A Phase 1, Randomized, Double-Blinded, Single-Dose Escalation Study Followed by a Multiple-Dose Escalation Study of SKL24741 in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: SK Life Science, Inc.

SK Life Science, Inc. 
 
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SKL24741 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 1, RANDOMIZED, DOUBLE-BLINDED, 
SINGLE-DOSE ESCALATION STUDY FOLLOWED 
BY A MULTIPLE-DOSE ESCALATION STUDY OF 
SKL24741 IN HEALTHY SUBJECTS 
 
SK Life Science, Inc. Study Number: SKL24741C001 
IND Number: 141225 
 
Sponsor: 
SK Life Science, Inc. 
461 From Road, 5th floor 
Paramus  
NJ 07652 
USA 
 
Original Protocol Date 
Amendment 1 
Amendment 2 
 
20 September 2019  
13 December 2019 
03 January 2020 
 
 
Version Number 
Amendment 3 
Version Date 
21 February 2020 
 
CONFIDENTIAL 

SK Life Science, Inc. 
 
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This document contains confidential information. Any use, distribution, or disclosure without 
the prior written consent of SK Life Science, Inc. is strictly prohibited except to the extent 
required under applicable laws or regulations. Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by 
them. 
 

SK Life Science, Inc. 
 
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PROTOCOL AMENDMENTS 
Amendment 1 
 
Section 
Old text / Content 
Amended text / 
Content 
Rationale / 
Description 
1. Protocol 
Synopsis – Number 
of Subjects 
104  
98 
Correction 
1. Protocol 
Synopsis – Study 
Population  
66 in Part A 
60 in Part A  
Correction  
1. Protocol 
Synopsis – Study 
Population 
aged 18 to 55 years 
(inclusive) 
 
aged 18 to 50 years 
(inclusive) 
 
Revised the age 
range to improve 
screening of 
healthy volunteers  
1. Protocol 
Synopsis – Study 
Treatment 
within 30 minutes after 
the end of a…breakfast 
approximately 30 
minutes after the 
start of 
a…breakfast  
Correction per 
FDA guidance on 
the food effect 
assessment 
4.1.1.3 Nonclinical 
Safety 
Based on these findings, 
the no observed adverse 
effect level (NOAEL) 
was 30 mg/kg/day 
(Day 28 mean combined 
sex Cmax and AUC24hr 
values of 6.94 µg/mL and 
121 µg*h/mL, 
respectively).  
Based on FDA 
recommendation, a 
NOAEL of 
15 mg/kg/day was 
considered for 
calculating the 
starting dose (mean 
combined sex Cmax 
values was 3.32 
µg/mL and 
AUC24hr 
61.2 µg*h/mL). 
Revised the rat 
NOAEL doses and 
systemic exposure 
at the NOAEL 
dose levels per 
FDA 
recommendation 
4.1.1.3 Nonclinical 
Safety 
Based on the mild 
severity of findings, the 
NOAEL was 40 
mg/kg/day (Day 28 mean 
combined sex Cmax and 
Based on FDA 
recommendation, a 
NOAEL of 10 
mg/kg/day was 
considered for 
Revised the dog 
NOAEL doses and 
systemic exposure 
at the NOAEL 
dose levels per 

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AUC24hr values of 
4.18 µg/mL and 
40.8 µg*h/mL, 
respectively).   
calculating the 
starting dose (mean 
combined sex Cmax 
values was 
2.61 µg/mL and 
AUC24hr 
21.7 µg*h/mL). 
FDA 
recommendation 
4.2.2. Dosing 
Rationale 
…the no observed 
adverse effect level 
(NOAEL) was 
established at 30 
mg/kg/day in rats and 40 
mg/kg/day (highest dose 
tested) in dogs…   
…the FDA-
recommended no 
observed adverse 
effect level 
(NOAEL) doses of 
15 mg/kg/day for 
rats and 
10 mg/kg/day for 
dogs were used for 
the human starting 
dose calculations…  
Revised the 
NOAEL doses, 
systemic 
exposure, HED 
and MRSD values 
per FDA 
recommendation 
throughout the 
text and table 
presented in this 
section 
7.1. Overview of 
Study Design  
… a total of 72 subjects 
(66 male… 
…a total of 66 
subjects (60 
male…  
Correction  
7.1. Overview of 
Study Design – 
Table 4 
N.A. 
Added a footnote 
of “* Refer to 
Section 7.1 
regarding the 
subjects returning 
to the CRU for the 
food effect 
assessment.” 
Added a footnote 
for the 
clarification 
8.1. Inclusion 
Criteria 
…18 to 55 years of age 
…18 to 50 years of 
age 
Revised the age 
range to improve 
screening of 
healthy volunteers 
8.1. Inclusion 
Criteria 
Normal 
electrocardiogram 
(ECG) (12-lead), arterial 
blood pressure 
(100-140/50-90 mmHg), 
Normal 
electrocardiogram 
(ECG) (12-lead), 
arterial blood 
pressure, and heart 
rate within the 
Revised to clarify 
the inclusion 
criteria   

