complete only the 
Coding subtest. 
If you qualify for the study, you will be required to stay at the study site for the following 
3 nights (from the evening of Day -1 to Day 3). 
In-House Stay Day 1 to Day 3: 
During these 3 days at the study site, the following procedures will be performed: 
• Randomization: you will be randomized to receive either KM-819 or placebo. 
This procedure will only be done once on Day 1. 


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On Day 1, randomization will be performed before the study medication is administered. 
One dose of study medication will be administered between 8:00 and 10:00. The study 
medication will only be administered once on Day 1 during the admission to the study 
site (Day -1 to Day 3). 
The following procedures will be performed at specific time points during these 3 days: 
• 
Vital signs: This will be the same as during Visit 1. On Day 1, your vital signs 
will be measured before you take the study medication, and 4 times within the 
4 hours after you had the study medication. Vital signs will be done once per day 
on Day 2 and Day 3. 
• ECG: This will be the same as during Visit 1. On Day 1, ECGs will be recorded 
before and 1 hour after you take study medication. An ECG will also be recorded 
on Day 2. All ECGs will be recorded 3 times. 
• Blood sampling for pharmacokinetics: This will be done within 30 minutes 
before you take the study medication on Day 1, and 6 mL (less than half 
tablespoon) of blood will be taken from you. The same volume of blood will be 
collected at 8 time points within the 12 hours after receiving study medication. On 
Day 2 and Day 3, the blood samples will only be collected once per day in the 
morning (24 and 48 hours after receiving study medication). 
• Urine sampling for KM-819 analysis: A urine sample will be collected from you 
within 1 hour before receiving study medication on Day 1, and urine will be 
continued to be collected from you until the morning of Day 2 (24 hours after 
receiving the study medication). 
• Scales: This will be the same as on Day -1. On Day 1, this will be done once 
before receiving study medication, and at 3 times within the 12 hours after 
receiving study medication. On Day 2 and Day 3, the scales will be done once per 
day in the morning (24 and 48 hours after receiving study medication). 
Other routine procedures are listed below for Day 1 to Day 3: 
• Adverse events: This will be the same as during Visit 1, and adverse events be 
checked frequently during your hospitalization. 
• Concomitant medications: This will be the same as on Day -1 (Visit 2), and will 
be checked frequently during your hospitalization. 
• Blood and urine samples for routine lab tests: These will be the same as on 
Day -1, and will only be done once on Day 2. The routine lab test will require you 
to fasting for a minimum of 8 hours before. 
• C-SSRS and Physical exam: These will be the same as Visit 1, and will only be 
done once on Day 3. 
5.2.1.3. Outpatient Visits (Visit 3 and Visit 4) 
You will need to return to the study site on Day 4 (Visit 3), and Day 7 (Visit 4). 
The following procedures will be performed: 
• Adverse events and Vital signs: These will be the same as during Visit 1 and 
will be done once at each visit. 
• Concomitant medications: This will be the same as during Visit 1, and will be 
checked and recorded when necessary at each visit. 


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• Blood sampling for pharmacokinetics and Scales: These will only be done in 
the morning of Visit 3 (72 hours after receiving study medication). 
• Blood and urine samples for routine lab tests, and ECG: These will be the 
same as during Visit 1, and only be done at Visit 4. 
5.2.1.4. Follow-up Visit (Visit 5) 
Visit 5 will take place on Day 14. On the day of Visit 5, you will have the following 
procedures performed the same as Visit 1: adverse events, concomitant medications, vital 
signs, physical examination, blood and urine samples for routine lab tests, and ECG. 
5.2.2. Part B 
If you qualify for the study, you will be randomized to receive KM-819 or placebo for 
7 Days, once per day. 
After an 8-hour overnight fast (no food or drink except water), you will be given KM-819 
or placebo on Day 1 to Day 7 with approximately 240 mL (around 16 tablespoons) of 
water. Your mouth and hands will be checked to make sure you have taken KM-819 or 
placebo as instructed. On Day 1 and Day 7, you will keep fasting for 4 hours after 
receiving study medication, and you will not be allowed to take water or any liquid 1 hour 
before and after the study medication administration; On Day 2 to Day 6, you will keep 
fasting for 2 hours after receiving study medication, and you will not be allowed to take 
water or any liquid 1 hour before and 2 hours after the study medication administration. 
The doses are planned to range from 30 mg to a high dose of 400 mg KM-819. 
Each dose cohort will be conducted in sequence, starting from 30 mg cohort. After all the 
8 subjects in a dose cohort have been dosed and observed to Day 8, and their study results 
have been reviewed; a decision will be made whether or not to proceed with dose 
escalation and whether enrollment of the next dose cohort should occur. 
The doses are planned; however, the dose level may be lowered for a cohort based on the 
data from previous cohort(s). 
If you are over 60-years-old, you will be enrolled once the previous 4 cohorts have 
finished. The dose level in your cohort is 200 mg. 
If you agree to take part in this study, you will have the tests and procedures described 
below. 
The study doctor will talk to you about the things you must do and things you must not do 
during participation. 
5.2.2.1. Screening (Visit 1) 
The procedures to be performed at Part B, Visit 1 are exactly the same as Part A, Visit 1, 
please see Section 5.2.1.1. If you are being screened for healthy elderly male and 
post-menopausal cohorts, you will have an additional spine X-ray assessment. 
5.2.2.2. Confinement Visit (Visit 2) 
The start day of Visit 2 (Day -1) will take place within 28 days after Visit 1, and you will 
be required to attend the study site after an 8-hour overnight fast on Day -1. 
On Day -1, the procedures: adverse events, physical exam, vital signs, ECG, alcohol 
breath test, blood and urine samples for routine lab tests (except the blood tests for HIV 


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and hepatitis A, B, and C) will be done the same as you have on Visit 1. You will also 
have the following tests: 
• Concomitant medications: You will be asked about what medications you are 
currently taking. 
• Scales: The following 3 tests will take you around 20 to 30 minutes to complete. 
o Bond and Lader Visual Analogue Scale (VAS): You will be asked to rate 
your feelings and your emotions in a 10 cm line in the scale. 
o Profile of Mood States (POMS): A questionnaire containing 
30 words/statements will be provided to you, and you will need to record 
your feelings. 
o Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV): This test 
contains 10 unique subtests; and you will be asked to complete only 
Coding subtest. 
If you are qualified for the study, you will be required to stay in study site for the 
following 8 nights (from the evening of Day -1 to Day 7). 
In-House Stay Day 1 to Day 7: 
During these 8 days in the study site, the following procedures will be performed: 
• Randomization: you will be randomized to receive either KM-819 or placebo. 
This procedure will only be done once on Day 1. 
• Cerebrospinal fluid (CSF) Sampling for Pharmacokinetics and 
Pharmacodynamics: You will also undergo a lumbar spinal tap to obtain samples 
of CSF, the fluid surrounding your brain and spinal cord. A local anesthetic will 
be administered to temporarily numb a small area of skin on the back. A catheter 
(a small plastic tube) will be inserted into the spinal fluid sac. Approximately 
3.5 mL (more than half teaspoon) of CSF will be taken from you. This sampling is 
for observing pharmacokinetic and pharmacodynamic changes in your body. 
Pharmacodynamics investigates how the study medication affects your body. This 
will be done within 2 hours prior to dosing on Day 1. 
• Plasma Pharmacodynamic Sampling: You will provide approximately 
3 mL blood, taken from venipuncture or cannulation of a forearm vein. This 
sample is also for looking at pharmacodynamics in your body. This will be done 
within 30 minutes prior to dosing on Day 1. 
• Blood and urine samples for routine lab tests: These will be the same as on 
Day -1, and will only be done within 1 hour before receiving study medication on 
Day 2 and Day 4 respectively. This test will require you to keep fasting for a 
minimum of 8 hours before. 
On Day 1, the randomization and vital signs assessment will be performed before the 
administration of study medication. One dose of study medication will be administered 
between 8:00 to 10:00. The study medication will administered once daily from Day 1 
to Day 7. 
The following procedures will be performed at specific time points during these 7 days: 
• 
Vital signs: This will be the same as Visit 1. On Day 1 and Day 4, your vital signs 
will be measured before you have study medication, and 1 hour after you had the 


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study medication. On Day 2, Day 3, Day 5, Day 6, and Day 7, vital signs will be 
done once per day before you take study medication. The schedule of this test 
might be shifted and/or added based on the need. 
• 
ECG: This will be the same as Visit 1. On Day 1 and Day 4, ECG will be done 
before and 1 hour after you take study medication. All ECGs will be recorded 
3 times. 
• Blood sampling for pharmacokinetics: This will be done within 30 minutes 
before you take the study medication on Day 1, and 6 mL (less than half 
tablespoon) of blood will be taken from you. The same volume of blood will be 
collected at 8 time points within the 12 hours after receiving study medication. On 
Day 2 to Day 6, the blood samples will be collected once per day in the morning 
(30 minutes before receiving study medication). 
• Scales: This will be the same as Day -1. On Day 1 and Day 7, this will be done 
once before receiving study medication, and at 3, 6, 12, and 24 hours after 
receiving study medication (thus 1 scales test will be done in the morning of 
Day 8). 
Other routine procedures are listed below for Day 1 to Day 7: 
• Adverse events, Concomitant medications: These will be the same as Visit 1, 
and will be checked frequently during your hospitalization. 
• C-SSRS: These will be the same as Visit 1 and will only be done once on Day 3. 
• CSF Sampling for Pharmacokinetics and Pharmacodynamics and Plasma 
Pharmacodynamics Sampling: These will be the same as on Day 1. These 
samples will only be taken once on Day 7. 
Day 8: 
Before you leave the study site in the morning of Day 8, you will have the following 
procedures to be performed: 
• Adverse events, Concomitant medications, Vital signs, Physical Examination, 
ECG, Blood and urine samples for routine lab tests, and C-SSRS: These will 
be the same as Visit 1. 
• 
Blood sampling for pharmacokinetics and Scales: These will be the same as on 
Day 1 of Visit 2. 
5.2.2.3. Follow-up Visit (Visit 3) 
Visit 3 will take place about 7 days after discharge from the study site during Visit 2. On 
the day of Visit 3, you will have the following procedures performed the same as during 
Visit 1: adverse events, concomitant medications, vital signs, ECG, physical examination, 
and blood and urine samples for routine laboratory tests. 
5.3. Withdrawal 
If you withdraw voluntarily or are withdrawn involuntarily, you will be asked to have the 
tests, examinations, and follow-up questions described above in Follow-up Visit. You 
have the right to refuse these tests and examinations. 


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Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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5.4. Blood Tests, Urinalysis and CSF Sampling 
Blood, urine and CSF samples will be taken from you for laboratory tests. The tests that 
will be done will include standard tests of your general health and a test of how much 
study medication is in your blood, urine and CSF. All your test results are confidential 
and will be disclosed only as required by law. If you agree, your primary and back-up 
samples will be stored up to 3 years after the study has finished, and may be used in other 
studies not related with this study; another informed consent form will be provided to you 
to ask for your consent for storage of your sample(s). If you do not agree, your sample(s) 
will be destroyed after the study has completed. Your decision will not affect your 
participation in this study, and all your blood, urine and CSF samples will be destroyed in 
an appropriate way. 
 
6. WHAT WILL I HAVE TO DO DURING THE STUDY? 
First, you will be asked to sign this consent form if you agree to be included in this study. 
If you take part in this study, you should follow the study procedures and attend all the 
study visits. You should report any side effects to the study doctor. You will have an 
8-hour overnight fast on some of the study days, and you may avoid any food and drink 
after receiving the study medication (except water) as requested by the study doctor. You 
will also be requested to control your total daily food intake and you are not allowed to 
have any alcohol, coffee, grapefruit, Seville oranges, star fruit, or other products 
mentioned by the study doctor. You will not be allowed to do any strenuous exercise. In 
addition, blood donation, any use of concomitant medications (prescribed/non-prescribed 
drugs) and vitamins will not be allowed throughout the duration of the study, with the 
exception of acetaminophen (up to 2000 mg/day). You will receive a subject 
identification card clarifying that you are participating in a clinical study with a new study 
medication. The address of the clinical study institute and an emergency telephone 
number are given in this card. Please carry this card with you during the entire duration of 
the clinical study. 
 
7. WHAT ARE THE POSSIBLE RISKS? 
In a multiple dose study in Beagle dogs, one male dog receiving daily doses of 
2000 mg/kg showed liver damage-related adverse effects including liver enzyme [alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyltransferase 
(γ-GT), etc] levels higher than control group and hypertrophy of hepatic bile duct. This 
was at a very high dose level far above the levels that will be tested in this study. Because 
the study was performed with a small number of animals, it was repeated up to doses of 
1000 mg/kg; no effects were observed in this second study.  
As with all clinical studies, the study medication and study procedures may involve 
unknown risks. Any medication can have temporary and permanent side effects and can 
cause unforeseen adverse reactions. 
Pregnancy 
The study medication may have unknown risks to the baby. If you are a sexually-active 
man, you and your female spouse/partner must use at least 2 forms of birth control 


Kainos Medicine, Inc. 
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Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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throughout the whole study, and until 90 days after your final study medication 
administration. The study doctor will discuss effective methods of birth control with you 
if needed. If your partner becomes pregnant or thinks she may be pregnant during the 
study, contact the study doctor’s office immediately. 
The study doctor must follow up and document the course and the outcome of all 
pregnancies, even if you withdraw from the study or if the study has finished. If your 
partner becomes pregnant during the study, the study doctor will ask to contact your 
partner and your partner’s physician for information about the pregnancy and the child 
until 3 months after the birth. 
Blood samples 
Blood samples will be taken from a vein in your arm during the study. The insertion of 
the cannula (small plastic tube) or the drawing of blood may be associated with some 
pain. The taking of a blood sample may cause some discomfort and bruising, and there is 
a potential for infection. Other risks, although rare, include dizziness and fainting. 
For Part A, a total of 123 mL blood (more than 1/4 of what you would give as a blood 
donor; or around 8 tablespoons) will be taken from you for all the tests. 
For Part B, a total of 201 mL blood (half of what you would give as a blood donor; or 
around 13 tablespoons) and 7 mL CSF (less than half tablespoon) will be taken from you 
for all the tests. 
Blood pressure and heart rate 
An inflatable cuff will be placed on your arm and a machine will measure your blood 
pressure and heart rate, after you have been rested in supine position for5 minutes. You 
may experience mild discomfort in your arm while the cuff is inflated. 
ECG 
Small sticky pads will be stuck to your chest and a machine will measure the electrical 
activity of your heart. The study staff may need to clip small patches of your hair in these 
areas. These sticky pads may cause some local irritation and may be uncomfortable to 
remove. 
X-ray 
You will be exposed to a low level of radiation. The risks associated with a lumbar X-ray 
(radiation) are considered to be minimal. The radiation resulting from the X-rays in the 
study is similar to the amount of natural radiation from living at a moderately high 
altitude for six months. 
CSF sampling 
The risks associated with CSF sampling are similar to those associated with a lumbar 
spinal tap. You may experience headache and/or backache. If a headache occurs, it is 
generally relieved by drinking fluids and lying down. If necessary, you may receive pain 
medication. Headaches can recur for several days, although on rare occasions headaches 
can last longer. If you experience a persistent headache, it is possible that a blood-patch 
will be performed. This involves the injection of a sample of your own blood into the 
region of the tap. The blood-patch has been effective in relieving headache in up to about 
95% of cases. Should you experience a headache during the period after the lumbar spinal 
tap, you must notify the study doctor or the nurse. 


Kainos Medicine, Inc. 
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Most people experience only the minor discomfort of a needle prick when local anesthetic 
is administered. Others experience a few moments of mild to moderate pain similar to 
that experienced when an injection is received. A hypersensitivity or allergic reaction to 
the local anesthetic may occur. The collection of CSF is usually painless. 
Another discomfort that can occur during and following a lumbar spinal tap is a brief pain 
or tingling sensation in either leg. This is caused by a brief stimulation of a nerve and 
ends quickly with no further complications. On rare occasions, a temporary weakness of 
the eye muscle that moves the eye from side to side may develop, producing double 
vision. This complication has been reported to be temporary, and normal vision was 
restored. Other complications are very rare and include nerve root damage, epidural (the 
area outside the covering of the spine) or subdural (spinal) bleeding, infection, and in very 
exceptional cases paralysis, or death. 
 
8. WHAT ARE THE POSSIBLE BENEFITS? 
This study is for research purposes only and as a healthy subject, you will receive no 
direct medical benefit from taking part in this study. However, the information that we get 
from this study may be helpful in treating patients with PD in the future. 
 
9. WILL I INCUR ANY EXPENSES OR RECEIVE ANY PAYMENTS? 
There will be no cost to you or your insurance company for the study medication or the 
study-related procedures and examinations. 
If you have failed the screening, you will not get receive any payment from this study. 
You will be compensated for taking part in the study. 
The compensations (before tax) are listed below for completion of the study: 
 
Healthy young male subjects 
Healthy elderly subjects (over 
60-year old) 
Part A 
800,000 KRW 
900,000 KRW 
Part B 
1,800,000 KRW 
2,000,000 KRW 
You may be chosen as a waiting subject in case you passed the screening procedures 
(You will be asked to come on Day -1 and wait at the study site overnight). If you are not 
enrolled to this study finally, you will be paid 100,000 KRW. 
 
10. WHAT IF I AM INJURED DURING THE STUDY? 
If you experience any unexpected symptoms or injury, and if emergency medical 
treatment is required, please report it immediately to your study doctor or his/her staff 
described in Section 13. 
If you have a physical injury or illness directly related to the study medication or study 
procedure which was properly performed in accordance with the protocol (referred to as a 
study-related injury), medical treatment will be provided to you. You will not be charged 
for this treatment. The Sponsor will cover the cost of reasonable and necessary medical 
treatment for a study-related injury and has insurance to cover the study-related injury. 
Study-related injuries do not include injuries that result from your own fault or intention. 


Kainos Medicine, Inc. 
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Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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Additionally, payment for such things as lost wages, expenses other than medical care, or 
pain and suffering is not available. 
 
11. WHAT WILL HAPPEN IF THERE IS ANY NEW INFORMATION? 
If any new information about the study medication becomes available which may 
influence your decision to continue in the study, you will be told in a timely manner. 
 
12. WILL INFORMATION ABOUT ME BE KEPT CONFIDENTIAL? 
By signing this form you consent to the study doctor and his or her staff collecting and 
using your personal data for the study. This includes: your age, your sex, your ethnic 
origin and information on your physical or mental health or condition. 
The information shared with the Sponsor is protected by the use of a code, which is a 
number specifically assigned to you. The study doctor is in control of the code needed to 
connect your data to you. 
All medical records and research materials that identify you by name will be held 
confidential (confidential data) so far as permitted by law. However the study doctor, the 
Sponsor and its representatives, the study monitor (who checks how the study is going 
and makes sure that the information is being collected properly) and, under certain 
circumstances, the regulatory authorities and ethics committees will be able to inspect 
confidential data that identify you by name. 
All personal data from this study will be treated in accordance with national data 
protection laws. 
By signing this consent form, you grant permission for medical information about you 
obtained during this study (your study data) to be made available to authorized 
representatives of the regulatory authorities and other government agencies. You also 
grant permission for your study data to be made available to the Sponsor, the study 
monitor, other study personnel, and ethics committees. The study doctor, the regulatory 
authorities, and the Sponsor may keep the study data indefinitely. 
You have the right to request information about your study data held by the study doctor 
and the Sponsor. You also have the right to request that any inaccuracies in such data be 
corrected. If you wish to make a request, then please contact the study doctor, who can 
help you contact the Sponsor if necessary. 
Your consent for the use of your study data as described above does not have an 
expiration date. If you withdraw your consent for participating in this study, your study 
data that were collected before you withdrew your consent may still be used as described 
above. Once you have withdrawn your consent for participating in the study, no further 
data will be collected about you for the purposes of this study unless you agree otherwise, 
for example, you agree to have further tests and examinations. If you do agree to have 
further data collected after you have withdrawn your consent, these study data may also 
be used as described above. 
The results of this study may be published in a medical journal and shown at medical 
meetings. You will not be identified (by name or any other means, e.g., photo) in any of 
these publications. 