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and heart rate 
(60-100 bpm) 
 
normal range of 
the study center or 
considered not 
clinically 
significant by the 
investigator and in 
agreement with the 
Sponsor 
9.3. Administration within 30 minutes after 
the end of a…breakfast 
approximately 30 
minutes after the 
start of 
a…breakfast  
Correction per  
FDA guidance on 
the food effect 
assessment (see 
above) 
9.3. Administration N.A. 
• The meal will 
be taken about 
30 minutes 
prior to the 
study drug 
administration. 
• The meal will 
be eaten in 30 
minutes or less. 
Added the 
additional 
instructions on the 
meal intake for the 
food effect 
assessment 
9.3. Administration N.A. 
Added the phrase – 
“with the exception 
of study-specific 
events or 
assessments”  
Added for the 
clarification 
9.4.1. 
Randomization 
The randomization code 
will be produced by SK 
Life Science, Inc. 
designee who will review 
and approve the 
randomization list.   
A copy of the 
randomization list (in a 
sealed tamper-evident 
envelope) will be 
archived at SK Life 
Science, Inc. 
The randomization 
list will be 
generated by the 
clinical research 
organization 
(vendor) and will 
be provided to the 
site pharmacist.  
The pharmacist 
will keep the 
randomization list 
Removed the 
phrase “Study Day 
1”; 
Revised to clarify 
the randomization 
process 

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Subjects who have 
completed screening 
evaluations and are 
eligible for participation 
in the study will be 
randomized on Study 
Day 1 for study drug 
administration. 
Each randomized subject 
will be assigned a unique 
subject number from the 
randomization list by the 
investigator or designee, 
which will be used to 
identify the individual 
subject for the duration of 
the study.  The unblinded 
authorized site personnel 
will prepare the 
appropriate study 
drug/placebo for each 
subject based on the 
randomization list.  
in a secure 
location.  
Subjects who have 
completed 
screening 
evaluations and are 
eligible for the 
study participation 
will be randomized 
for study drug 
administration. 
Each randomized 
subject will be 
assigned with a 
unique 
randomization 
number. 
9.4.2. Allocation of 
Subject Numbers 
Subjects fulfilling the 
eligibility criteria will be 
randomized and assigned 
subject numbers at dosing 
in the morning of Study 
Day 1. 
Subject numbers will be 
allocated in consecutive 
order and correspond to a 
number on the computer-
generated randomization 
list, which determines the 
treatment (active drug) 
group.  Any replacement 
subjects will receive the 
subject number from the 
subject that they are 
replacing + 100 (e.g., 
replacement for subject 
Subjects fulfilling 
the eligibility 
criteria will be 
randomized to 
receive their 
treatment 
according to the 
randomization list. 
Randomized 
subjects will be 
assigned with a 4-
digit randomization 
number in the 
order in which they 
are enrolled.  The 
first digit of the 
randomization 
number will refer 
to the Cohort 
Removed the 
phrase “Study Day 
1”; 
Revised to clarify 
the randomization 
process 

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number 01105 would be 
subject number 01205).   
 
number.  For 
example, subjects 
in Cohort 1 will 
have the 
randomization 
numbers 1xxx; 
subjects in Cohort 
2 will have the 
randomization 
numbers 2xxx.  In 
a case where a 
subject needs to be 
replaced, the last 2 
digits of the 
randomization 
number for 
replacement 
participants will be 
identical to those 
of the original 
participant’s 
randomization 
number.  The 
second digit, 
however, will be 
replaced with a 2.  
For example, if the 
original 
participant’s 
randomization 
number is 1101, 
then the 
randomization 
number for the 
replacement 
participant will be 
1201. Participants 
who prematurely 
discontinue from 
the study may be 
replaced at the 
sponsor’s 
discretion.  

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9.10.1. Blinding 
…assigned to a dosing 
group linked to their 
subject number by an 
unblinded pharmacist at 
the clinical site.   
…assigned to their 
randomization 
number linked to 
the dosing group 
by an unblinded 
pharmacist at the 
clinical site.   
Grammar 
correction; 
Replaced the 
“subject number” 
with 
“randomization 
number” for the 
clarification 
9.10.1. Blinding 
SK Life Science, Inc. 
Drug Metabolism and 
Pharmacokinetics 
[DMPK] group 
SK Life Science, 
Inc. Toxicology 
group 
Revised to reflect 
the change of 
department name 
9.10.1. Blinding 
randomization code 
randomization list 
Replaced the 
“code” with “list” 
throughout the 
protocol 
9.10.2. Unblinding 
…break the code… 
…break the 
blinding… 
Replaced the 
“code” with 
“blinding” for the 
clarification 
10.3.2. Urine 
Sampling 
N.A. 
Added the time 
window (Table 9) 
for PK urine 
sampling 
To allow a time 
window for PK 
urine sampling 
10.3.3.1 Blood 
Sample Processing 
N.A. 
… on wet ice… 
Added the new 
text to clarify the 
sample processing 
procedure  
10.3.3.1 Blood 
Sample Processing 
3000 rpm 
2000 xg 
Correction for the 
centrifuge speed 
10.6.2. Clinical 
Laboratory 
Assessments -
Table 10 
(Urinalysis) 
Occult Blood 
Blood 
Correction 