Kainos Medicine, Inc. 
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Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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By signing this consent form, you authorize the study doctor and his/her staff to use this 
information in conducting the study and to disclose and provide access to or copies of this 
information to the following: 
1. Sponsor Kainos Medicine, Inc., 
2. PAREXEL International (contract research organization conducting the study on the 
Sponsor’s behalf) and other organizations working with the Sponsor to monitor the 
progress of the study or analyze the study data, 
3. The Ministry of Food and Drug Safety (MFDS) or similar, foreign, regulatory 
authorities, 
4. [Insert IRB Name] (Institutional Review Board) to ensure that a subject’s safety and 
rights are protected.  
Access to this information is necessary to ensure that the study is being done correctly, 
and to collect and analyze data about the safety and effectiveness of the study medication. 
The Sponsor and those working with the Sponsor on this study will only use and disclose 
your information as described in this consent form. If reports or articles are written about 
the study, your name will not appear on any report or publication. 
You agree that, while the study is still in progress, you may not be given access to health 
information about you that is related to the study. This may include, for example, 
information about whether you are receiving study medication or placebo, or any other 
information that is “blinded” (that is, kept secret during the study to prevent bias). While 
a request for access to health information can be denied, the study doctor and staff will 
consider whether it is medically appropriate under the circumstances to allow access. 
Your agreement that you may be denied access to your study-related health information 
during the study will not be used to deny you access to that information after the study is 
completed and study results are analyzed. 
You can only participate in the study if you authorize the use and disclosure of the 
information as described above. If you decide not to sign this consent form, you will not 
be enrolled in the study. If you sign this consent form and decide later to withdraw your 
consent, you will not be permitted to continue your participation in the study. Information 
collected up to the time that you withdraw your consent may continue to be used and 
disclosed as described above, but only as necessary to protect the integrity of the study. 
This authorization to use or disclose the information as described above is not time 
limited (that is, will not automatically expire). 
You may decide not to sign this consent form, or you may revoke (withdraw) this 
authorization at any time. You can do this by giving written notice to your study doctor, 
informing him or her that you are revoking your consent to use and disclose your health 
information. The contact information for your study doctor is provided below. 
 
 


Kainos Medicine, Inc. 
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Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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13. WHAT IF I HAVE QUESTIONS? 
If you have questions about the study, or have a problem related to the study, you may 
contact the study doctor or his/her staff at the telephone number below. 
 
Name:_______________________________Telephone: (_____)  ________________ 
 
If you are calling after hours or on a weekend, you may contact. 
 
Name:_______________________________Telephone: (_____)  ________________ 
 
If you have questions about your rights as a research participant, you should contact the 
[Insert IRB Name]. 
 
Telephone: ____________________________________________________________ 
Address: ______________________________________________________________ 
 
 


Kainos Medicine, Inc. 
Model Informed Consent Form 
Protocol Number: KMCP-819-K101, Final 5.0, 13 Feb 2017 
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14. CONSENT STATEMENT OF SUBJECT 
I agree to take part in: 
□ Single dose cohort of 10 mg KM-819 
□ Single dose cohort of 30 mg KM-819 
□ Single dose cohort of 100 mg KM-819 
□ Single dose cohort of 200 mg KM-819 
□ Single dose cohort of 400 mg KM-819 
□ Single dose cohort of 200 mg KM-819 for Elderly male or post-menopausal 
female subjects 
□ Multiple doses cohort of 30 mg KM-819 
□ Multiple doses cohort of 100 mg KM-819 
□ Multiple doses cohort of 200 mg KM-819 
□ Multiple doses cohort of 400 mg KM-819 
□ Multiple doses cohort of 200 mg KM-819 for Elderly male or 
post-menopausal female subjects 
I have received verbal information on the above study and have read the attached written 
information. I have been given the chance to discuss the study and ask questions. 
I voluntarily consent to participate in this study, including all assessments, lifestyle 
restrictions, contraception requirements, and taking of blood, urine and CSF samples. 
I understand that I am free to withdraw at any time. I understand that if I choose to not 
participate or to withdraw, my current medical care will not be affected by this decision. 
I agree that my personal data, including data relating to my physical or mental health or 
condition, and ethnic origin, may be used as described in this consent form. 
I understand that I will receive and may keep a copy of this signed and dated consent 
form. 
By signing and dating this consent form, I have not waived any of the legal rights that I 
would have if I were not a participant in a medical research study. 
 
 
 
 
AM/PM 
 
Signature of Subject 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of Subject 
 
 
 
 
 
 
 
 


Kainos Medicine, Inc. 
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15. STATEMENT OF PERSON CONDUCTING INFORMED CONSENT 
DISCUSSION 
I, the undersigned, certify that to the best of my knowledge, the subject signing this 
consent form had the study fully and carefully explained and clearly understands the 
nature, risks, and benefits of participation in this research study. 
 
 
 
 
AM/PM 
 
Signature of Person Obtaining 
Consent 
Date 
(mm/dd/yyyy) 
Time 
Printed Name of Person 
Obtaining Consent 
 

Prot_000.pdf: 
A First-in-Human, Randomized, Double-blind, Dose Escalation Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Following Single 
and Multiple Oral Doses of KM-819 in Healthy Young Adult and Elderly Subjects 
 
 
Sponsor: 
Kainos Medicine, Inc. 
16, 712 beon-gil, Daewangpankyo-ro, 
Bundang-gu, Seongnam-si, Gyeonggi-do, 
13488, Korea 
Clinical Research Organization: 
PAREXEL International 
Principal Investigator 
Kyoung Soo Lim, MD, PhD 
Assistant Professor 
Department of Clinical Pharmacology and 
Therapeutics 
CHA University School of Medicine and 
CHA Bundang Medical Center 
Sponsor Protocol No.: 
KMCP-819-K101 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Drug Name: 
KM-819 
Development Phase: 
Phase 1 
Date of Protocol: 
13 Feb 2017, Final 5.0 
Date of Previous Protocol: 
28 Dec 2016, Final 4.0 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki,1 and with other applicable 
regulatory requirements. 
This document contains confidential information of Kainos Medicine, Inc. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 


Kainos Medicine, Inc. 
 
Clinical Study Protocol 
Protocol Number: KMCP-819-K101 
 
CONFIDENTIAL 
Final 5.0 
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SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
Title: A First-in-Human, Randomized, Double-blind, Dose Escalation Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Following Single and Multiple 
Oral Doses of KM-819 in Healthy Young Adult and Elderly Subjects 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, 2013 and the guidelines on Good Clinical Practice (GCP). 
 
 
_____________________________________ 
_____________________ 
Name 
Date 
Title 
Institution 
 
 
_____________________________________ 
_____________________ 
Name 
Date 
Title 
Institution 
 


Kainos Medicine, Inc. 
 
Clinical Study Protocol 
Protocol Number: KMCP-819-K101 
 
CONFIDENTIAL 
Final 5.0 
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13 Feb 2017 
Declaration of the Principal Investigator 
 
Title: A First-in-Human, Randomized, Double-blind, Dose Escalation Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Following Single and Multiple 
Oral Doses of KM-819 in Healthy Young Adult and Elderly Subjects 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, as amended in 2013 and the guidelines on Good Clinical 
Practice. 
 
 
Principal Investigator 
 
 
 
_____________________________________ 
_____________________ 
Name 
Date 
Title 
Institution 
 


Kainos Medicine, Inc. 
 
Clinical Study Protocol 
Protocol Number: KMCP-819-K101 
 
CONFIDENTIAL 
Final 5.0 
4 of 72 
13 Feb 2017 
PROTOCOL SYNOPSIS 
Title 
A First-in-Human, Randomized, Double-blind, Dose Escalation Study to 
Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics 
Following Single and Multiple Oral Doses of KM-819 in Healthy Young 
Adult and Elderly Subjects 
Sponsor Study No. 
KM-819 
Phase 
1 
Sponsor 
Kainos Medicine, Inc. 
Principal Investigator 
Kyoung Soo Lim 
Assistant Professor 
Department of Clinical Pharmacology and Therapeutics 
CHA University School of Medicine and CHA Bundang Medical Center 
Study Center 
This study will be conducted in site CHA Bundang Medical Center, Korea. 
Objectives 
Primary objective: 
To evaluate the safety and tolerability of single and multiple ascending oral 
doses of KM-819 in healthy young adult male subjects. 
 
Secondary objectives: 
• 
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) 
of single and multiple ascending oral doses of KM-819 in healthy 
young adult male subjects. 
• 
To evaluate the safety and tolerability of single and multiple oral 
doses of KM-819 in elderly male or post-menopausal female 
subjects. 
• 
To evaluate the PK and PD of single and multiple oral doses of 
KM-819 in elderly male or post-menopausal female subjects. 
Design 
This first-in-human, single-center, randomized, placebo-controlled, 
double-blind, sequential group Phase 1 study in healthy subjects will be 
conducted to evaluate the safety, tolerability, PK, and PD following the 
escalation of single and multiple doses of KM-819. 
The study will consist of 2 parts. In Part A, up to 5 cohorts of young adult 
male subjects, and 1 single-dose cohort of elderly male or post-menopausal 
female subjects will receive escalating single doses of KM-819. In Part B, up 
to 4 cohorts of healthy young adult male subjects and 1 multiple-dose cohort 
of elderly male or post-menopausal female subjects will receive escalating 
multiple doses of KM-819. Part B will be conducted after completion of all 
cohorts of young adult male subjects in Part A. 
Dose escalation to the next level will be determined using safety, tolerability, 
and PK data of the previous cohort. 
 
Part A, Single Ascending Dose (SAD) 
Up to 40 healthy young adult male subjects and 8 healthy elderly male or 
post-menopausal female subjects will be enrolled and randomized to receive 
either KM-819 or placebo. 
Each of the 5 dose escalation cohorts consists of 8 healthy young adult male 
subjects; 6 subjects will receive 10, 30, 100, 200, or 400 mg of KM-819 and 
2 subjects will receive placebo. In each single dose cohort, dosing of subjects 
will be sentinel, i.e., 2 subjects will be dosed on the first day (1 subject will 
receive active treatment and 1 subject will receive placebo) and the remaining 
6 subjects will be dosed at least 24 hours after the first 2 subjects. 
Cohorts will be dosed sequentially with escalating doses. 
Eight elderly male or post-menopausal female subjects will be enrolled into 


Kainos Medicine, Inc. 
 
Clinical Study Protocol 
Protocol Number: KMCP-819-K101 
 
CONFIDENTIAL 
Final 5.0 
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an additional cohort; 6 subjects will receive 200 mg KM-819 and 2 subjects 
will receive placebo. 
 
Part A consists of a Screening period of up to 28 days, and a 3-day 
Confinement period when subjects are hospitalized for study activities. 
Subjects are required to return for outpatient visits on Day 4, 7 and for the 
Follow-up Visit on Day 14. 
 
Part B, Multiple Ascending Dose (MAD) 
Up to 32 healthy young adult male subjects and 8 healthy elderly male or 
post-menopausal female subjects will be enrolled and randomized to receive 
either KM-819 or placebo. 
Each of the 4 dose escalation cohorts consists of 8 healthy young adult male 
subjects; 6 subjects will receive 30, 100, 200, or 400 mg of KM-819 once a 
day (QD) for 7 days and 2 subjects will receive placebo. Cohorts will be 
dosed sequentially with escalating doses. 
Eight elderly male or post-menopausal female subjects will be enrolled into 
an additional cohort; 6 subjects will receive 200 mg KM-819 QD for 7 days 
and 2 subjects will receive placebo. 
 
Part B consists of a Screening period of up to 28 days and an 8-day 
confinement period when they are hospitalized for study activities. Subjects 
are required to return for a Follow-up Visit on Day 14. 
Treatment 
The following treatments will be administered orally to subjects in this study: 
Part A: 
KM-819: 10 mg (1 × 10 mg tablet), 30 mg (3 × 10 mg tablet), 100 mg 
(1 × 100 mg tablet), 200 mg (2 × 100 mg tablet), or 400 mg (4 × 100 mg 
tablet) 
Placebo: KM-819-matched placebo tablet 
 
Part B: 
KM-819: 30 mg (3 × 10 mg tablet), 100 mg (1 × 100 mg tablet), 200 mg 
(2 × 100 mg tablet), or 400 mg (4 × 100 mg tablet) 
Placebo: KM-819-matched placebo tablet 
Number of Subjects 
Part A: up to 40 healthy young adult male and 8 healthy elderly male or 
post-menopausal female subjects will be enrolled. 
Part B: up to 32 healthy young adult male and 8 healthy elderly male or 
post-menopausal female subjects will be enrolled. 
Population 
For Parts A and B: healthy young adult male (19 to 45 years old) or healthy 
elderly male or post-menopausal female (over 60 years old). 
 
Inclusion/Exclusion Criteria: 
Waivers for inclusion/exclusion criteria will not be granted. 
Inclusion: 
1. Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approved written informed consent and privacy 
language as per national regulations must be obtained from the 
subject prior to any study-related procedures (including withdrawal 
of prohibited medication, if applicable). 
2. Male subject should be 19 to 45 years old (for young adult cohorts) 
or over 60 years old (for elderly cohorts). 
3. Subject has a body mass index (BMI) range of 18.5 to 30 kg/m2 
inclusive at Screening. 


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Clinical Study Protocol 
Protocol Number: KMCP-819-K101 
 
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4. Male subject and his female spouse/partner who is of childbearing 
potential must be using highly effective contraception consisting of 
2 forms of birth control (at least one of which must be a barrier 
method) starting at Screening and continuing throughout the study 
period and for 90 days after final study drug administration. 
Highly effective contraception is defined as: 
• 
Established use of oral, injected, or implanted hormonal 
methods of contraception 
• 
Placement of an intrauterine device or intrauterine system 
• 
Barrier methods of contraception: condom with spermicidal 
foam, gel, film, cream, suppository or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam, 
gel, film, cream, or suppository 
5. Male subject must not donate sperm starting at Screening, 
throughout the study period and for at least 90 days after final study 
drug administration. 
6. Female subject must be over 60 years old and post-menopausal 
(defined as at least 1 year without any menses) prior to Screening. 
7. Subject agrees not to participate in another investigational study 
while on study treatment. 
 
Exclusion: 
For all subjects: 
1. Subject has a known or suspected hypersensitivity to KM-819, or 
any components of the formulation(s) used. 
2. Subject has previously participated in a clinical study with KM-819. 
3. Subject has any of the liver enzymes (aspartate aminotransferase 
[AST], alanine transaminase [ALT], alkaline phosphatase, 
γ-glutamyl transferase) or total bilirubin (TBIL) above the upper 
limit of normal (ULN). If any liver enzyme is > 1 × ULN but 
< 1.5 × ULN, the assessment may be repeated once during the 
Screening period or on check-in. If the repeated assessment is above 
the ULN, it is exclusionary. If the initial value is > 1.5 × ULN, it 
cannot be repeated and is exclusionary. 
4. Subject has any clinically significant history of allergic conditions 
(including drug allergies, asthma, eczema, or anaphylactic reactions, 
but excluding untreated, allergic rhinitis or rhino-conjunctivitis, or 
house dust mite allergy at time of dosing). 
5. Subject with a history of a suicide attempt or suicidal behavior. Any 
recent suicidal ideation (a level of 4 or 5) within the last 3 months, 
or having a positive Columbia Suicide Severity Rating Scale 
(C-SSRS) at check-in (Day -1), or who is at significant risk to 
commit suicide, as judged by the Investigator using the C-SSRS at 
Screening. 
6. Subject has/had febrile illness or symptomatic viral, bacterial 
(including upper respiratory infection) or fungal (non-cutaneous) 
infection within 1 week before site check-in. 
7. Subject has any clinically significant abnormality following the 
Investigator’s review of the physical examination, electrocardiogram 
(ECG), and protocol-defined clinical laboratory tests at Screening or 
site check-in. 
8. Subject has a mean pulse < 40 or > 90 beats per minute (bpm); mean 
systolic blood pressure (SBP) > 140 mmHg; or mean diastolic blood 
pressure (DBP) > 90 mmHg (measurements taken in triplicate after 


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subject has been resting in the supine position for 5 minutes; pulse 
will be measured automatically) at Screening or check-in. If the 
mean pulse, mean SBP, or mean DBP is out of the range specified 
above, 1 additional triplicate measurement may be taken at 
Screening and check-in. 
9. Subject has a mean QTcF interval of > 430 msec (for males) and 
> 450 msec (for females) at Screening or check-in. If the mean 
QTcF exceeds the limits above, 1 additional triplicate ECG can be 
taken. If this triplicate also gives an abnormal result, the subject 
should be excluded. 
10. Subject has a history of unexplained syncope, cardiac arrest, 
unexplained cardiac arrhythmias or torsade de pointes, structural 
heart disease, or a family history of Long QT Syndrome. 
11. Subject has use of any prescribed or non-prescribed drugs (including 
vitamins, hormone replacement therapy, natural and herbal 
remedies, e.g., St. John’s Wort) in the 2 weeks before study drug 
administration. Acetaminophen up to 2000 mg/day is allowed. 
12. Subject has had any use of tobacco- or nicotine-containing products 
within 6 months prior to Screening. 
13. Subject has history of consuming more than 14 units of alcoholic 
beverages per week within 6 months prior to Screening or has a 
history of alcoholism or abuse of amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates 
(drugs-of-abuse) within the past 2 years prior to Screening (Note: 
1 unit = 355 mL of beer, 118 mL of wine, or 29 mL of spirits/hard 
liquor) or the subject tests positive at Screening or site admission for 
alcohol or drugs-of-abuse. 
14. Subject has used any drugs-of-abuse within 3 months before 
check-in. 
15. Subject has used any inducers of metabolism (e.g., barbiturates, 
rifampin) in the 3 months prior to check-in. 
16. Subject has any significant blood loss, donated 1 unit (450 mL) of 
blood or more, or received a transfusion of any blood or blood 
products within 60 days, or donated plasma within 7 days before 
check-in. 
17. Subject has a positive serology test for hepatitis B surface antigen 
(HbsAg), anti-hepatitis A virus Immunoglobulin M (HAV IgM), 
anti-hepatitis C virus (HCV Ab), or anti-human immunodeficiency 
virus (HIV Ab). 
18. Subject has participated in any interventional clinical study or has 
been treated with any investigational drugs within 3 months or 
5 half-lives, whichever is longer, before the initiation of Screening. 
19. Subject has (recent history of) any other condition which, in the 
opinion of the Investigator, precludes the subject’s participation in 
the trial. 
20. Subject is an employee of the Kainos Medicine, Inc. or vendors 
involved in the study. 
 
Additional Exclusion Criteria for Young Adult Subjects 
21. For young adult cohorts, subject has any history or evidence of any 
clinically significant cardiovascular, gastrointestinal, endocrinologic, 
hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, 
neurologic, dermatologic, psychiatric, renal, and/or other major 
disease or malignancy, as judged by the Investigator or designee. 


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Exclusion Criteria for Elderly Subjects 
Replacement for Exclusion No. 8 above 
8. Subject has a mean pulse < 50 or > 90 bpm; mean SBP 
> 160 mmHg; mean DBP > 100 mmHg (measurements taken in 
triplicate after subject has been resting in supine position for 
5 minutes; pulse will be measured automatically). 
Replacement for Exclusion No. 21 above 
21. For elderly cohorts, subject has any history or evidence of any 
clinically significant cardiovascular, gastrointestinal, endocrinologic, 
hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, 
neurologic, dermatologic, psychiatric, renal, and/or other major 
disease or malignancy that is not well managed and stable, as judged 
by the Investigator or designee. 
Additional Exclusion Criteria 
22. Elderly subject is excluded if the Glomerular Filtration Rate 
(calculated based on Cockcroft-Gault formula) is 
< 60 mL/min/1.73 m2. 
23. Clinically significant abnormal findings in the lumbar X-ray 
examination (only for elder subjects for MAD study). 
 
Dose Escalation Criteria: 
In Part A, escalation to the next dose level will take place only after the safety 
and tolerability data for all subjects in the cohort (through Day 4) and 
available plasma PK data (through the 72-hour sample postdose) from the 
previously administered dose cohort has been reviewed. Data from 
exploratory PD assessments and central nervous system (CNS) scales will not 
be included in the review for dose escalation decisions. Within the planned 
dose range a dose lower than the next planned dose level may be tested, 
depending on the emerging safety, tolerability and/or other relevant data (e.g., 
plasma PK data). 
 
Stopping Criteria for Dose Escalation: 
Dosing will be stopped if 1 (or more) of the following apply. Depending on 
the nature of the adverse events (AE)s, it could be decided to investigate a 
lower dose level (intermediate between the current and the prior one) in the 
next group. 
1. If 1 or more subjects experiences a study drug-related serious 
adverse event (SAE), unblinding of the subject(s) will be done. If the 
subject(s) was (were) on active treatment, dosing will be stopped. 
2. If 2 subjects in 1 dose group show the following findings in 
2 consecutive postdose measurements within 24 hours and if 
unblinding reveals that both subjects received active treatment, 
dosing will be stopped: 
a. 
ALT or AST ≥ 3 x ULN or, 
b. ALT or AST ≥ 2 x ULN and ALT or AST ≥ 5 x baseline 
value or, 
c. 
TBIL ≥ 2 x ULN 
3. If 2 or more subjects in 1 cohort experience AEs of severe intensity 
or 4 or more subjects in 1 cohort experience AEs of moderate 
intensity, which are considered by the Principal Investigator (PI) 
and/or Sponsor to be possibly or probably related to the 
investigational product, and of clinical concern, and if unblinding 
reveals that these subjects received active treatment, dosing will be 


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stopped. 
 
PK stopping criteria 
The decision to escalate to the next planned dose will also be based on review 
of PK exposure data from previous dose cohort(s). All available PK data will 
be used to estimate the expected exposures (AUC and Cmax) of the next dose 
level using modeling. If predicted mean AUC and Cmax for the next dose level 
is higher than 41.3 ug.h/mL and 9.3 ug/mL, respectively, then the dose 
escalation will stop and the Sponsor and PI will need to review the totality of 
data, including safety and PK before make any dose escalation decision. 
 
Discontinuation of Individual Subject(s): 
A discontinued subject is a subject who is enrolled in the clinical study and 
for whom study treatment is permanently discontinued prematurely for any 
reason. 
A subject may withdraw from the study at any time without penalty and for 
any reason without prejudice to his/her future medical care. Participation of 
subjects may also be discontinued based on the medical judgment of the PI in 
conjunction with the Sponsor for any of the following reasons: 
• 
ECG abnormalities: 
Any increases in QTcF > 500 msec or increase > 60 msec from 
baseline as confirmed with 3 consecutive ECGs taken within 
5 minutes, with at least a 1-minute interval. 
• 
Suicidality: 
Any suicide attempt or any recent suicidal ideation (a level of 4 or 5) 
since the last assessment, or a significant risk to commit suicide, as 
judged by the PI using the C-SSRS. 
• 
Liver Safety Monitoring: 
Please refer to Stopping Criteria No. 2. 
• 
After enrolment, the subject is found to violate the inclusion and/or 
exclusion criteria 
• 
AE(s) 
• 
Subject lost to follow-up 
• 
Major protocol violation 
• 
Use of prohibited medications 
• 
Any serious safety concern 
• 
Premature termination of the study 
• 
Others 
A clear and concise reason for discontinuation will be recorded in the 
electronic case report form (eCRF). Subjects who are discontinued will have 
an Early Discontinuation (ED) Visit per the Schedules of Assessments. 


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Criteria for Evaluation 
of Pharmacokinetic and 
Pharmacodynamic 
Pharmacokinetic Endpoints: 
KM-819 
Plasma PK parameters for KM-819 include the following for single dose 
and/or multiple dose analysis: AUCtau, AUCinf, AUCinf (%extrap), AUClast, 
CL/F, Cmax, Ctrough, λz, Rac (AUC), Rac (Cmax), t1/2, tlag, tmax, Vz/F, and other 
parameters, as appropriate, including dose-adjusted parameters. 
Cerebrospinal fluid (CSF) PK parameters for KM-819 include the following 
for multiple dose analysis: KM-819 concentration in CSF. 
Pharmacodynamic Endpoints: 
In both Parts A and B, mean and absolute value change from baseline at each 
post-baseline measurement for Bond and Lader Visual Analogue Scale 
(VAS), Profile of Mood States (POMS), Korean Wechsler Adult Intelligence 
Scale-IV (K-WAIS-IV), and C-SSRS. 
In Part B only, PD parameters in plasma and CSF including: alpha synuclein 
oligomer, total Tau, phospho-Tau, and ratio of CSF concentration/Plasma 
Cmax. 
Criteria for Evaluation 
of Safety 
Safety Endpoints: 
Parts A and B 
• 
Reporting AEs (nature, frequency, severity, time of onset/offset) 
• 
Standard clinical laboratory evaluations 
• 
Vital signs measurements (tympanic temperature, supine pulse, and 
supine blood pressure [BP]) 
• 
12-lead ECGs 
Statistical Methods 
Study Part A and B will be analyzed separately. Three analysis sets will be 
used. 
• 
The safety analysis set (SAF) will be the primary analysis set for all 
safety displays and consists of all subjects who received at least one 
dose. 
• 
The PK analysis set (PKAS) will be the primary analysis set for all 
PK displays and analyses, consists of all subjects from the SAF for 
whom sufficient plasma concentration data are available to facilitate 
the calculation of at least one PK parameter and no important 
protocol deviations affecting the PK variables, as confirmed during 
a pre-analysis review of the data prior to database lock. 
• 
The PD analysis set (PDAS) consists of all subjects from the SAF 
for whom sufficient data for neuropsychologic testing (Parts A and 
B) or plasma and CSF concentration data are available (Part B) to 
facilitate the calculation of at least one PD parameter and had no 
important protocol deviations affecting the PD analysis, as 
confirmed during a pre-analysis review of the data prior to database 
lock. 
 
Continuous variables will be summarized using descriptive statistics (number 
of observations, mean, standard deviation [SD], minimum, median, 
maximum, geometric mean, and coefficient of variation [CV]). Categorical 
variables will be described using absolute and relative frequency. 
 
Dose-proportionality analysis will be performed as an exploratory analysis. 


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Dose proportionality for primary PK parameter (Cmax and AUCinf will be 
examined via the power model and will be summarized and reported 
graphically. The PK parameters and the dose will be logarithmically (ln) 
transformed prior to analysis. An alpha level of 5% will be used. 
 
Additionally, an analysis of variance (ANOVA) of the natural 
log-transformed dose-normalized PK parameters AUCinf/dose and Cmax/dose 
with log-transformed KM-819 dose as a covariate and subject as random 
effect, will be performed to estimate the slope of the effect of dose level on 
the PK parameter and its 95% Confidence Interval (CI). 
 
The PK parameters will be plotted versus dose level of KM-819 including the 
regression line from the statistical analysis. Plots will be presented for 
dose-normalized parameters based on absolute dose. 
 
Sample Size Justification: 
The sample size of 8 subjects each cohort in both parts is standard in 
First-in-Human studies for dose escalation. The number of subjects planned 
for both parts of this study is considered sufficient to achieve the study 
objectives (safety, tolerability, PK, and PD). 
 
Subjects who discontinue from study may be replaced at the discretion of the 
Sponsor. 
 
Efficacy: 
Efficacy will not be tested in this study. 
 
Pharmacokinetics: 
Descriptive statistics (number of subjects, mean, SD, CV%, median, 
minimum, and maximum) will be used to summarize plasma KM-819 PK 
continuous parameters and plasma KM-819 concentrations by dose group 
where appropriate. Geometric means will also be provided for AUCtau, 
AUClast, AUCinf, and Cmax. Individual and mean plasma KM-819 
concentration-time curves on normal and semi-logarithmic scales will be 
provided. Overlay plots by treatment group will also be provided. 
 
Pharmacodynamics: 
Part A and B: 
To evaluate the effect of KM-819, descriptive statistics for continuous and 
categorical variables will be used to summarize PD parameters: VAS, POMS, 
K-WAIS-IV, and C-SSRS. 
Part B: 
Descriptive statistics variables will be used to summarize PD parameters by 
dose group where appropriate. Modeling of PK/PD variables may be 
performed if considered necessary. 
No formal interim analysis is planned. 
 
Details of the statistical analysis will be provided in Statistical Analysis Plan 
(SAP). 
 
Schedule of Procedures 
Schedule of Procedures for Part A and for Part B are described in Section 7.1. 
 
 


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LIST OF STUDY PERSONNEL 
 
Sponsor 
Kainos Medicine, Inc. 
16, 712 beon-gil, Daewangpankyo-ro, Bundang-gu, 
Seongnam-si, Gyeonggi-do, 13488, Korea 
Principal or Global 
Coordinating Investigator 
Kyoung Soo Lim, MD, PhD 
Assistant Professor 
Department of Clinical Pharmacology and Therapeutics 
CHA University School of Medicine and CHA Bundang 
Medical Center 
Contract Research 
Organization 
PAREXEL International 
70 Sir John Rogerson’s Quay, 
Dublin 2, Ireland 
Telephone number: +3531 473 9500 
Adverse Event Reporting 
PAREXEL International  
Room 1505, 15F, KunTai International Mansion, 
Yi No. 12, Chao Yang Men Wai Street, Chaoyang 
District, 
Beijing, 100020, China 
Telephone number: +65-62218582 
Toll free fax number: 00308-13-2766 
Specific Laboratory 1 
Bioinfra 
7F, Kyunggi Bio-Center, 147, Gwanggyo-ro, 
Yeongtong-gu, Suwon-si, Gyeonggi-do, 16229, Korea 
Telephone number: +82-31 888 6270 
Specific Laboratory 2 
Green Cross Lab. Cell Corp. 
107 (Bojeong-dong), 30, Ihyeon-ro, Giheung-gu, 
Yongin-si, Gyeonggi-do, 16924, Korea 
Telephone number: +82-2 2669 0481 
 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 4 
LIST OF STUDY PERSONNEL ............................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 17 
1 
INTRODUCTION........................................................................................................... 19 
1.1 
Background ................................................................................................................. 19 
1.2 
KM-819 ........................................................................................................................ 19 
1.2.1 
Non-clinical Data ............................................................................................ 20 
1.2.1.1 
Pharmacology ........................................................................................... 20 
1.2.1.2 
Safety Pharmacology ................................................................................ 20 
1.2.1.3 
Pharmacokinetics ...................................................................................... 21 
1.2.1.4 
Toxicology ................................................................................................. 21 
1.2.2 
Clinical Data ................................................................................................... 21 
1.3 
Rationale ..................................................................................................................... 22 
1.4 
Risk-Benefit Assessment ............................................................................................ 22 
2 
STUDY OBJECTIVES ................................................................................................... 23 
2.1 
Primary Objective ...................................................................................................... 23 
2.2 
Secondary Objectives ................................................................................................. 23 
3 
OVERALL DESIGN AND PLAN OF THE STUDY .................................................. 24 
3.1 
Overview ..................................................................................................................... 24 
3.2 
Criteria for Evaluation of the Study ......................................................................... 26 
3.2.1 
Safety Endpoints ............................................................................................. 26 
3.2.2 
Pharmacokinetic Endpoints ............................................................................ 26 
3.2.3 
Pharmacodynamic Endpoints .......................................................................... 27 
3.3 
Justification of the Study Design .............................................................................. 28 
3.4 
Dose Escalation Criteria ............................................................................................ 28 
3.5 
Stopping Criteria for Dose Escalation ...................................................................... 28 
3.5.1 
PK stopping criteria ........................................................................................ 29 
4 
STUDY POPULATION ................................................................................................. 30 
4.1 
Inclusion Criteria ....................................................................................................... 30 
4.2 
Exclusion Criteria ...................................................................................................... 30 
4.3 
Subject Withdrawal and Replacement ..................................................................... 33 
4.4 
Planned Sample Size and Number of Study Centers .............................................. 33 
4.5 
Subject Identification and Randomization .............................................................. 34 
4.5.1 
Subject Identification ...................................................................................... 34 
4.5.2 
Randomization Scheme .................................................................................. 34 
4.5.3 
Allocation/Randomization of Subjects to Treatment ...................................... 34 
5 
STUDY DRUG ................................................................................................................ 35 
5.1 
Identity ........................................................................................................................ 35 
5.2 
Administration ............................................................................................................ 35 


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5.3 
Rationale for Selection of Starting Dose .................................................................. 36 
5.4 
Packaging, Labeling and Storage ............................................................................. 36 
5.5 
Blinding and Breaking the Blind .............................................................................. 36 
5.6 
Drug Accountability ................................................................................................... 37 
5.7 
Compliance ................................................................................................................. 37 
5.8 
Previous and Concomitant Medications .................................................................. 37 
5.9 
Restrictions during the Study ................................................................................... 37 
6 
VARIABLES AND METHODS OF ASSESSMENT .................................................. 39 
6.1 
Pharmacokinetics and Pharmacodynamics Assessment ........................................ 39 
6.1.1 
Pharmacokinetics Assessment ........................................................................ 39 
6.1.2 
Pharmacodynamic Assessment ....................................................................... 39 
6.2 
Pharmacokinetic Variables ....................................................................................... 39 
6.2.1 
KM-819 Pharmacokinetic Blood Sampling .................................................... 39 
6.2.2 
KM-819 Urine Sampling ................................................................................ 39 
6.2.3 
KM-819 Pharmacokinetic CSF Sampling ...................................................... 40 
6.3 
Pharmacodynamic Variables .................................................................................... 40 
6.3.1 
Scales .............................................................................................................. 40 
6.3.1.1 
Bond and Lader VAS ................................................................................. 40 
6.3.1.2 
Profile of Mood States .............................................................................. 40 
6.3.1.3 
Korean Wechsler Adult Intelligence Scale-IV .......................................... 40 
6.3.2 
Columbia Suicide Severity Rating Scale ........................................................ 41 
6.3.3 
KM-819 Pharmacodynamic Blood Sampling ................................................. 41 
6.3.4 
KM-819 Pharmacodynamic CSF Sampling.................................................... 41 
6.4 
Safety Variables .......................................................................................................... 41 
6.4.1 
Adverse Events ............................................................................................... 41 
6.4.1.1 
Collection of Adverse Events .................................................................... 41 
6.4.1.2 
Definitions ................................................................................................. 41 
6.4.1.3 
Assessment of Adverse Events ................................................................... 42 
6.4.1.4 
Recording Adverse Events ........................................................................ 43 
6.4.1.5 
Reporting Serious Adverse Events ............................................................ 44 
6.4.1.6 
Follow-up of Adverse Events .................................................................... 44 
6.4.1.7 
Suspected Unexpected Serious Adverse Reactions ................................... 44 
6.4.1.8 
Pregnancy ................................................................................................. 45 
6.4.2 
Laboratory Variables ...................................................................................... 45 
6.4.3 
Vital Signs ....................................................................................................... 47 
6.4.4 
Electrocardiograms ......................................................................................... 47 
6.4.5 
Physical Examinations .................................................................................... 48 
6.5 
Demographics and Baseline Characteristics ........................................................... 48 
6.5.1 
Subject Demography ....................................................................................... 48 
6.5.2 
Body Measurements........................................................................................ 48 
6.5.3 
Medical History .............................................................................................. 48 
6.5.4 
Previous and Concomitant Medications ......................................................... 49 
7 
STUDY CONDUCT ........................................................................................................ 50 
7.1 
Schedule of Procedures .............................................................................................. 50 
7.2 
Procedures by Visit .................................................................................................... 56 


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7.2.1 
Screening (Visit 1) for Part A and Part B ....................................................... 56 
7.2.2 
Visits for Part A Single Ascending Dose ........................................................ 56 
7.2.2.1 
Confinement Visit (Visit 2) ........................................................................ 56 
7.2.2.2 
Outpatient Visits (Visit 3 to Visit 4) .......................................................... 58 
7.2.2.3 
Follow-up Visit (Visit 5)............................................................................ 58 
7.2.3 
Visits for Part B Multiple Ascending Dose .................................................... 58 
7.2.3.1 
Confinement Visit (Visit 2) ........................................................................ 58 
7.2.3.2 
Follow-up Visit (Visit 3)............................................................................ 60 
7.2.4 
Early Termination Visit .................................................................................. 60 
8 
STATISTICAL METHODS .......................................................................................... 62 
8.1 
Study Subjects ............................................................................................................ 62 
8.1.1 
Disposition of Subjects ................................................................................... 62 
8.1.2 
Protocol Deviations ......................................................................................... 62 
8.1.3 
Analysis Sets ................................................................................................... 62 
8.2 
General Considerations ............................................................................................. 63 
8.2.1 
Missing Data ................................................................................................... 63 
8.3 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications ................................................................................................................. 63 
8.4 
Treatment Compliance .............................................................................................. 64 
8.5 
Efficacy Analyses ........................................................................................................ 64 
8.5.1 
Primary Efficacy Analysis .............................................................................. 64 
8.5.1.1 
Hypothesis to be Tested ............................................................................ 64 
8.5.1.2 
Statistical Methods .................................................................................... 64 
8.5.1.3 
Subgroup Analyses .................................................................................... 64 
8.5.2 
Secondary Efficacy Analyses ......................................................................... 64 
8.6 
Safety Analyses ........................................................................................................... 64 
8.6.1 
Adverse Events ............................................................................................... 64 
8.6.2 
Vital Signs and Electrocardiogram ................................................................. 65 
8.6.3 
Safety Laboratory Parameters ......................................................................... 65 
8.6.4 
Other Analyses ................................................................................................ 65 
8.7 
Pharmacokinetic Analysis ......................................................................................... 65 
8.7.1 
Dose Proportionality (Part A) ......................................................................... 65 
8.8 
Pharmacodynamic Analysis ...................................................................................... 66 
8.9 
Interim Analyses ......................................................................................................... 66 
8.10 
Determination of Sample Size ................................................................................... 66 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ..................................... 67 
9.1 
Data Quality Assurance ............................................................................................. 67 
9.1.1 
Database Management and Quality Control ................................................... 67 
9.2 
Case Report Forms and Source Documentation ..................................................... 67 
9.2.1 
Data Collection ............................................................................................... 67 
9.3 
Access to Source Data ................................................................................................ 68 
9.4 
Data Processing .......................................................................................................... 68 
9.5 
Archiving Study Records ........................................................................................... 69 
9.6 
Good Clinical Practice ............................................................................................... 69 
9.7 
Informed Consent ....................................................................................................... 69 


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9.8 
Protocol Approval and Amendment ......................................................................... 69 
9.9 
Duration of the Study ................................................................................................. 69 
9.10 
Premature Termination of the Study ....................................................................... 70 
9.11 
Confidentiality ............................................................................................................ 70 
9.12 
Other Ethical and Regulatory Issues (Optional) ..................................................... 70 
9.13 
Liability and Insurance .............................................................................................. 70 
9.14 
Publication Policy ....................................................................................................... 71 
10 
REFERENCE LIST ........................................................................................................ 72 
 
Tables in Text 
Table 3-1: Dose Groups for Part A ............................................................................................... 24 
Table 3-2: Dose Groups for Part B ............................................................................................... 25 
Table 5-1: Identity of the Study Drugs ......................................................................................... 35 
Table 5-2: Composition of Each Study Drug Tablet .................................................................... 35 
Table 6-1: Causal Relationship of Adverse Event to Study Drug ................................................ 43 
Table 6-2: Laboratory Assessments .............................................................................................. 46 
Table 7-1: Schedule of Assessments for Part A (SAD) ................................................................ 50 
Table 7-2: Schedule of Assessments for Part B (MAD) ............................................................... 52 
Table 7-3: Pharmacokinetic Sampling Time points for Part A (SAD) ......................................... 54 
Table 7-4: Pharmacokinetic Sampling Time points for Part B (MAD) ........................................ 55 
 
Figures in Text 
Figure 3-1: Part A Single Ascending Dose Study Design ............................................................ 25 
Figure 3-2: Part B Multiple Ascending Dose Study Design ......................................................... 26 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse event 
AEI 
Adverse event of interest 
ALD 
Approximate lethal dose 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence interval 
CNS 
Central nervous system 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED 
Early discontinuation 
EDC 
Electronic data capture 
FAF1 
Fas (TNFRSF6)-associated factor 1 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAV 
Hepatitis A virus 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 


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IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
K-WAIS-IV 
Korean Wechsler Adult Intelligence Scale-IV 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
NOAEL 
No Observed Adverse Effect Level  
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PO 
Per oral 
PPS 
Per-Protocol Set 
SAD 
Single Ascending Dose 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reaction 
TBIL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VAS 
Visual Analogue Scale 


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1 
INTRODUCTION 
1.1 
Background 
There are approximately 90 million patients with central nervous system (CNS) disease 
worldwide in 2005, and it is expected to increase up to 130 million in 2030. Parkinson’s disease 
and Alzheimer patients are expected to increase by 66% from 2005 to 2030.2 High number of 
new incidents of both diseases is expected in 7 countries (US, Japan, France, Germany, Italy, 
Spain, and England), estimated to be more than 1.5 million.3 In the US, the incidence is 50,000-
60,000 every year, and in Korea it is also increasing rapidly due to recent increase of the aging 
population. In Korea, the number of Parkinson’s disease patients was 39,000 in 2004, increased 
1.7 folds to 66,000 in 2008, and has increased further to between 100,000 and 150,000 in 2010. 
Ninety-five percent of patients are over 50 years old.4 
Parkinson’s disease is a progressive neurodegenerative disease caused by loss of dopaminergic 
neurons in substantia nigra in mid brain. The symptoms include bradykinesia, resting tremor, 
rigidity, unstable posture, and postural reflex impairment. The therapeutic drugs for its cause and 
progression are limited and not sufficient for medical needs. 
Although mechanism for the neuron loss is unknown, the movement control ability can be 
temporally improved by the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA). 
Current drugs are classified largely into 4 classes (dopamine supplements, dopamine catechol-O-
methyl transferase (COMT) inhibitor, dopamine precursors, and MAO-B inhibitors). These 
medicines supplement dopamine or help for relieving symptoms, but there is no remedy for the 
cause of disease such as inhibiting the death of dopaminergic neuron cells. Also, the current 
medicines require increasing dose over time and have serious side effects such as insomnia, 
movement impairment, and tremors. 
1.2 
KM-819 
KM-819 is an innovative new drug that protects neuron cells from death through inhibition of the 
function of Fas (TNFRSF6)-associated factor 1 (FAF1), a cell death inducing protein in 
dopamine neuron cells. 
It has been reported that the expression of FAF1 is increased in Parkinson’s patient’s brain 
tissue.5 Animal models relevant to Parkinson’s disease have confirmed a significant increase of 
FAF1 in the midbrain. Parkinson’s disease cell and animal models have confirmed an inhibition 
of cell death when FAF1 expression is reduced.6 Therefore, FAF1 is validated as a potential 
novel target for new drug discovery for Parkinson’s disease. KM-819 has been developed as a 
compound targeting FAF1 as a therapy drug for Parkinson’s disease. 
KM-819 not only protects dopaminergic neuron cell from death (neuroprotection), but may also 
improve behavior similar to other drugs. Therefore, if KM-819 becomes successful as a new 
drug, it is expected to replace the current market and create new market by fulfilling unmet 
medical needs. 


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1.2.1 Non-clinical Data 
1.2.1.1 Pharmacology 
KM-819 is a drug candidate with EC50 value of nM range for in vitro cell death protection assay 
study (in human neuronal cell line 200.3 nM and rat primary neuron 134.5 nM), and confirmed 
to exhibit dopaminergic neuron cell protection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
(MPTP)-induced Parkinson’s disease animal models, and to have a superior neuron cell 
protection effects and the similar behavioral improvement effects compared to L-dopa. In 
addition, it demonstrates specific binding to the target protein FAF1 upon cell death related to 
Parkinson’s disease. 
In vitro efficacy of the FAF1 inhibitor KM-819 in Parkinson’s disease cell model was evaluated 
using dopaminergic neuron cells obtained from rat substantia nigra. The cells treated with KM-
819 showed better protection from death to MPTP compared to untreated cells in a dose-
dependent manner (0.1, 1, and 10 uM). 
Inhibitory effect of KM-819 on FAF1 signaling in Parkinson’s disease cell model was evaluated 
using the human neuroblast cell line SH-SY5Y. Treatment with KM-819 inhibited the interaction 
of FAF1 with Caspase-8 and JNK1, 2 downstream targets of FAF1, in Parkinson’s disease cell 
model induced by H2O2, and the subsequent studies done by Western blotting gave results that 
the drug inhibited the activation of Caspase-8 and JNK1 from 100 nM to 10 uM in a dose-
dependent manner. 
In acute Parkinson’s disease models induced by MPTP in vivo, treatment with KM-819 at 20 
mg/kg for 6 consecutive days orally protected dopaminergic neuron cells both in substantia nigra 
and striatum, compared to non-treated controls, and also improved the behavioral impairments in 
these models. These effects were dose-dependent at 1, 10, and 20 mg/kg. 
In sub-acute Parkinson’s disease models induced by MPTP, the effects of KM-819 were 
compared to a current Parkinson’s disease drug L-dopa. Treatment with KM-819 at 20 mg/kg for 
6 consecutive days orally protected dopaminergic neuron cells better than treatment with L-dopa 
which was injected into abdominal cavity at 20 mg/kg. And the improvement of behavior was 
very similar in these 2 groups. The effects of KM-819 on neuron cells in brain was also studied 
by MRI imaging and compared with a current Parkinson’s disease drug ropinirole. Treatment 
with KM-819 for one week orally gave results in higher Fractional Anisotrophy (FA) value from 
KM-819 than ropinirole, demonstrating the superior cell protection effects of KM-819 compared 
with ropinirole. Also, detecting dopamine transporters (DAT) scanning data by positron emission 
tomography (PET) imaging showed that both KM-819 and ropinirole treatments gave the higher 
Standardized Update Value (SUV) compared to non-treated controls, demonstrating the 
protective effects in dopaminergic neuron cells in striatum. 
In chronic Parkinson’s disease models induced by MPTP, pre- or post-treatment with KM-819 at 
30 mg/kg for 3 months orally protected dopaminergic neuron cells both in substantia nigra and 
striatum, compared to non-treated controls. 
Therefore, the efficacy of KM-819 in the protection of cell protection and behavior improvement 
were found in both in vitro and in vivo Parkinson’s disease animal models. 
1.2.1.2 Safety Pharmacology 
Safety of KM-819 on various organs was evaluated by core battery of safety pharmacology tests. 
No changes in various neuronal behaviors and body temperature at up to 1000 mg/kg of KM-819 


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in male and female rats were observed. No changes in heart rate, blood pressure (BP), and 
electrocardiogram (ECG) variables including QT intervals at up to 500 mg/kg per oral (PO) dose 
in male dogs were observed. KM-819 did not inhibit the human ether-a-go-go related gene 
(hERG potassium channel) at up to 10 uM. KM-819 did not inhibit any respiratory functions in 
rats at up to 1000 mg/kg PO dose. 
1.2.1.3 Pharmacokinetics 
A pharmacokinetic (PK) study in male rats, by administering single intravenous (IV) injection of 
5 mg/kg KM-819 showed: Cmax: 62.73 ug/ml, tmax: 0.083 hr, and t1/2: 7.08 hr. Single dose oral 
administration of 5 mg/kg KM-819 resulted in: Cmax: 3.89 ug/ml, tmax: 3 hr, and t1/2: 6.06 hr. Oral 
bioavailability assessed by comparing AUC0-∞ for oral and IV administration was 35.97%. 
A PK study in male dogs, by administering single IV injection of 1 mg/kg KM-819 showed: tmax: 
0.08 hr, Cmax: 11.91 ug/ml, and t1/2: 8.61 hr. Single dose oral administration of 5 mg/kg and 10 
mg/kg KM-819 resulted in: tmax: 0.83 hr and 0.58 hr, Cmax: 6.01 ug/ml and 9.48 ug/ml, and t1/2: 
4.96 hr and 5.03 hr, bioavailability: 32.3% and 28.9%, respectively. 
In vitro plasma protein binding is 99.96 %, 99.79%, and 99.96% in rat, dog and human, 
respectively. KM-819 at 10 uM did not inhibit CYP450s (including 1A2, 2C9, 2C19, 2D6, 3A4) 
and P-gp. 
1.2.1.4 Toxicology 
Toxicity of KM-819 was evaluated in rats (up to 28 days) and dogs (up to 14 days) by single and 
multiple PO dose. The toxicity was also tested by single IV injection in rats. 
Repeated dose toxicity test in rats and dogs did not reveal any drug-related pathological tissue 
changes (including reproductive organ) or significant clinical symptoms at tested highest dose. 
Single dose toxicity test in SD rats with oral doses of KM-819 at 500, 1000, and 2000 mg/kg did 
not result in any death, change in clinical observations, body weight, or biopsy results. Therefore, 
the approximate lethal dose (ALD) is above 2000 mg/kg. And from the test of KM-819 for 4 
week repeated oral dose (2 weeks recovery) in SD rats, No Observed Adverse Effect Level 
(NOAEL) is 500 mg/kg/day. 
Single IV injection of KM-819 at 25, 50, and 100 mg/kg did not result in any death, change in 
clinical observations, BW change, or biopsy results in SD rats. 
In beagle dogs, single oral doses of KM-819 at 500, 1000, and 2000 mg/kg did not result in any 
death, or changes in clinical observations, body weight, or biopsy results except contamination of 
test materials in feces, therefore, the ALD is above 2000 mg/kg/day. During a 2-Week repeated 
dose study in male and female Beagle dogs (with 1 week recovery), KM-819 at 50, 250, and 
1000 mg/kg did not result in any death, or changes in clinical observations, body weight, or 
biopsy results except contamination of test materials in feces. Liver damage (higher ALT, ALP, 
GGT, and enlargement in common bile duct in liver) was reported in one male dog following 
multiple dosing at 2000 mg/kg for 7 days. Therefore, NOAEL is 1000 mg/kg/day for both male 
and female Beagle dogs. 
KM-819 did not show any genotoxicity from mutation reversion test, chromosome abnormality 
test, and bone marrow micronucleus test. 
1.2.2 Clinical Data 
KM-819 has not been investigated in humans yet, therefore, no clinical study data is available. 


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1.3 
Rationale 
KM-819 has not previously been administered to humans. This First-in-Human study is therefore 
designed to provide safety, tolerability, PK, and pharmacodynamic (PD) data of KM-819 in 
healthy young adult male and elderly male or female subjects following ascending single and 
multiple dose administration. Data from this study will be used to guide rational drug dosing and 
therapeutic regimen choices in subsequent clinical studies. 
1.4 
Risk-Benefit Assessment 
Given the favorable toxicity profile and the positive results of in vitro and animal models, it is 
suggested that the present clinical study has an acceptable risk-benefit ratio. 
The safety monitoring practices employed by this protocol are standard for a First-in-Human, 
single and multiple ascending dose study and are considered adequate to protect the subjects’ 
safety. Subjects will be admitted to the Clinical Study Unit, where they will be monitored to 
detect adverse events (AE)s during the study and followed appropriately to ensure resolution of 
AEs. Sentinel dosing will be employed within each single dose cohort, and available safety and 
PK data will be assessed after each dose level to determine if it is safe to escalate the dose. 
Subjects participating in this study will not benefit from administration of KM-819. None of the 
findings in non-clinical safety pharmacology or toxicology studies precludes further 
development of KM-819 in Phase 1 First-in-Human clinical trials. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To evaluate the safety and tolerability of single and multiple ascending oral doses of KM-819 
in healthy young adult male subjects. 
2.2 
Secondary Objectives 
• To evaluate the pharmacokinetics and pharmacodynamics of single and multiple ascending 
oral doses of KM-819 in healthy young adult male subjects. 
• To evaluate the safety and tolerability of single and multiple oral doses of KM-819 in elderly 
male or post-menopausal female subjects. 
• To evaluate the PK and PD of single and multiple oral doses of KM-819 in elderly male or 
post-menopausal female subjects. 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a first-in-human, single-center, randomized, placebo-controlled, double-blind, sequential 
group Phase 1 study in healthy subjects. The aim of this study is to evaluate the safety, 
tolerability, PK, and PD following the escalation of single and multiple doses of KM-819. 
The study will consist of 2 parts (Part A and Part B). 
• 
Part A includes up to 5 cohorts of healthy young adult male subjects receiving single 
ascending doses (SAD)s of KM-819, and 1 additional single-dose cohort of elderly male or 
post-menopausal female subjects. 
• 
Part B includes up to 4 cohorts of healthy young adult male subjects receiving multiple 
ascending doses (MAD)s of KM-819, and 1 additional multiple-dose cohort of elderly male 
or post-menopausal female subjects. 
Dose escalation to the next level will be determined using the safety, tolerability, and PK data of 
the previous cohort. 
Part A, Single Ascending Dose (SAD) 
Up to 40 healthy young adult male subjects and 8 healthy elderly male or post-menopausal 
female subjects will be enrolled and randomized to receive either KM-819 or placebo. 
Each of the 5 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects 
will receive single dose of 10, 30, 100, 200, or 400 mg KM-819 and 2 subjects will receive 
placebo. 
Cohorts will be dosed sequentially with escalating doses, escalation to the next dose level will 
take place only after the safety, tolerability data, and available PK data from the previously 
treated dose cohort has been reviewed; see Section 3.4 for dose escalation criteria. In each of the 
5 single dose cohorts, dosing of subjects will be sentinel, i.e., 2 subjects will be dosed on the first 
day (1 subject will receive active treatment and 1 subject will receive placebo) and the remaining 
6 subjects will be dosed at least 24 hours after the first 2 subjects. 
After completion of the 5 dose escalation cohorts, 8 elderly male or post-menopausal female 
subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 and 
2 subjects will receive placebo. 
See Table 3-1 for Part A dose groups. 
Table 3-1: Dose Groups for Part A 
KM-819 
Dose (mg) 
Subjects on KM-
819 (n) 
Subjects on 
Placebo (n) 
Total Subjects in 
Group (n) 
Age Group 
10† 
6 
2 
8 
Young adult male subjects 
30† 
6 
2 
8 
100† 
6 
2 
8 
200† 
6 
2 
8 
400† 
6 
2 
8 
200 
6 
2 
8 
Elderly male or post-menopausal 
female subjects 
† Doses between the current planned range may be assigned or a dose may be repeated depending on safety, 
tolerability, and pharmacokinetic data from previous subjects and cohorts. 


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All subjects will undergo a Screening period of up to 28 days and a 3-day Confinement period 
when they are hospitalized for study activities (Day -1 to Day 3). Subjects are required to return 
for outpatient visits on Day 4, Day 7, and for Follow-up Visit on Day 14. See Figure 3-1 for Part 
A SAD study design. 
 
Figure 3-1: Part A Single Ascending Dose Study Design 
Part B, Multiple Ascending Dose (MAD) 
Part B will be conducted after completion of all cohorts of young adult male subjects in Part A. 
Up to 32 healthy young adult male subjects and 8 healthy elderly male or post-menopausal 
female subjects will be enrolled and randomized to receive either KM-819 or placebo. 
Each of the 4 dose escalation cohorts will consist of 8 healthy young adult male subjects; 
6 subjects will receive 30, 100, 200, or 400 mg of KM-819 once a day (QD) for 7 days and 
2 subjects will receive placebo. Cohorts will be dosed sequentially with escalating doses. 
After completion of the 4 dose escalation cohorts, 8 elderly male or post-menopausal female 
subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 QD 
for 7 days and 2 subjects will receive placebo. 
See Table 3-2 for Part B dose groups. 
Table 3-2: Dose Groups for Part B 
KM-819 
Dose (mg) 
Subjects on KM-
819 (n) 
Subjects on 
placebo (n) 
Total Subjects in 
Group (n) 
Age Group 
30† 
6 
2 
8 
Young adult male subjects 
100† 
6 
2 
8 
200† 
6 
2 
8 
400† 
6 
2 
8 
200 
6 
2 
8 
Elderly male or post-
menopausal female subjects 
† Doses between the current planned range may be assigned depending on safety, tolerability, and pharmacokinetic 
data from previous subjects and cohorts. 
All subjects will undergo a Screening period of up to 28 days and an 8-day Confinement period 
when they are hospitalized for study activities (Day -1 to Day 8). Subjects are required to return 
for a Follow-up Visit on Day 14. See Figure 3-2 for Part B MAD study design. 


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Figure 3-2: Part B Multiple Ascending Dose Study Design 
3.2 
Criteria for Evaluation of the Study 
The study involves safety, PK, and PD assessments. The specific endpoints are listed below. 
3.2.1 Safety Endpoints 
Parts A and B 
• Reporting AEs (nature, frequency, severity, time of onset/offset) 
• Standard clinical laboratory evaluations 
• Vital signs measurements (tympanic temperature, supine pulse, and supine BP) 
• 12-lead ECGs 
3.2.2 Pharmacokinetic Endpoints 
KM-819 
Plasma PK parameters for KM-819 include the following for single dose and/or multiple dose 
analysis: 
Single Dose and Day 1 of multiple doses 
• AUClast: area under the plasma concentration-time from predose (time 0) to the last 
quantifiable concentration 
• AUCinf: area under the plasma concentration-time curve from predose (time 0) extrapolated 
to infinity 
• AUCinf (%extrap): Percentage of AUCinf that is due to extrapolation beyond tlast 
• CL/F: apparent oral clearance 
• Cmax: maximum plasma concentration determined directly from the concentration-time 
profile 
• λz: terminal elimination rate constant 
• t1/2: apparent terminal elimination half-life 
• tlag: lag time 


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• tmax: time to achieve maximum observed plasma concentration determined directly from the 
concentration-time profile 
• Vz/F: volume of distribution 
• Other parameters, as appropriate, including dose-adjusted parameters. 
Day 7 of multiple doses 
• 
AUCtau: area under the plasma concentration-time curve for a dosing interval 
• 
AUClast: area under the plasma concentration-time from predose (time 0) to the last 
quantifiable concentration 
• 
CL/F: apparent oral clearance 
• 
Cmax: maximum plasma concentration determined directly from the concentration-time 
profile 
• 
Cmin: minimum plasma concentration determined directly from the concentration-time 
profile 
• 
Ctrough: observed plasma concentration before dosing 
• 
Rac (AUC): observed accumulation by AUC 
• 
Rac (Cmax): observed accumulation by Cmax 
• 
tlag: lag time 
• 
tmax: time to achieve maximum observed plasma concentration determined directly from the 
concentration-time profile 
• 
Vz/F: volume of distribution 
• 
Other parameters, as appropriate, including dose-adjusted parameters 
 
Cerebrospinal fluid (CSF) PK parameter for KM-819 includes the following after multiple dose 
CSF sample collection: 
• KM-819 concentration in CSF 
3.2.3 Pharmacodynamic Endpoints 
In both Parts A and B, mean and absolute value change from baseline at each post-baseline 
measurements for: 
• Bond and Lader Visual Analogue Scale (VAS) 
• Profile of Mood States (POMS) 
• Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV) 
• C-SSRS 
In Part B only, PD parameters in plasma and CSF including: 
• alpha synuclein oligomer 
• total Tau 
• phospho-Tau 
• ratio of CSF concentration/Plasma Cmax 


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3.3 
Justification of the Study Design 
This is a study of safety, tolerability, PK, and PD of KM-819 administered orally to healthy adult 
and elderly subjects. A double-blind, placebo-controlled study is appropriate and standard for a 
SAD and MAD study. This design will minimize bias and provide reference data (i.e., data from 
placebo-treated subjects) which will aid in the interpretation of results. 
Five SAD levels and four MAD levels are planned. The Principal Investigator (PI) and the 
Sponsor (both in a blinded state) will review available safety and PK data after each cohort to 
confirm whether it is safe to proceed with the next planned ascending dose, dose escalation 
should be stopped or the dose should be lowered or repeated in the subsequent cohort. 
The safety assessments for the study are accepted measures for ensuring safety of patients during 
a clinical study. The times allowed for collection of PK/PD samples for KM-819 concentration 
are considered appropriate given the information available. 
3.4 
Dose Escalation Criteria 
In Part A, escalation to the next dose level will take place only after the safety and tolerability 
data for all subjects in the cohort (through Day 4) and available plasma PK data (through the 
72-hour sample postdose) from the previously administered dose cohort has been reviewed. Data 
from exploratory PD assessments and CNS scales will not be included in the review for dose 
escalation decisions. Within the planned dose range a dose lower than the next planned dose 
level may be tested, depending on the emerging safety, tolerability, and/or other relevant data 
(e.g., plasma PK data). 
3.5 
Stopping Criteria for Dose Escalation 
Dosing will be stopped if 1 (or more) of the following apply. Depending on the nature of the AEs, 
it could be decided to investigate a lower dose level (intermediate between the current and the 
prior one) in the next group. 
1. If 1 or more subjects experiences a study drug-related serious adverse event (SAE), 
unblinding of the subject(s) will be done. If the subject(s) was (were) on active treatment, 
dosing will be stopped. 
2. If 2 subjects in 1 dose group show the following findings in 2 consecutive postdose 
measurements within 24 hours and if unblinding reveals that both subjects received active 
treatment, dosing will be stopped: 
a. ALT or AST ≥ 3 x upper limit of normal (ULN) or, 
b. ALT or AST ≥ 2 x ULN and ALT or AST ≥ 5 x baseline value or, 
c. TBIL ≥ 2 x ULN 
3. If 2 or more subjects in 1 cohort experience AEs of severe intensity or 4 or more subjects 
in 1 cohort experience AEs of moderate intensity, which are considered by the PI and/or 
Sponsor to be possibly or probably related to the investigational product, and of clinical 
concern, and if unblinding reveals that these subjects received active treatment, dosing 
will be stopped. 


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3.5.1 PK stopping criteria 
Due to the liver damage (higher ALT, ALP, GGT, and enlargement in common bile duct in liver) 
reported in one male dog following multiple dosing at 2000 mg/kg for 7 days, and NOAEL in 
male and female beagle dog at 1000 mg/kg/day for 14 days, the decision to escalate to the next 
planned dose will be based on review of PK exposure data from previous dose cohort(s). This 
will involve use of best available modeling practices of the observed AUC (i.e., AUCtau or AUC0-
inf) and Cmax from each dose, resulting in a predictive distribution of AUC and Cmax at higher 
dose levels. If predicted mean AUC and Cmax for the next dose level is higher than 41.3 ug.h/mL 
and 9.3 ug/mL, respectively, then the dose escalation will stop and the Sponsor and PI will need 
to review the totality of data, including safety and PK before make any dose escalation decision. 
This PK stopping criteria are based on dog 2-Week study NOAEL exposure at 1000 mg/kg/day 
(the most conservative species and gender). 


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4 
STUDY POPULATION 
For Parts A and B: healthy young adult male (19 to 45 years old) or healthy elderly male or 
post-menopausal female (over 60 years old). 
The study population will consist of healthy subjects. Subjects must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
Waivers for inclusion/exclusion criteria will not be granted. 
4.1 
Inclusion Criteria 
Subjects will be entered into this study only if they meet all of the following criteria: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations must be obtained from the 
subject prior to any study-related procedures (including withdrawal of prohibited medication, 
if applicable). 
2. Male subject should be 19 to 45 years old (for young adult cohorts) or over 60 years old (for 
elderly cohorts). 
3. Subject has a body mass index (BMI) range of 18.5 to 30 kg/m2 inclusive at Screening. 
4. Male subject and his female spouse/partner who is of childbearing potential must be using 
highly effective contraception consisting of 2 forms of birth control (at least one of which 
must be a barrier method) starting at Screening and continuing throughout the study period 
and for 90 days after final study drug administration. Highly effective contraception is 
defined as: 
• 
Established use of oral, injected, or implanted hormonal methods of contraception 
• 
Placement of an intrauterine device or intrauterine system 
• 
Barrier methods of contraception: condom with spermicidal foam, gel, film, cream, 
suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, 
gel, film, cream, or suppository 
5. Male subject must not donate sperm starting at Screening, throughout the study period and 
for at least 90 days after final study drug administration. 
6. Female subject must be over 60 years old and post-menopausal (defined as at least 1 year 
without any menses) prior to Screening. 
7. Subject agrees not to participate in another investigational study while on study treatment. 
4.2 
Exclusion Criteria 
Subjects will be entered into this study only if they meet none of the following criteria: 
1. Subject has a known or suspected hypersensitivity to KM-819, or any components of the 
formulation(s) used. 
2. Subject has previously participated in a clinical study with KM-819. 


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3. Subject has any of the liver enzymes (aspartate aminotransferase [AST], alanine 
transaminase [ALT], alkaline phosphatase, γ-glutamyl transferase) or total bilirubin (TBIL) 
above the ULN. If any liver enzyme is > 1 × ULN but < 1.5 × ULN, the assessment may be 
repeated once during the Screening period or on check-in. If the repeated assessment is above 
the ULN, it is exclusionary. If the initial value is > 1.5 × ULN, it cannot be repeated and is 
exclusionary. 
4. Subject has any clinically significant history of allergic conditions (including drug allergies, 
asthma, eczema, or anaphylactic reactions, but excluding untreated, allergic rhinitis or rhino-
conjunctivitis, or house dust mite allergy at time of dosing). 
5. Subject with a history of a suicide attempt or suicidal behavior. Any recent suicidal ideation 
(a level of 4 or 5) within the last 3 months, or having a positive C-SSRS at check-in (Day -1), 
or who is at significant risk to commit suicide, as judged by the Investigator using the 
C-SSRS at Screening. 
6. Subject has/had febrile illness or symptomatic viral, bacterial (including upper respiratory 
infection) or fungal (non-cutaneous) infection within 1 week before site check-in. 
7. Subject has any clinically significant abnormality following the Investigator’s review of the 
physical examination, ECG, and protocol-defined clinical laboratory tests at Screening or site 
check-in. 
8. Subject has a mean pulse < 40 or > 90 beats per minute (bpm); mean systolic blood pressure 
(SBP) > 140 mmHg; or mean diastolic blood pressure (DBP) > 90 mmHg (measurements 
taken in triplicate after subject has been resting in the supine position for 5 minutes; pulse 
will be measured automatically) at Screening or check-in. If the mean pulse, mean SBP, or 
mean DBP is out of the range specified above, 1 additional triplicate measurement may be 
taken at Screening and check-in. 
9. Subject has a mean QTcF interval of > 430 msec (for males) and > 450 msec (for females) at 
Screening or check-in. If the mean QTcF exceeds the limits above, 1 additional triplicate 
ECG can be taken. If this triplicate also gives an abnormal result, the subject should be 
excluded. 
10. Subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias 
or torsade de pointes, structural heart disease, or a family history of Long QT Syndrome. 
11. Subject has use of any prescribed or non-prescribed drugs (including vitamins, hormone 
replacement therapy, natural and herbal remedies, e.g., St. John’s Wort) in the 2 weeks 
before study drug administration. Acetaminophen up to 2000 mg/day is allowed. 
12. Subject has had any use of tobacco- or nicotine-containing products within 6 months prior to 
Screening. 
13. Subject has history of consuming more than 14 units of alcoholic beverages per week within 
6 months prior to Screening or has a history of alcoholism or abuse of amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates (drugs-of-abuse) within the 
past 2 years prior to Screening (Note: 1 unit = 355 mL of beer, 118 mL of wine, or 29 mL of 
spirits/hard liquor) or the subject tests positive at Screening or site admission for alcohol or 
drugs-of-abuse. 
14. Subject has used any drugs-of-abuse within 3 months before check-in. 


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15. Subject has used any inducers of metabolism (e.g., barbiturates, rifampin) in the 3 months 
prior to check-in. 
16. Subject has any significant blood loss, donated 1 unit (450 mL) of blood or more, or received 
a transfusion of any blood, or blood products within 60 days or donated plasma within 7 days 
before check-in. 
17. Subject has a positive serology test for hepatitis B surface antigen (HbsAg), anti-hepatitis A 
virus Immunoglobulin M (HAV IgM), anti-hepatitis C virus (HCV Ab), or anti-human 
immunodeficiency virus (HIV Ab). 
18. Subject has participated in any interventional clinical study or has been treated with any 
investigational drugs within 3 months or 5 half-lives, whichever is longer, before the 
initiation of Screening. 
19. Subject has (recent history of) any other condition which, in the opinion of the Investigator, 
precludes the subject’s participation in the trial. 
20. Subject is an employee of the Kainos Medicine, Inc. or vendors involved in the study. 
 
Additional Exclusion Criteria for Young Adult Subjects 
21. For young adult cohorts, subject has any history or evidence of any clinically significant 
cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, 
metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other 
major disease or malignancy, as judged by the Investigator or designee. 
 
Exclusion Criteria for Elderly Subjects 
Replacement for Exclusion No. 8 above 
8. Subject has a mean pulse < 50 or > 90 bpm; mean SBP > 160 mmHg; mean DBP > 100 
mmHg (measurements taken in triplicate after subject has been resting in supine position for 
5 minutes; pulse will be measured automatically). 
Replacement for Exclusion No. 21 above 
21. For elderly cohorts, subject has any history or evidence of any clinically significant 
cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, 
metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other 
major disease or malignancy that is not well managed and stable, as judged by the 
Investigator or designee. 
Additional Exclusion Criteria 
22. Elderly subject is excluded if the Glomerular Filtration Rate (calculated based on Cockcroft-
Gault formula) is < 60 mL/min/1.73 m2. 
23. Clinically significant abnormal findings in the lumbar X-ray examination (only for elder 
subjects for MAD study). 


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4.3 
Subject Withdrawal and Replacement 
A subject may withdraw from the study at any time without penalty and for any reason without 
prejudice to his/her future medical care. Participation of subjects may also be discontinued based 
on the medical judgment of the PI in conjunction with the Sponsor for any of the following 
reasons: 
• 
ECG abnormalities: 
Any increases in QTcF > 500 msec or increase > 60 msec from baseline as confirmed with 
3 consecutive ECGs taken within 5 minutes, with at least a 1-minute interval. 
• 
Suicidality: 
Any suicide attempt or any recent suicidal ideation (a level of 4 or 5) since the last 
assessment, or a significant risk to commit suicide, as judged by the PI using the C-SSRS. 
• 
Liver Safety Monitoring: 
Please refer to Stopping Criteria No. 2. 
• After enrolment, the subject is found to violate the inclusion and/or exclusion criteria 
• AE(s) 
• Subject lost to follow-up 
• Major protocol violation 
• Use of prohibited medications mentioned in Section 5.8 
• The Investigator may, after discussion with the subject, withdraw the subject due to any 
serious safety concerns 
• The study is terminated prematurely 
• Other 
In all cases, the reason(s) for withdrawal, and the primary reason, must be recorded on the 
electronic case report form (eCRF). Subjects who are withdrawn will have an Early 
Discontinuation (ED) Visit per the Schedules of Assessments (see Table 7-1 and Table 7-2). 
A subject may also be withdrawn from study by the Sponsor, Regulatory Authorities, or 
IECs/IRBs. 
Subjects will also be withdrawn if the entire study is terminated prematurely as described in 
Section 9.10. 
Withdrawn subjects may be replaced at the discretion of the Sponsor with agreement of the 
Investigator. Subjects who are discontinued because of treatment-emergent AE (TEAE) or 
possible toxic effects of the drug will not be replaced. 
4.4 
Planned Sample Size and Number of Study Centers 
It is planned to recruit in total 72 healthy young adult subjects and 16 healthy elderly subjects at 
1 center in Korea for this study. 
Part A: up to 40 healthy young adult male and 8 healthy elderly male or post-menopausal female 
subjects will be enrolled. 
Part B: up to 32 healthy young adult male and 8 healthy elderly male or post-menopausal female 
subjects will be enrolled. 


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See Section 8.10 for a discussion of sample size. 
4.5 
Subject Identification and Randomization 
4.5.1 Subject Identification 
Upon enrolment, each subject will receive a unique screening number. Enrolled subjects who 
drop out of the study before randomization will retain their screening number. 
4.5.2 Randomization Scheme 
In each dose cohort, 8 subjects will be randomized to have 6 subjects receiving KM-819 and 2 
subjects receiving placebo in both Part A and Part B.  
In each single dose cohort (Part A), dosing of subjects will be sentinel, i.e., 2 subjects will be 
dosed on the first day (1 subject will receive active treatment and 1 subject will receive placebo) 
and the remaining 6 subjects will be dosed at least 24 hours after the first 2 subjects. 
Randomization will occur on Day 1 (of the first treatment period for Part A) after all predose 
procedures have been performed and eligibility for the clinical study has been confirmed. Each 
eligible subject will receive a 4-digit randomization number. Randomization numbers will be 
sequential and will be assigned as follows: 
Part A: 
Cohort 1: 1101-1108 
Cohort 2: 1201-1208 
Cohort 3: 1301-1308 
Cohort 4: 1401-1408 
Cohort 5: 1501-1508 
Cohort 6: 1601-1608 
Replacement subjects will be assigned the same randomisation number as the subject they are 
replacing plus 50, i.e., a subject replacing Subject 1101 will be assigned the subject number 1151. 
Part B: 
Cohort 1: 2101-2108 
Cohort 2: 2201-2208 
Cohort 3: 2301-2308 
Cohort 4: 2401-2408 
Cohort 5: 2501-2508 
4.5.3 Allocation/Randomization of Subjects to Treatment 
Prior to dosing on Day 1, subjects will be assigned a randomization number in accordance with 
the randomization code generated by PAREXEL using PROC PLAN method of SAS. The 
assigned randomization number will determine the treatment the subject receives. 
Once a randomization number has been allocated to one subject, it may not be assigned to 
another subject. If subjects withdraw prematurely from the study and are replaced under the 
direction of the Sponsor, a replacement randomization number will be assigned. A replacement 


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randomization code will be generated such that replacement subjects are assigned to the same 
treatment as the discontinued subjects. 
 
5 
STUDY DRUG 
5.1 
Identity 
The Sponsor will provide the Investigator with adequate quantities of the study drugs, as 
described in Table 5-1. 
Table 5-1: Identity of the Study Drugs 
Study Drug 
Formulation 
Strength 
Route 
Manufacturer 
KM-819 
White circular tablet 
10 mg 
Oral 
HanAll BioPharma Co., Ltd. 
100 mg 
Placebo 
White circular tablet 
0 mg 
Oral 
HanAll BioPharma Co., Ltd. 
The composition of each KM-819 tablet is presented below (see Table 5-2): 
 
Table 5-2: Composition of Each Study Drug Tablet 
Ingredient 
Function 
Quantity 
KM-819 
10 mg strength 
KM-819 
100 mg strength 
Placebo 
KM-819 
Main ingredient 
10 mg 
100 mg 
0 mg 
Crystallized 
cellulose 
Diluting agent 
245 mg 
157 mg 
216 mg 
Pre-gelatinized 
starch 
Diluting agent 
44 mg 
44 mg 
55 mg 
Povidone 
Bonding agent 
24 mg 
22 mg 
27 mg 
Crosscarmellose 
sodium 
Disintegrating agent 
11 mg 
11 mg 
29 mg 
Colloidal silicone 
dioxide 
Fluidizing agent 
15 mg 
15 mg 
19 mg 
Stearic magnesium 
Lubricant Agent 
11 mg 
11 mg 
14 mg 
5.2 
Administration 
Study drug (KM-819 or placebo) will be administered orally at the study center. 
The study drug should be administered with approximately 240 mL of water (room temperature), 
after an overnight fasting for a minimum of 8 hours. No food should be allowed for at least 4 
hours postdose. Water will be allowed as desired except for 1 hour before and after drug 
administration. 
For Part B (MAD) study, on Day 2 to Day 6, the study drug should be administered with 
approximately 240 mL of water (room temperature), after an overnight fasting for a minimum of 
8 hours. No food should be allowed for at least 2 hours postdose. Water will be allowed as 
desired except for 1 hour before and 2 hours after drug administration. 


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Each dispensing of study drug will be documented in the eCRF. 
5.3 
Rationale for Selection of Starting Dose 
The FDA Guidance “Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in 
Adult Healthy Volunteers”7 and allometric scaling modeling and simulation were used for the 
initial calculation of the starting human dose in this study. Based on the FDA Guidance 
document and the 4-week rat toxicology study NOAEL of 500 mg/kg/day, the human equivalent 
dose (HED) is estimated to be 5600 mg for a 70 kg human subject. A 10-fold safety factor is 
applied to the HED, resulting in an estimated Maximum Recommended Starting Dose (MRSD) 
was 560 mg per person for a 70 kg person. In addition to the FDA Guidance method, an 
allometric scaling method was used to predict human PK. The human PK parameters were 
predicted as followed: CL= 2.93 L/h, V = 39.2 L, and half-life =9.27 hours. Using these 
predicted human PK parameters, simulation was conducted based on the assumption that human 
PK behaves with one compartment model with first order absorption and first order elimination 
rate and the bioavailability was assumed to be 35% (mean F from animal data). 
Based on simulated human PK profile and animal efficacy data, a lower dose was chosen for the 
starting dose. 
The first-in-human Phase 1 single ascending dose study will have an initial starting dose of 10 
mg, which is x56-fold below the estimated MRSD derived from the rat NOAEL. 
5.4 
Packaging, Labeling and Storage 
Study drug will be packaged by Kainos Medicine, Inc. according to all local legal requirements. 
Study drug will be labeled in accordance with applicable regulatory requirements. 
All study drug supplies must be stored in accordance with the manufacturer’s instructions (stored 
at a temperature of 1–30ºC). Until dispensed to the subjects, the study drug will be stored in a 
securely locked area, accessible to authorized personnel only. 
5.5 
Blinding and Breaking the Blind 
The study will be performed in a double-blind manner. All study drugs will be supplied in 
identical tablets and will be similar in color, smell, taste, and appearance, thereby enabling 
double-blind conditions. 
For this study, the bioanalyst will be unblinded for dose escalation PK analysis. 
For each randomized subject, an individual emergency (randomization) code break envelope will 
be stored in a secure location with access by designated staff members to open in the event of a 
medical emergency requiring knowledge of a subject’s treatment assignment. 
The blind must only be broken following discussion on a case-by-case basis, at the discretion of 
the Sponsor/PI. 
If the blind is broken, the date, time, and reason must be recorded in the subject’s eCRF, and any 
associated AE report. 
If an emergency unblinding becomes necessary, the Investigator should notify the Sponsor/PI, if 
possible, prior to unblinding. The Investigator is responsible for opening the specified envelope, 
in the presence of a witness, both of whom must sign and date the envelope. 
All envelopes, whether sealed or opened, must be returned to PAREXEL at the end of the study. 


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Serious unexpected suspected adverse reactions (SUSARs), which are subject to expedited 
reporting, should be unblinded before submission to the Regulatory Authorities. 
The overall randomization code will be broken only for reporting purposes. This will occur once 
all final clinical data have been entered into the database and all data queries have been resolved, 
and the assignment of subjects to the analysis sets has been completed. 
5.6 
Drug Accountability 
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. 
The Investigator is responsible for returning all unused or partially used study drug to the 
Sponsor and must verify that all unused or partially used drug supplies have been returned by the 
subject and that no remaining supplies are in the Investigator’s possession. 
5.7 
Compliance 
Dosing will take place at the study center. The dose and schedule of study drugs administered to 
each subject will be recorded on the appropriate form. The administration of KM-819 (or 
placebo) will be supervised by the Investigator or a medically qualified staff member to ensure 
treatment compliance. After medication intake, the subject’s hands and mouth will be inspected 
to ensure that the tablets have been swallowed completely. Treatment compliance should be 
monitored closely and any deviation in compliance should be reported to the Sponsor. 
5.8 
Previous and Concomitant Medications 
Any medication that the subject takes other than the study drug, including herbal and other non-
traditional remedies, is considered a concomitant medication. All concomitant medications must 
be recorded in the eCRF. The following information must be recorded in the eCRF for each 
concomitant medication: generic name, route of administration, start date, stop date, dosage, and 
indication. Any changes in the dosage or regimen of a concomitant medication must be recorded 
in the eCRF. 
At Screening, subjects will be asked what medications they have taken during the last 3 months. 
At each subsequent study visit, subjects will be asked what concomitant medications they are 
currently taking. 
In all study cohorts, no concomitant medications will be allowed, with the exception of 
acetaminophen (up to 2000 mg/day) (as per Exclusion Criteria 11). 
5.9 
Restrictions during the Study 
• Alcohol use is prohibited from 48 hours prior to check-in and throughout the duration of the 
study. 
• Caffeine-containing products (coffee, tea, chocolate) are prohibited from 48 hours prior to 
check-in and throughout the duration of the study (except for ambulatory period before 
Follow-up Visit). 
• Grapefruit, Seville oranges, star fruit, or any products containing these items are prohibited 
within 48 hours days prior to dosing and throughout the duration of the study. 


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• Subjects will not be allowed to consume food or drinks, which may interact with circulatory, 
gastrointestinal, liver or renal function (e.g. alcohol, caffeine, or caffeine containing products, 
or grapefruit juice) throughout the duration of the study. Subjects will be served normal 
balanced caloric drinks and meals at standardized times during their stay in the study center. 
Total daily caloric intake will preferably not exceed normal daily limits (2500 kcal). 
• Smoking and other nicotine-containing products are prohibited within 6 months prior to 
Screening and throughout the duration of the study. 
• Strenuous activity is prohibited from 48 hours prior to check-in until discharge. After 
discharge, mild physical activity can be resumed, but strenuous physical activity is prohibited 
until the Follow-up Visit. 
• Blood donation is prohibited throughout the duration of the study. 


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6 
VARIABLES AND METHODS OF ASSESSMENT 
6.1 
Pharmacokinetics and Pharmacodynamics Assessment 
6.1.1 Pharmacokinetics Assessment 
Plasma and CSF samples for PK analysis of KM-819 will occur at the time points relative to 
dosing described on Table 7-1 and Table 7-2. 
The actual date and time of PK blood and CSF samples collection will be captured in the eCRFs. 
Blood and CSF collection, handling, storage, and shipping details will be addressed in the 
Laboratory Manual. 
6.1.2 Pharmacodynamic Assessment 
Scales (Bond and Lader VAS, POMS, and K-WAIS-IV) and C-SSRS will be evaluated at the 
time points described on Table 7-1 and Table 7-2. 
CSF and plasma samples for MAD PD analysis will occur at the time points described on 
Table 7-1 and Table 7-2. 
6.2 
Pharmacokinetic Variables 
6.2.1 KM-819 Pharmacokinetic Blood Sampling 
Blood (approximately 6 mL) will be taken by venipuncture or cannulation of a forearm vein(s) 
and collected into anticoagulant EDTA K2 tubes. Blood will be processed for plasma by 
centrifuging at 4°C, 3000 rpm for 10 min. The obtained plasma will be transferred into 3 
polypropylene tubes (1.5 mL) with a volume of 0.8 mL, respectively. The tubes will be 
immediately stored at -70°C freezer. Two aliquots of plasma samples will be transferred to 
Bioinfra Co., Ltd and be analyzed by a validated method for the concentration of KM-819 (Parts 
A and B); one aliquot will be stored in study center as a back-up until completion of the clinical 
study report (CSR). 
The PK parameters listed in Section 3.2.2 will be calculated from the plasma concentration-
actual time profiles. The non-compartmental analysis will be performed using Phoenix® 
WinNonlin® Software Version 6.3 or higher (Certara, L.P., 9666 Olive Blvd, Suite 425, St. Louis 
MO 63132). 
The total volume of PK blood drawn from each subject will be approximately 72 mL in Part A 
SAD and 144 mL in Part B MAD. 
6.2.2 KM-819 Urine Sampling 
Urine samples for possible analysis of KM-819 and qualitative analysis of any metabolites will 
be collected at intervals relative to study drug dosing as detailed in the Schedule of Procedures 
(Table 7-1 and Table 7-2). Within 60 minutes prior to dosing on Day 1, each subject will be 
instructed to void their bladder and no more than 20 mL of this urine sample will be retained as a 
control. Urine collection will begin immediately following dose administration. A 0 to 24 hour 
urine collection will be made for each subject and the volume will be recorded. After sampling, 
urine samples will be transferred into 3 polypropylene tubes (1.5 mL) with a volume of 1 mL, 
respectively. The tubes will be immediately stored at -70°C freezer. 


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At the completion of Part A, the urine sample collections obtained from the highest single dose 
cohort from Part A will be shipped to the analytical site and analysed for KM-819 metabolites. 
Two aliquots of urine samples will be transferred to Bioinfra Co., Ltd and 1 aliquot will be 
stored in study center as a back-up until completion of the CSR. Results will be reported under a 
separate protocol, if metabolite profiling was completed. All other urine samples from earlier 
periods will be defrosted and discarded by the Clinical Research Unit. 
6.2.3 KM-819 Pharmacokinetic CSF Sampling 
CSF (approximately 2 mL) will be taken by lumbar puncture between the 3rd and 4th lumbar 
vertebrae. CSF samples will be transferred into 3 polypropylene tubes (1.5 mL) with a volume of 
0.5 mL, respectively. The tubes will be immediately stored at -70°C freezer. Two aliquots of 
CSF samples will be transferred to Bioinfra Co., Ltd and be analyzed by a validated method for 
the concentration of KM-819 (Part B only); one aliquot will be stored in study center as a back-
up until completion of the CSR. 
6.3 
Pharmacodynamic Variables 
6.3.1 Scales 
6.3.1.1 Bond and Lader VAS 
The Bond-Lader VAS will be used to rate subjects’ feelings in terms of 16 dimensions. The 
dimensions will be presented as 100 mm lines, the 2 extremes of the emotion (i.e., 'alert' and 
'drowsy') written at each end, and subjects will be asked to record their current state on each line. 
The Bond-Lader VAS will be analyzed using 3 factor scores: alertness, contentedness, and 
calmness. Calculation of these 3 scores is based on the main factors resulting from statistical 
factor analysis. A high score indicates impairment. 
1. Alertness (9 subscales): [Q1 + Q3 + (100 – Q4) + Q5 + (100 – Q6) + (100 – Q9) + Q11 + 
(100 – Q12) + Q15] / 9 
2. Contentedness (5 subscales): [Q7 + (100 – Q8) + Q13 + (100 – Q14) + (100 – Q16)] / 5 
3. Calmness (2 subscales): [Q2 + (100 – Q10)] / 2 
Ratings will be performed at the time points detailed in Schedule of Procedures (Table 7-1 and 
Table 7-2). 
6.3.1.2 Profile of Mood States 
POMS will be used to describe subjects’ feelings with a questionnaire containing 
65 words/statements. Feelings will be scored using different statement: "Not at All", "A Little", 
"Moderately", "Quite a lot", and "Extremely". 
Assessments will be performed at the time points detailed in Schedule of Procedures (Table 7-1 
and Table 7-2). 
6.3.1.3 Korean Wechsler Adult Intelligence Scale-IV 
The K-WAIS-IV consists of an assessment of the cognitive ability using a core battery of 
10 unique subtests (Block Design, Similarities, Digit Span, Matrix Reasoning, Vocabulary, 
Arithmetic, Symbol Search, Visual Puzzles, Information, and Coding) that focus on four specific 


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domains of intelligence: verbal comprehension, perceptual reasoning, working memory, and 
processing speed. 
Only the Coding subtest will be assessed at the time points detailed in Schedule of Procedures 
(Table 7-1 and Table 7-2). 
6.3.2 Columbia Suicide Severity Rating Scale 
The C-SSRS is a scale that captures the occurrence, severity and frequency of suicide-related 
thoughts and behaviors during the assessment period. The scale includes suggested questions to 
solicit the type of information needed to determine if a suicide-related thought or behavior 
occurred. The C-SSRS must be administered by appropriately trained site personnel. The 
C-SSRS will be administered at the times specified in Schedule of Procedures (Table 7-1 and 
Table 7-2). 
6.3.3 KM-819 Pharmacodynamic Blood Sampling 
Blood (approximately 3 mL) will be taken by venipuncture or cannulation of a forearm vein(s) 
and collected into appropriate collection tubes (only on Part B). The PD parameters listed in 
Section 3.2.2 will be calculated. 
The total volume of PD blood drawn from each subject will be approximately 6 mL. 
6.3.4 KM-819 Pharmacodynamic CSF Sampling 
CSF (approximately 1.5 mL) will be taken by lumbar puncture between the 3rd and 4th lumbar 
vertebrae (only on Part B). The PD parameters listed in Section 3.2.2 will be calculated. 
6.4 
Safety Variables 
6.4.1 Adverse Events 
6.4.1.1 Collection of Adverse Events 
It is responsibility of the Investigator to collect all AEs (both serious and non-serious) derived by 
spontaneous, unsolicited reports of subjects, by observation and by routine open questionings 
e.g., "How have you felt since I last saw you?" 
6.4.1.2 Definitions 
An AE is any untoward medical occurrence that occurs in a subject or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not considered related to the product. 
All AEs, including intercurrent illnesses, occurring during the study will be documented in the 
eCRF. Concomitant illnesses, which existed before entry into the study, will not be considered 
AEs unless they worsen during the treatment period. All AEs, regardless of the source of 
identification (e.g., physical examination, laboratory assessment, ECG, reported by subject), 
must be documented. 
Pre-existing conditions will be recorded in the eCRF on the medical history or appropriate page. 


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A TEAE will be defined as an AE that begins or that worsens in severity after at least one dose 
of study drug has been administered. 
6.4.1.3 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the following categories. 
6.4.1.3.1 Seriousness 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening; 
This means that the subject is 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 inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly or birth defect; 
• Is an important medical event(s) that may not be immediately life-threatening or result in 
death or hospitalization but that may jeopardize the subject or require intervention to prevent 
one of the above outcomes. Examples of such events are 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. 
Medical and scientific judgment should be exercised in deciding whether a case is serious and 
whether expedited reporting is appropriate. 
6.4.1.3.2 Intensity 
The intensity of each AE must be assessed by the Investigator using one of the following 
categories, and recorded in the eCRF: 
• Mild: The AE was transient and easily tolerated by the subject. 
• Moderate: The AE caused discomfort and interferes with the subject's general condition. 
• Severe: The AE caused considerable interference with the subject's general condition and 
may have been incapacitating. 
6.4.1.3.3 Causality 
The Investigator will assess the causality / relationship between the study drug and the AE and 
record that assessment in the eCRF. 
The most likely cause of an SAE (e.g., disease under treatment, concomitant disease, 
concomitant medication, other) will be indicated on eCRF with details of the concomitant 
disease or medication or other cause. 
The causal relationship of the AE to study drug will be described as one of the following terms: 


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Table 6-1: Causal Relationship of Adverse Event to Study Drug 
Causal relationship 
Description 
Definite 
A clinical event with a plausible time relationship to drug administration and which cannot 
be explained by concurrent disease or other drugs or chemicals. Response to withdrawal 
plausible (pharmacologically, pathologically), Event definitive pharmacologically or 
phenomenologically (i.e., an objective and specific medical disorder or a recognized 
pharmacological phenomenon), Rechallenge satisfactory, if necessary. 
Probable 
A clinical event with a reasonable time relationship to drug administration is unlikely to be 
attributed to concurrent disease or other drugs or chemicals. Response to withdrawal 
clinically reasonable (Rechallenge not required). 
Possible 
A clinical event with a reasonable time relationship to drug administration, but which could 
also be explained by concurrent disease or other drugs or chemicals. 
Unlikely 
A clinical event whose time relationship to drug administration makes a causal connection 
improbable, which could be plausibly explained by underlying disease or other drugs or 
chemicals. 
Not related 
A clinical event with no time relationship to drug administration, or with no causal 
relationship to drug administration (e.g., definitely induced by the clinical conditions of the 
subject or by the test procedures/requirements or by external events which are not 
associated with study treatments). 
Unassessable 
A clinical event with insufficient or contradictory information to permit assessment and 
identification of the cause. 
The causal relationship of definite, probable, possible and unassessable will be considered as 
related to study drug. 
6.4.1.3.4 Adverse Events of Interest 
An adverse event of interest (AEI) is an event which, in the evaluation of safety, has a special 
focus. An AEI is an AE (SAE or non-serious AE) which fulfils below defined AEI criteria: 
• 
Potential Hy’s law cases 
Potential Hy’s law, defined as ≥ 3 x ULN ALT with co-existing ≥ 2 x ULN bilirubin in the 
absence of ≥ 2 xULN ALP, with no alternative explanation for the biochemical abnormality, 
must always be reported as an AE of interest (i.e., without waiting for any additional 
etiologic investigations to have been concluded). Follow-up information should then be 
reported if an alternative etiology is identified during investigation and monitoring of the 
subject. 
AEI should be reported to the Sponsor/PAREXEL immediately (within 24 hours of the site being 
aware of the event). 
6.4.1.4 Recording Adverse Events 
AE reporting will extend from signing of informed consent until completion of Follow-up Visit. 
AEs occurring after the end of the study should be reported to the Sponsor by the Investigator if 
the Investigator considers there is a causal relationship with the study drug. 
All AEs, regardless of the relationship to study drug, will be recorded in the eCRF. 
All AE reports should contain a brief description of the event, date and time of onset, date and 
time of resolution, intensity, treatment required, relationship to study drug, action taken with the 
study drug, outcome, and whether the event is classified as serious. 


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6.4.1.5 Reporting Serious Adverse Events 
All SAEs that occur during the period of observation, and all SAEs occurring up to 30 days after 
receiving the last dose of study drug, whether considered to be associated with the study drug or 
not, must be reported within 24 hours by telephone, fax, or eCRF to the PAREXEL Safety 
Contact using the numbers in the List of Study Personnel. 
SAEs occurring after the end of the study should be reported to the Sponsor/PAREXEL by the 
Investigator if the Investigator considers there is a causal relationship with the study drug. 
The minimum information required for an initial report is: 
• Name of person sending the report (i.e., name, address of Investigator); 
• Subject identification (screening/randomization number, initials, NOT subject name); 
• Protocol number; 
• Description of SAE; 
• Causality assessment, if possible. 
However, as far as possible all points on the SAE form should be covered in the initial report, or 
the completed SAE form itself must be faxed to the PAREXEL Safety Contact. The original 
SAE form must then be sent by mail to the PAREXEL Safety Contact. In addition, the event 
must be documented in the EDC system. 
In case the PAREXEL Safety Contact cannot be contacted (e.g., out of normal working hours or 
at weekends), an automated reporting service is available. The required information should be 
faxed and a message should be left on the voicemail service (for phone/fax numbers see the 
numbers in the List of Study Personnel). 
After receipt of the initial report, the safety center will review the information and, if necessary, 
contact the Investigator, to obtain further information for assessment of the event. PAREXEL 
will be responsible for all information processing and reporting according to local legal 
requirements. Where necessary, Investigators will inform Regulatory Authorities in their own 
countries. 
 
PAREXEL International 
Toll free SAE fax number: 00308-13-2766 (24-hour service) 
SAE hotline: +65-62218582 
Email: Medical_Singapore@parexel.com 
 
6.4.1.6 Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the AE has resolved, any abnormal laboratory values have returned to baseline or stabilized at a 
level acceptable to the PI, until there is a satisfactory explanation for the changes observed, until 
the subject is lost to follow-up, or until the subject has died. 
6.4.1.7 Suspected Unexpected Serious Adverse Reactions 
Any AE that is serious, associated with the use of the study drug, and unexpected (SUSAR) has 
additional reporting requirements, as described below. 


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• If the SUSAR is fatal or life-threatening, associated with the use of the study drug, and 
unexpected, Regulatory Authorities and IECs/IRBs will be notified within 7 calendar days 
after the Sponsor learns of the event. Additional follow-up (cause of death, autopsy report, 
and hospital report) information should be reported within an additional 8 days (15 days 
total). 
• If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with the use 
of the study drug, and unexpected, Regulatory Authorities and IECs/IRBs will be notified 
within 15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information about 
SUSARs that could adversely affect the safety of subjects. Follow-up information may be 
submitted if necessary. 
The Sponsor will also provide annual safety updates to the Regulatory Authorities and 
IECs/IRBs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 
6.4.1.8 Pregnancy 
If a female partner of a male study subject who has been exposed to the study drug becomes 
pregnant, the pregnancy and outcome of pregnancy should be monitored. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. 
All pregnancies in female partners of male subjects must be reported by the Investigator to 
PAREXEL/Sponsor on the initial pregnancy report form within 30 days after becoming aware of 
the pregnancy. The Investigator must follow-up and document the course and the outcome of all 
pregnancies even if the study has finished. 
All outcomes of pregnancy must be reported by the Investigator to PAREXEL/Sponsor on the 
pregnancy outcome report form within 30 days after he or she has gained knowledge of the 
normal delivery or elective abortion. 
6.4.2 Laboratory Variables 
Laboratory assessments will be performed locally at study center’s laboratory by means of their 
established and validated methods. Before starting the study, the Investigator will supply 
PAREXEL/Kainos with a list of the normal ranges and units of measurement. 
The Investigator may decide to repeat the tests, should the results be outside normal ranges and 
considered clinically relevant, or if the original sample could not be analyzed. 
The following laboratory variables will be determined in accordance with the Schedule of 
Procedures (Table 7-1 and Table 7-2): 


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Table 6-2: Laboratory Assessments 
Test Group 
Analyte/Component 
Test Group 
Analyte/Component 
Hematology: 
erythrocytes 
mean corpuscular volume (MCV) 
mean corpuscular hemoglobin (MCH) 
neutrophils 
eosinophils 
basophils 
lymphocytes 
monocytes 
platelets 
leukocytes 
hemoglobin 
hematocrit 
Urinalysis: 
pH 
protein 
glucose 
ketone 
bilirubin 
blood 
nitrite 
Clinical 
chemistry: 
albumin 
creatinine 
glucose 
urea 
uric acid 
total bilirubin (TBIL) 
direct bilirubin 
total protein 
triglycerides (TG) 
total cholesterol 
low-density lipoprotein (LDL) cholesterol 
high-density lipoprotein (HDL) cholesterol 
Liver enzymes: alkaline phosphatase 
(ALP) 
aspartate aminotransferase 
(AST) 
alanine aminotransferase 
(ALT)gamma-glutamyl 
transpeptidase (GGT) 
Electrolytes: 
sodium 
potassium 
calcium 
chloride 
 
Serological 
marker: 
Hepatitis B surface antigen 
(HbsAg) 
Anti-Hepatitis A Virus 
Immunoglobulin M (HAV 
IgM) 
Anti-Hepatitis C Virus 
(HCV Ab) 
Anti-Human 
immunodeficiency virus 
(HIV Ab) 


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Test Group 
Analyte/Component 
Test Group 
Analyte/Component 
Urine drug and 
cotinine 
screening, 
alcohol breath 
test 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Opiates 
Cotinine 
Alcohol 
Clinical significance of out-of-range laboratory findings is to be determined and documented by 
the Investigator/sub-Investigator who is a qualified physician. Clinically relevant changes will be 
recorded as AEs in the eCRF (see Section 6.4.1.2). 
For safety laboratory tests, the total volume of blood drawn will be approximately 51 mL for 
subject in Part A SAD and approximately 51 mL for subject in Part B MAD. Additional safety 
samples may be collected if clinically indicated at the discretion of the Investigator. 
6.4.3 Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Procedures 
(Table 7-1 and Table 7-2): 
• BP, supine (systolic and diastolic; mmHg) 
• Pulse, supine (beats per minute) 
• 
Body temperature (°C) (tympanic) 
BP and pulse will be measured using the normal practice at study center; after the subject has 
been in a supine position for at least 5 minutes. 
If the subject experiences any changes during the visits which fulfill the criteria of an AE it must 
be recorded as such (see Section 6.4.1). 
6.4.4 Electrocardiograms 
Standard 12-lead ECGs will be performed in accordance with the Schedule of Procedures 
(Table 7-1 and Table 7-2). 
ECG will be performed using an internationally recognized 12-lead cardiograph (10 sec. rhythm 
strip) after the subject has been resting in a supine position for 5 minutes. All records will be 
done in triplicate within 5 minutes, with at least a 1-minute interval. ECG printouts will include: 
date, time, at least 2-3 complexes for 12 leads data, HR, QRS duration, P-R interval, R-R 
interval, QT interval, and QTcF (QT interval corrected for HR according to Fridericia). 
• 
QTcF=QT x R-R1/3 
ECG recording will be performed according to the relevant site SOP. The review of the ECG 
must be done by the Investigator or delegate. The interpretation of the ECG result must follow 
the categories: “normal”, “abnormal, not clinically significant”, or “abnormal, clinically 
significant”. Clinically significant findings must be recorded as AEs, or if present at Screening, it 
should be documented as concomitant illness (see Section 6.4.1). 


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6.4.5 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Table 7-1 and Table 7-2). 
The examinations will include: 
• General appearance 
• Head, ears, eyes, nose, throat, neck 
• Lymph node palpation 
• Abdomen 
• Skin 
• Extremities 
• Respiratory system 
• Cardiovascular system 
• Gastrointestinal system 
• Musculoskeletal system 
• Central and peripheral nervous system 
If the subject experiences any changes during the visits which fulfill the criteria of an AE it must 
be recorded as such (see Section 6.4.1). 
6.5 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be assessed at Screening (Visit 1). 
6.5.1 Subject Demography 
The following demography information will be collected at Visit 1: 
• age 
• sex 
• race 
6.5.2 Body Measurements 
The following body measurements will be performed at Visit 1: 
• Body weight (kg) 
• Height (cm) 
• BMI 
6.5.3 Medical History 
Thorough medical examination will be performed by interview and checking medical chart 
history at Screening (Visit 1); the medical and medication history of subjects should be 
investigated and recorded in detail. 
The medical history will be obtained by interviewing the subject or by inspecting his/her medical 
records. 
For coding of medical history, see Section 9.4. 


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6.5.4 Previous and Concomitant Medications 
Previous and concomitant medication will be documented as described in Section 5.8. 


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7 
STUDY CONDUCT 
7.1 
Schedule of Procedures 
Table 7-1: Schedule of Assessments for Part A (SAD) 
Assessments 
Screening 
Period (V1) 
Confinement Days 
(V2) 
Outpatient 
Visit Day 
(V3-V4) 
Follow-up 
Visit (V5) 
Day -28 to  
Day -2 
-1 
11 
2 
32 
Day 4 
Day 7 
Day 14 
(±1 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
Randomization and Study Drug 
Administration3 
 
 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X4 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
Assessment of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG6 
X 
X 
X 
X 
 
 
X 
X 
Physical Examination 
X 
X 
 
 
X 
X 
X 
X 
Height, Weight, BMI7 
X 
 
 
 
 
 
 
 
Serology8 
X 
 
 
 
 
 
 
 
Drug/Alcohol/Cotinine Screen 
X 
X 
 
 
 
 
 
 
Safety laboratory: Hematology, 
Serum Chemistry, Urinalysis9 
X 
X 
 
X 
 
 
X 
X 
Blood Pharmacokinetic Sampling10 
 
 
X 
X 
X 
X 
 
 
Urine Sampling11 
 
 
X 
X 
 
 
 
 
Scales12 
 
X 
X 
X 
X 
X 
 
 
C-SSRS13 
X 
 
 
 
X 
 
 
 
AE: adverse event; BMI: body mass index; BP: blood pressure; C-SSRS: Columbia Suicide Severity Rating 
Scale; K-WAIS-IV: Korean Wechsler Adult Intelligence Scale-IV; ECG: electrocardiogram;  
ED: Early Discontinuation; HCV: hepatitis C virus; HBsAg: hepatitis B surface antigen; HAV: hepatitis A 
virus; HIV: human immunodeficiency virus; VAS: Visual Analogue Scale; POMS: Profile of Mood States 
1. 
On Day 1, any predose procedures should be performed within 2 hour before study drug administration. 
2. 
Discharge assessments to be performed for ED are the Day 3 assessments supplemented with an ECG and 
safety labs, see Section 7.2.4. 
3. 
Randomization occurs on Day 1 prior to dosing. 
4. 
Confirmation of inclusion and exclusion criteria. 
5. 
Vital signs include tympanic temperature, supine pulse and supine BP. Vital signs will be collected after the 
subject has been in a supine position for at least 5 minutes. On Day 1, vital signs will be measured at predose, 
and at 0.5, 1, 2, and 4 hour postdose. 
6. 
12-lead ECGs will be obtained in triplicate within 5 minutes, with at least a 1-minute interval. On Day 1, 
ECGs will be recorded at predose and at 1 hour postdose. ECGs should be performed prior to 
pharmacokinetic and safety laboratory blood draws. 
7. 
Screening height and weight will be used for BMI calculation for assessment of eligibility. 
8. 
Blood will be tested for HBsAg, anti-HAV IgM, anti-HCV Ab, and anti-HIV Ab. 
9. 
All hematology and serum chemistry labs will be taken after fasting for a minimum of 8 hours. 
10. Plasma samples for pharmacokinetics of KM-819 will be obtained on Day 1 predose (within 30 minutes prior 


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to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours postdose. 
11. Urine samples will be taken at: Day 1 predose (within 1 hour before study drug administration) and from 0 to 
24 hours postdose. 
12. Bond and Lader VAS, POMS, and K-WAIS-IV will be performed on Day -1, Day 1 (predose) and at 3, 6, 12, 
24, 48, and 72 hours postdose (± 30 minutes for each time point). 
13. The version of the C-SSRS to be performed at Screening is the “Baseline-Screening for Phase 1,” and the 
version of the C-SSRS to be performed on Day 3 (or at ED) is the “Since Last Visit”. 


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Table 7-2: Schedule of Assessments for Part B (MAD) 
Assessments 
Screening 
Period (V1) 
Confinement Days (V2) 
Follow-up 
Visit (V3) 
Day -28 to 
Day -2 
-1 
11 
2 
3 
4 
5 
6 
7 
82 
Day 14 
(±1 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomization and Study Drug 
Administration3 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG5 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
X 
X 
Height, Weight, BMI 6 
X 
 
 
 
 
 
 
 
 
 
 
Serology7 
X 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol/Cotinine Screen 
X 
X 
 
 
 
 
 
 
 
 
 
Safety Laboratory: Hematology, 
Serum Chemistry, Urinalysis8 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
Spine X-ray examination9 
X 
 
 
 
 
 
 
 
 
 
 
Blood Pharmacokinetic Sampling10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CSF Pharmacokinetic Sampling11 
 
 
X 
 
 
 
 
 
X 
 
 
CSF Pharmacodynamic Sampling12 
 
 
X 
 
 
 
 
 
X 
 
 
Plasma Pharmacodynamic 
Sampling13 
 
 
X 
 
 
 
 
 
X 
 
 
Scales14 
 
X 
X 
X 
 
 
 
 
X 
X 
 
C-SSRS15 
X 
 
 
 
X 
 
 
 
 
X 
 
AE: adverse event; BMI: body mass index; BP: blood pressure; CSF: Cerebrospinal fluid; C-SSRS: Columbia 
Suicide Severity Rating Scale; K-WAIS-IV: Korean Wechsler Adult Intelligence Scale-IV; ECG: 
electrocardiogram; ED: Early Discontinuation; HCV: hepatitis C virus; HBsAg: hepatitis B surface antigen; 
HAV: hepatitis A virus; HIV: human immunodeficiency virus; VAS: Visual Analogue Scale; POMS: Profile of 
Mood States 
1. 
On Day 1, any predose procedures should be performed within 2 hour before study drug administration. 
2. 
Discharge assessments to be performed for ED. 
3. 
Randomization occurs on Day 1 prior to dosing. 
4. 
Vital signs include tympanic temperature, supine pulse, and supine BP. Vital signs will be collected after the 
subject has been in a supine position for at least 5 minutes. On Day 1 and Day 4, vital signs will be measured 
at predose and at 1 hour postdose; On Day 2, Day 3, Day 5, Day 6, and Day 7, vital signs will be measured at 
predose. Timing of vital signs measurements may be shifted and/or added based on the results of Part A. 
5. 
12-lead ECGs will be obtained in triplicate within 5 minutes, with at least a 1-minute interval. On Day 1 and 
Day 4, ECGs will be recorded at predose and at 1 hour postdose. ECGs should be performed prior to 
pharmacokinetic and safety laboratory blood draws. 
6. 
Screening height and weight will be used for BMI calculation for assessment of eligibility. 
7. 
Blood will be tested for HBsAg, anti-HAV IgM, anti-HCV Ab, and anti-HIV Ab. 
8. 
All hematology and serum chemistry labs will be taken after fasting for a minimum of 8 hours. 
9. 
Simple spine X-ray examination will only be conducted at Screening for healthy elderly cohort. 
10. Plasma samples for pharmacokinetics of KM-819 will be obtained on Day 1 predose (within 30 minutes prior 
to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, 


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and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 
and 24 hours postdose. 
11. CSF samples for pharmacokinetic of KM-819 will be obtained on Day 1 (at -120 minutes to 0 minute prior to 
the first dosing) and on Day 7 (at 1 hour after last dosing). 
12. CSF samples for pharmacodynamic of KM-819 will be obtained on Day 1 (at -120 minutes to 0 minute prior 
to the first dosing) and on Day 7 (at 1 hour after last dosing). 
13. Plasma samples for pharmacodynamic of KM-819 will be obtained on Day 1 (within 30 minutes prior to study 
drug administration) and on Day 7 (at 1 hour after last dosing). 
14. Bond and Lader VAS, POMS, and K-WAIS-IV will be performed on Day -1, on Day 1 and Day 7 at predose, 
3, 6, 12, and 24 hours postdose (± 30 minutes for each time point). 
15. The version of the C-SSRS to be performed at Screening is the “Baseline-Screening for Phase 1,” and the 
version of the C-SSRS to be performed on Day 3 and Day 8 (or at ED) is the “Since Last Visit”. 


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Table 7-3: Pharmacokinetic Sampling Time points for Part A (SAD) 
Visits 
Nominal time 
Remark 
Sampling time 
Sampling windows 
Visit 2, Day 1 
Predose 
- 30 min 
Baseline sample 
 
 
Study drug administration 
0.25 hour 
+ 2 min 
 
0.5 hour 
± 3 min 
 
1 hour 
± 5 min 
 
2 hour 
± 10 min 
 
4 hour 
± 10 min 
 
6 hour 
± 10 min 
 
8 hour 
± 10 min 
 
12 hour 
± 15 min 
 
Visit 2, Day 2 
24 hour 
± 15 min 
 
Visit 2, Day 3 
48 hour 
± 60 min 
 
Visit 3, Day 4 
72 hour 
± 60 min 
 
 
 


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Table 7-4: Pharmacokinetic Sampling Time points for Part B (MAD) 
 
 
Visits 
Nominal time 
Remark 
Sampling time 
Sample 
windows 
Visit 2, Day 1 
Predose 
- 30 min 
Baseline sample 
 
 
First study drug 
administration 
0.25 hour 
+ 2 min 
 
0.5 hour 
± 3 min 
 
1 hour 
± 5 min 
 
2 hour 
± 10 min 
 
4 hour 
± 10 min 
 
6 hour 
± 10 min 
 
8 hour 
± 10 min 
 
12 hour 
± 15 min 
 
Visit 2, Day 2 
Predose 
- 30 min 
24 hour after first dose 
Visit 2, Day 3 
Predose 
- 30 min 
Trough sample 
Visit 2, Day 4 
Predose 
- 30 min 
Trough sample 
Visit 2, Day 5 
Predose 
- 30 min 
Trough sample 
Visit 2, Day 6 
Predose 
- 30 min 
Trough sample 
Visit 2, Day 7 
Predose 
- 30 min 
Predose sample 
 
 
Last study drug 
administration 
0.25 hour 
+ 2 min 
 
0.5 hour 
± 3 min 
 
1 hour 
± 5 min 
 
2 hour 
± 10 min 
 
4 hour 
± 10 min 
 
6 hour 
± 10 min 
 
8 hour 
± 10 min 
 
12 hour 
± 15 min 
 
Visit 2, Day 8 
24 hour 
± 15 min 
 


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7.2 
Procedures by Visit 
Visits should occur within visit windows (defined in Table 7-1 and Table 7-2) of the scheduled 
visits. All times should be recorded using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
7.2.1 Screening (Visit 1) for Part A and Part B 
The subjects will receive verbal and written information about the study and the procedures 
involved before Screening. Before any study-related activities are performed, the subject must 
have given written informed consent to study participation. 
The Screening Period may extend up to 27 days from the time the informed consent form (ICF) 
is signed. The subject may visit the site more than one time during this period. 
The assessments to be performed at this visit are listed below: 
• inclusion/exclusion criteria assessment 
• demographic and medical/medication history data collection 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment 
• body measurements (weight, height, and BMI) 
• hematology and biochemistry blood sampling 
• serology blood sampling 
• urinalysis sampling 
• urine drug/cotinine tests  
• alcohol breath test 
• C-SSRS assessment 
• spine X-ray examination (only for healthy elderly cohort in Part B) 
7.2.2 Visits for Part A Single Ascending Dose 
7.2.2.1 Confinement Visit (Visit 2) 
Visit 2 for SAD will occur within 28 days after Screening. 
On Day -1 (check-in), subjects will need to attend the study center, the following assessments 
will be performed: 
• confirmation of inclusion/exclusion criteria 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment 
• hematology and biochemistry blood sampling 
• urinalysis sampling 


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• urine drug/cotinine tests 
• alcohol breath test 
• scales assessment 
All results necessary for evaluation of the inclusion and exclusion criteria must be available 
before determining whether or not the subject can continue in the study. 
Once verified eligible to the study, the subjects will be required to stay in study center for 3 
nights (confined from the evening of Day -1 to Day 3). 
 
On Day 1, the procedures to be performed at predose are listed below: 
• Randomization: eligible subjects will be randomized to receive either KM-819 or placebo 
• vital signs measurement (predose) 
• ECG assessment (predose) 
• scales assessments (predose) 
• Urine sampling within 1 hour before dosing 
• PK blood sampling within 30 minutes before dosing 
Study drug will be administered from 8:00 to 10:00. 
The procedures to be performed at postdose are listed below: 
• postdose PK blood sampling at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours (see Table 7-1) 
• postdose vital signs measurements at 0.5, 1, 2, and 4 hours 
• postdose ECG assessment at 1 hour 
• postdose urine sampling from 0 to 24 hours 
• postdose scales assessments at 3, 6, and 12 hours 
The following assessments will also be performed during Day 1: 
• concomitant medication 
• assessment of AE 
 
On Day 2 to Day 3, the procedures to be performed are listed below: 
• concomitant medication 
• assessment of AE 
• vital signs measurement 
• ECG assessment (only on Day 2) 
• hematology and biochemistry blood sampling (only on Day 2) 
• urinalysis sampling (only on Day 2) 
• postdose PK blood sampling at 24 hour and 48 hours 
• postdose scales assessments at 24 hours and 48 hours 
• physical examination (only on Day 3) 
• C-SSRS assessment (only on Day 3) 


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Subjects will be allowed to leave the study center after completing all the procedures on Day 3. 
7.2.2.2 Outpatient Visits (Visit 3 to Visit 4) 
Subjects will need to attend the study center on Day 4 for Visit 3 and on Day 7 for Visit 4. The 
following assessments will be performed on each visit: 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment (only on Visit 4) 
• hematology and biochemistry blood sampling (only on Visit 4) 
• urinalysis sampling (only on Visit 4) 
• postdose PK blood sampling at 72 hours (only on Visit 3) 
• postdose scales assessments at 72 hours (only on Visit 3) 
7.2.2.3 Follow-up Visit (Visit 5) 
Subjects will need to attend the study center on Day 14 for Follow-up Visit (Visit 5). The 
following assessments will be performed: 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment 
• hematology and biochemistry blood sampling 
• urinalysis sampling 
7.2.3 Visits for Part B Multiple Ascending Dose 
7.2.3.1 Confinement Visit (Visit 2) 
Visit 2 for MAD will occur within 28 days after Screening. 
On Day -1 (check-in), subjects will need to attend the study center, the following assessments 
will be performed: 
• confirmation of inclusion/exclusion criteria 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment 
• hematology and biochemistry blood sampling 
• urinalysis sampling 
• urine drug/cotinine tests 
• alcohol breath test 


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• scales assessment 
All results necessary for evaluation of the inclusion and exclusion criteria must be available 
before determining whether or not the subject can continue in the study.  
Once verified eligible to the study, the subjects will be required to stay in study center for 8 
nights (confined from the evening of Day -1 to Day 8). 
 
On Day 1, the procedures to be performed at predose are listed below: 
• Randomization: eligible subjects will be randomized to receive either KM-819 or placebo 
• vital signs measurement (predose) 
• ECG assessment (predose) 
• scales assessments (predose) 
• CSF PK and PD sampling (at -120 minutes to 0 minutes before dosing) 
• PK blood sampling within 30 minutes before dosing 
• plasma PD sampling within 30 minutes before dosing 
Study drug will be administered from 8:00 to 10:00. 
The procedures to be performed at postdose are listed below: 
• postdose PK blood sampling at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours (see Table 7-2) 
• postdose vital signs measurements at 1 hour 
• postdose ECG assessment at 1 hour 
• postdose scales assessments at 3, 6, and 12 hours 
The following assessments will also be performed during Day 1: 
• concomitant medication 
• assessment of AE 
 
On Day 2 to Day 6, the procedures to be performed on each day are listed below: 
• concomitant medication 
• assessment of AE 
• vital signs measurement (at predose and at 1 hour postdose on Day 4; at predose on Day 2, 
Day 3, Day 5, and Day 6) 
• ECG assessment (at predose and at 1 hour postdose on Day 4) 
• hematology and biochemistry blood sampling (only on Day 2 and Day 4) 
• urinalysis sampling (only on Day 2 and Day 4) 
• PK blood sampling within 30 minutes before each dosing 
• study drug administration from 8:00 to 10:00 
• scales assessments at 24 hours after first dosing (only on Day 2) 
• C-SSRS assessment (only on Day 3) 
On Day 7, the procedures to be performed before last dose are listed below: 
• vital signs measurement (predose) 


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• scales assessments (predose) 
• PK blood sampling within 30 minutes before dosing 
Study drug will be administered from 8:00 to 10:00. 
The procedures to be performed at postdose are listed below: 
• postdose PK blood sampling at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours (see Table 7-2) 
• Plasma PD sampling (at 1 hour postdose) 
• CSF PK and PD sampling (at 1 hour postdose) 
• postdose scales assessments at 3, 6, and 12 hours 
The following assessments will be also performed during Day 7: 
• concomitant medication 
• assessment of AE 
 
On Day 8, the procedures to be performed are listed below: 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment 
• hematology and biochemistry blood sampling 
• urinalysis sampling 
• PK blood sampling at 24 hour after last dosing 
• scales assessments at 24 hours after last dosing 
• C-SSRS assessment 
Subjects will be allowed to leave the study center after completing all the procedures on Day 8. 
7.2.3.2 Follow-up Visit (Visit 3) 
Subjects will need to attend the study center on Day 14 for Follow-up Visit (Visit 3). The 
following assessments will be performed: 
• concomitant medication 
• assessment of AE 
• vital signs measurement and physical examination 
• ECG assessment 
• hematology and biochemistry blood sampling 
• urinalysis sampling 
7.2.4 Early Termination Visit 
Subjects who discontinue early from the study should, if possible, have an ED Visit. This visit 
should take place as soon as possible after the subject stops taking study drug/after it was learned 
that the subject will not be able to complete Follow-up. The observations and procedures 
scheduled for Day 3 (Part A, safety laboratory and ECG assessment also needed) or Day 8 (Part 


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B) should be performed at the ED Visit. For subjects who discontinue early from the study 
during out-patient period (i.e., after completion of hospitalization period), C-SSRS will not be 
done at ED visit. Scales (Bond and Lader VAS, POMS, and K-WAIS-IV) will not be assessed 
for all the early discontinued subjects. 


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8 
STATISTICAL METHODS 
All statistical analyses and programming of tables, figures, and listings will be performed by 
PAREXEL International Early Phase Biostatistics using the latest available version of SAS® 
(SAS Institute Inc., Cary, North Carolina, USA) version 9.2 or higher. Pharmacokinetic 
parameters will be calculated by a PK analyst and reviewed by a PK scientist from the 
PAREXEL Quantitative Clinical Development department, using Phoenix® WinNonlin® 
(Certara, L.P., 1699 S Hanley Road, St Louis MO 63144 USA) Version 6.2 (or higher). 
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 as mentioned in detail in the SAP will be described in 
a SAP Addendum and justified in the final integrated Clinical Study Report. 
8.1 
Study Subjects 
8.1.1 Disposition of Subjects 
The assignment of subjects to analysis populations will be listed and summarized by group for 
Parts A and B. The tabulation will include the following information: number of subjects dosed, 
number and percentage of subjects completing the study, number and percentage of subjects who 
were withdrawn (including reasons for withdrawal), number and percentage of subjects in each 
of the analysis populations. A listing of withdrawals from the study will be presented. 
Disposition data will be presented using the safety population. 
8.1.2 Protocol Deviations 
Protocol deviations as recorded in the protocol deviations log by Project Management will be 
listed. Time window deviations as derived by Data Management will also be included in this 
listing. 
8.1.3 Analysis Sets 
Safety Analysis Set (SAF): 
The safety analysis set (SAF) will be the primary analysis set for 
all safety displays and consists of all subjects who received at least 
one dose. 
Pharmacokinetic Analysis Set (PKAS): 
The pharmacokinetic analysis set (PKAS) will be 
the primary analysis set for all PK displays and 
analyses, consists of all subjects from the SAF for 
whom sufficient plasma concentration data are 
available to facilitate the calculation of at least one 
PK parameter, had no important protocol deviations 
affecting the PK variables, as confirmed during a 
pre-analysis review of the data prior to database 
lock. 
Pharmacodynamic Analysis Set (PDAS): 
The pharmacodynamic analysis set (PDAS) consists 
of all subjects from the SAF for whom sufficient 
data for neuropsychologic testing (Parts A and B) or 
plasma and CSF concentration data are available 


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(Part B) to facilitate the calculation of at least 1 PD 
parameter, had no important protocol deviations 
affecting the PD analysis, as confirmed during a 
pre-analysis review of the data prior to database 
lock. 
8.2 
General Considerations 
All statistical tests will be two-sided and will be performed at the 5% level of significance, 
unless otherwise stated. 
Study Part A and Part B will be analyzed separately. 
All original and derived parameters as well as demographic and disposition data will be listed 
and described using summary statistics. Frequency counts (number of subjects [n] and 
percentages) will be made for each qualitative variable. Descriptive statistics (n, mean, standard 
deviation [SD], median, minimum, maximum, geometric mean, and coefficient of variation [CV]) 
will be calculated for each quantitative variable (unless otherwise stated). 
The following rules will apply to any repeated safety measurements (including measurements 
performed in triplicate): 
• If the repeated measurement occurs prior to study drug administration (in each treatment 
period if applicable) then the last obtained value (or last obtained set of triplicate 
measurements) prior to dosing will be used in the descriptive statistics and in the calculation 
of changes from baseline (for results measured in triplicate the mean of the triplicates will be 
used in the calculation of changes from baseline). 
• If the repeated measurement occurs after study drug administration (in each treatment period 
if applicable) then the first (non-missing) value of any repeated measurements (or first set of 
triplicate measurements) will be used in the descriptive statistics and in the calculation of 
changes from baseline (for results measured in triplicate the mean of the triplicates will be 
used in the calculation of changes from baseline). 
• If not otherwise specified, baseline refers to the last scheduled measurement (or mean of the 
set of triplicate measurements) before study drug administration (using the rules described 
above for repeated measurements). Further details regarding handling of repeated triplicate 
measurements will be described in the SAP. 
8.2.1 Missing Data 
Missing dates/times in AE and concomitant medication data will be handled as described in the 
SAP. There will be no imputation schemes applied to missing PK and/or PD data. Values that are 
below the limit of quantification (BLQ) in the PK data will be handled as described in the SAP. 
8.3 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic and anthropometric information (height, weight, BMI, age, race) will be listed and 
summarized. 
Medical history data will be listed by subject. All medical history will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 


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Prior medications are defined as those taken from Screening until the time of the first study drug 
administration. Concomitant medications are defined as those taken at the time of or after the 
first study drug administration. 
Prior and concomitant medication will be coded according to the latest available version of the 
World Health Organization’s Drug Dictionary (WHO-DD) and the Anatomical Therapeutic 
Chemical (ATC) classification system. Prior and concomitant medication will be listed. 
8.4 
Treatment Compliance 
Exposure to study drug will be listed by subject.  
8.5 
Efficacy Analyses 
Efficacy will not be tested in this study. 
8.5.1 Primary Efficacy Analysis 
8.5.1.1 Hypothesis to be Tested 
Not applicable 
8.5.1.2 Statistical Methods 
Not applicable 
8.5.1.3 Subgroup Analyses 
Not applicable 
8.5.2 Secondary Efficacy Analyses 
Not applicable 
8.6 
Safety Analyses 
Safety data will be summarized by using descriptive statistics (n, mean, SD, minimum, median 
and maximum). Categorical data will be summarized using frequencies and percentages. 
8.6.1 Adverse Events 
All AEs will be coded according to MedDRA. All reported AEs will be included in the subject 
data listings. The following listings will be produced: 
• All AEs 
• All AEs leading to withdrawal 
• SAEs 
Treatment-emergent AEs will be summarized by System Organ Class (SOC) and preferred term. 
In addition, TEAEs will be summarized by intensity and causality. Only AEs with onset during 
the treatment period (i.e., TEAEs) will be included in summary tables. 


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8.6.2 Vital Signs and Electrocardiogram 
Vital signs and ECG parameters will be listed by subject and time point including changes from 
baseline and repeat/unscheduled measurements. The baseline for each measurement will be the 
mean of the triplicate assessments obtained on Day -1. Descriptive statistics will be presented for 
both absolute values and changes from baseline. The mean of any triplicate assessments 
performed at a given time point will be used in all calculations of changes from baseline and in 
all tabulations. Further details will be provided in the SAP. 
8.6.3 Safety Laboratory Parameters 
Safety laboratory parameters (hematology and clinical chemistry) will be listed by subject and 
time point including changes from baseline and repeat/unscheduled measurements. The baseline 
for each of these measurements will be the assessment obtained on Day -1. All values outside the 
reference ranges will be flagged in the subject data listings. Descriptive statistics (for non-
categorical data) will be presented for both absolute values and changes from baseline. 
Urinalysis data will be listed by subject and time point including repeat/unscheduled 
measurements. 
Serology and drugs-of-abuse (including alcohol and cotinine) assessments will be listed by 
subject and time point (where appropriate). 
8.6.4 Other Analyses 
Abnormal physical examination results will be listed by subject and time point. Listing of spinal 
X-ray will be provided (if appropriate). 
8.7 
Pharmacokinetic Analysis 
Plasma and CSF KM-819 concentration data will be listed by subject including actual sampling 
times. Plasma and CSF KM-819 concentrations will be summarized by treatment (dose level) 
and nominal time point. The following descriptive statistics will be presented for plasma 
concentrations obtained at each nominal time point: n, arithmetic mean, SD, CV%, median, 
geometric mean, minimum, and maximum values. 
Individual and mean plasma KM-819 concentration time curves on normal and semi-logarithmic 
scales will be provided. Overlay plots by treatment group will also be provided. 
The KM-819 PK parameter data will be listed and summarized by treatment (dose level). 
Summary statistics will include n, arithmetic mean, SD, CV%, median, geometric mean, 
minimum, and maximum values. 
Further details will be provided in the SAP. 
8.7.1 Dose Proportionality (Part A) 
Dose proportionality analysis will be performed as an exploratory analysis. 
Dose proportionality for Cmax and AUCinf will be examined via the power model and will be 
summarized and reported graphically. The PK parameters and the dose will be logarithmically 
(ln) transformed prior to analysis.8 An alpha level of 5% will be used. 
The power model assumes that the PK parameters are log-normally distributed with equal 
variances (constant coefficient of variation for untransformed data). A linear model with ln (dose) 
as continuous independent variable will be estimated. Estimates of β0 and β1, their standard 


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errors, 95% Confidence Interval (CI) and the CV for β0 for each PK parameter will be reported. 
Dose proportionality plots of individual primary PK parameters will be displayed versus dose 
(log-log scale) along with the regression line and the 95% CI. Plots of dose-normalized 
parameters versus dose will also be provided. 
Additionally, an analysis of variance (ANOVA) of the natural log-transformed dose-normalized 
PK parameters AUCinf/dose and Cmax/dose with log-transformed KM-819 dose as a covariate and 
subject as random effect, will be performed to estimate the slope of the effect of dose level on 
the PK parameter and its 95% CI. 
Further details will be provided in the SAP. 
8.8 
Pharmacodynamic Analysis 
Part A and Part B: 
To evaluate the effect of KM-819, descriptive statistics for continuous and categorical variables 
will be used to summarize PD parameters: VAS, POMS, K-WAIS-IV, and C-SSRS. 
Part B: 
Descriptive statistics variables will be used to summarize PD parameters by dose group where 
appropriate. Modeling of PK/PD variables may be performed if considered necessary. 
Further details will be provided in SAP. 
8.9 
Interim Analyses 
No interim analysis is planned for this study. 
8.10 Determination of Sample Size 
The sample size of 8 subjects each cohort in both parts is standard in first-in-human study for 
dose escalation. The number of subjects planned for both parts of this study is considered 
sufficient to achieve the study objectives (safety, tolerability, PK, and PD). 


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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of each 
Investigator, inspect the site facilities, and inform the Investigator of responsibilities and the 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the EDC system for this study must be consistent with 
the subjects’ source documentation (i.e., medical records). 
9.1.1 Database Management and Quality Control 
Case report forms (CRFs) are provided for each subject in electronic format as eCRF. All data 
generated by the site personnel will be captured electronically at each study center using eCRFs. 
Data from external sources (such as laboratory data) will be imported into the database. Once the 
eCRF clinical data have been submitted to the central server at the independent data center, 
corrections to the data fields will be captured in an audit trail. The reason for change, the name of 
the person who performed the change, together with the time and date will be logged to provide 
an audit trail. 
If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the EDC application. The appropriate staff at the study site will answer queries sent to the 
Investigator. The name of the staff member responding to the query, and time and date stamp 
will be captured to provide an audit trail. Once all source data verification is complete and all 
queries are closed, the monitor will freeze the eCRF page. 
The specific procedures to be used for data entry and query resolution using the EDC system will 
be provided to study sites in a training manual. In addition, site personnel will receive training on 
the EDC system. 
9.2 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the EDC system promptly. All source 
documents from which EDC entries are derived should be placed in the subject’s medical 
records. Measurements for which source documents are usually available include laboratory 
assessments and ECG etc. 
Data that will be entered directly into the EDC system (i.e., for which there is no prior written or 
electronic record of data, such as Quality of Life assessments) are considered to be source data. 
The original EDC entries for each subject may be checked against source documents at the study 
site by the PAREXEL site monitor. 
After review by the site monitor, completed EDC entries will be uploaded and forwarded to 
Kainos Medicine, Inc. and PAREXEL. Instances of missing or uninterpretable data will be 
discussed with the Investigator for resolution. 
9.2.1 Data Collection 
The Investigators (and appropriately authorized staff) will be given access to an online web-
based EDC) system which is 21 CFR Part 11 compliant. This system is specifically designed for 


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the collection of the clinical data in electronic format. Access and right to the EDC system will 
be carefully controlled and configured according to each individual’s role throughout the study. 
In general, only the Investigator and authorized staff will be able to enter data and make 
corrections in the eCRFs. 
The eCRF should be completed for each subject included in the study and should reflect the 
latest observations on the subjects participating in the study. Therefore, the eCRFs are to be 
completed as soon as possible during or immediately after the subject’s visit or assessment. The 
Investigator must verify that all data entries in the eCRF are accurate and correct. If some 
assessments cannot be done, or if certain information is unavailable, not applicable or unknown, 
the Investigator should indicate this in the eCRF. 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the site 
will be informed about new issues to be resolved online. All discrepancies will be solved online 
directly by the Investigator or by authorized staff. Off-line edit checks will be done to examine 
relationships over time and across panels to facilitate quality data. 
After completion, the Investigator will be required to electronically sign off the clinical data 
Data about all study drugs dispensed to the subject and any dosage changes will be tracked on 
the eCRF. 
9.3 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare EDC 
entries and individual subject’s medical records, assess drug accountability, and ensure that the 
study is being conducted according to pertinent regulatory requirements. EDC entries will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that subject confidentiality is maintained. 
Checking of the EDC entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, Regulatory 
Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
PAREXEL and the Sponsor of the necessary support at all times. 
9.4 
Data Processing 
All data will be entered by site personnel into the EDC system (See Section 9.2.1). 
The data-review and data-handling document, to be developed during the initiation phase of the 
study, will include specifications for consistency and plausibility checks on data and will also 
include data-handling rules for obvious data errors. Query/correction sheets for unresolved 
queries will be sent to the study monitors for resolution with the Investigator. The database will 
be updated on the basis of signed corrections. 
Previous and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Reference List (DRL), which employs the ATC classification system. Medical 
history/current medical conditions and AEs will be coded using the MedDRA terminology. 
Previous and concomitant diseases as well as AEs will be coded with MedDRA. 


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The versions of the coding dictionaries will be provided in the Clinical Study Report. 
9.5 
Archiving Study Records 
According to International Conference on Harmonization (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 investigational product. However, these documents should be retained for a longer period 
if required by the applicable legal requirements. 
9.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH, and of the Declaration of 
Helsinki (2013). The study also will be carried out in keeping with local legal requirements. 
9.7 
Informed Consent 
Before each subject is admitted to the study, informed consent will be obtained from the subject 
(or his/her legally authorized representative) according to the regulatory and legal requirements 
of the participating country. This consent form must be dated and retained by the Investigator as 
part of the study records. The Investigator will not undertake any investigation specifically 
required only for the clinical study until valid consent has been obtained. The terms of the 
consent and when it was obtained must also be documented in the EDC system. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the consent form is revised, it must be reviewed and approved by the appropriate 
IEC/IRB, and signed by all subjects subsequently enrolled in the study as well as those currently 
enrolled in the study. 
9.8 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, 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 study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). 
Administrative changes (not affecting the subject benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
9.9 
Duration of the Study 
For an individual subject, the maximum duration of the study for each subject will be: 
• Part A (SAD): up to 42 days (including up to 28 days for Screening, up to 7 days treatment 
and up to 7 days Follow-up). 


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• Part B (MAD): up to 42 days (including up to 28 days for Screening, up to 8 days treatment 
and up to 6 days Follow-up). 
The study will close when all subjects have completed the Final Follow-up Visit. 
9.10 Premature Termination of the Study 
If the PI and the Sponsor becomes aware of conditions or events that suggest a possible hazard to 
subjects if the study continues, the study may be terminated after appropriate consultation 
between the relevant parties. The study may also be terminated early at the Sponsor’s discretion 
in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study; 
• Failure to enroll subjects at an acceptable rate; 
• A decision on the part of the Sponsor to suspend or discontinue development of the drug. 
9.11 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified on EDC 
system and other documents submitted to PAREXEL by their subject number. Documents not to 
be submitted to PAREXEL that identify the subject (e.g., the signed informed consent) must be 
maintained in confidence by the Investigator. 
9.12 Other Ethical and Regulatory Issues (Optional) 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators, and IRB/IECs. 
A significant safety issue is one that has a significant impact on the course of the clinical study or 
program (including the potential for suspension of the development program or amendments to 
protocols) or warrants immediate update of informed consent. 
9.13 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance with all 
local legal requirements. The civil liability of the Investigator, the persons instructed by him or 
her and the hospital, practice, or institute in which they are employed and the liability of the 
Sponsor with respect to financial loss due to personal injury and other damage that may arise as a 
result of the carrying out of this study are governed by the applicable law. 
The Sponsor will arrange for subjects participating in this study to be insured against financial 
loss due to personal injury caused by the pharmaceutical products being tested or by medical 
steps taken in the course of the study. 


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9.14 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication and information for medical and 
pharmaceutical professionals. If necessary, Regulatory Authorities will be notified of the 
Investigator's name, address, qualifications and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with the Sponsor in advance. Details are provided in a separate document. 


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10 REFERENCE LIST 
 
 
 
1 
World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical 
research involving human subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 
1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996, the 52nd WMA General 
Assembly, Edinburgh, Scotland, October 2000, Note of Clarification on Paragraph 29 added by the WMA 
General Assembly, Washington 2002, Note of Clarification on Paragraph 30 added by the WMA General 
Assembly, Tokyo 2004, and 59th WMA General Assembly, Seoul, South Korea, October 2008, 64rd WMA 
General Assembly, Fortaleza, Brazil, October 2013. JAMA 2013; 310(20):2191-2219. 
2 
Datamonitor, 2010 
3 
Datamonitor, 2011 
4 
Health Insurance Evaluation Committee, 2008 
5 
Betarbet R, Anderson LR, Gearing M, et al. Fas Associated Factor 1 and Parkinson’s disease. Neurobiol Dis. 
2008; 31(3): 309–315. 
6 
Sul JW, Park MY, Shin J, et al. Accumulation of the parkin substrate, FAF1, plays a key role in the 
dopaminergic neurodegeneration. Hum Mol Genet. 2013; 22(8):1558-1573. 
7 
Food and Drug Administration. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers, Jul 2005 
8 
Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of dose 
proportionality. Pharm Res. 2000; 17(10): 1278-1283.