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10.6.3. Physical 
Examinations and 
Vital Signs 
Vital sign evaluations 
include blood pressure 
(systolic and diastolic), 
temperature, heart rate, 
respiratory rate, and 
arterial oxygen saturation 
(SaO2) (using pulse 
oximetry).  These will be 
assessed following a 5-
minute rest in the supine 
position.   
Vital sign 
evaluations include 
blood pressure 
(systolic and 
diastolic 
measurements in 
supine and 
standing in the 
same sequence in 
each subject, in 
order to allow 
orthostatic 
measurements), 
temperature, heart 
rate, respiratory 
rate, and arterial 
oxygen saturation 
(SaO2) (using pulse 
oximetry).  
Revised and added 
the orthostatic 
measurements 
with vital sign 
assessments per 
FDA 
recommendation 
10.6.4. 
Electrocardiograms 
The device will remain 
connected to the subject 
during the collection 
periods. 
The device will 
remain connected 
to the subject 
during the 
collection periods 
as appropriate.   
Added a phrase 
“as appropriate” to 
clarify the 
procedure  
10.6.4.1. Safety 12-
Lead ECGs 
 
…for 5 minutes… 
…for at least 5 
minutes… 
Correction to keep 
the time of supine 
rest consistent 
throughout the 
ECG collection 
10.6.4.2. Extensive 
Triplicate ECGs 
at least 10 minutes before 
and 5 minutes during the 
ECG extraction window 
to allow for quality ECG 
data 
for at least 5 
minutes before the 
ECG time point in 
order to allow for 
quality ECG data 
Correction to keep 
the time of supine 
rest consistent 
throughout the 
ECG collection  
10.6.6. Peak 
Expiratory Flow 
Rate (PEFR) 
Measurement 
Peak expiratory flow rate 
(PEFR) will be measured 
as specified in… 
Peak expiratory 
flow rate (PEFR) 
will be measured 
within a 30-minute 
time window 
Added the time 
window around 
PEFR 

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around the targeted 
time points as 
outlined in the 
Schedule of 
Assessments in… 
10.6.7.1. 
Contraception 
Subjects who can father a 
child must agree to use 
2 highly effective method 
of contraception, 
including at least one 
barrier method.  Subjects 
must use a condom… 
Subjects who can 
father a child must 
agree to use 
2 highly effective 
methods of 
contraception, 
including at least 
one barrier method, 
as follows.  Male 
subjects must use a 
condom… 
Grammar 
correction by 
adding the phrase, 
such as “, as 
follows” and 
“Male” 
10.6.7.1. 
Contraception 
…, must be in use from… …, must be used 
from… 
Grammar 
correction by 
replacing “in use” 
to “used”  
10.6.7.2. 
Pregnancy 
The investigator must 
notify the Medical 
Monitor and SK Life 
Science, Inc. within 24 
hours of the site’s 
knowledge of the 
partner’s pregnancy.   
The investigator 
must notify the 
Medical Monitor, 
SK Life Science, 
Inc., and IQVIA by 
completing the 
Pregnancy Report 
form, faxing and 
emailing the form 
as per the Table of 
Contact (Table 13 
and Table 14), 
within 24 hours of 
the site’s 
knowledge of the 
partner’s 
pregnancy.   
Correction to 
clarify the  
reporting plans for 
pregnancy 
11. Statistical and 
Analytical Plans 
PK analysis set 
PK population 
Revised the 
dataset names - 
“set” to 

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“population” 
throughout the 
section per FDA 
guidance – E9(R1) 
Statistical 
Principles for 
Clinical Trials: 
Addendum: 
Estimands and 
Sensitivity 
Analysis in 
Clinical Trials 
(2017) 
11.2. Analysis 
Populations 
Analysis Sets 
Analysis 
Populations 
Revised the 
section header and 
definition per 
FDA guidance 
(see above) 
11.2. Analysis 
Populations 
Assignment of subjects to 
analysis sets will be done 
prior to clinical database 
lock.  The following 
analysis sets will be 
defined: Full Analysis 
(FA) set, Safety set, and 
pharmacokinetic (PK) 
set. 
• FA set: All 
randomized subjects, 
whether or not they 
received study drug.  
Subjects will be analyzed 
according to the study 
drug to which they were 
randomized.  All non-
safety summaries (e.g., 
demographics) will be 
prepared using the FA 
set, as appropriate. 
N.A. (Removed the 
old text as shown) 
Deleted the old 
text to revise the 
dataset names (see 
above); 
Replaced the 
phrase “FA set” 
with “Safety 
Population” 
throughout the 
section 

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11.2. Analysis 
Populations 
Safety set: All subjects 
who received at least 1 
dose of study drug.  
Subjects will be analyzed 
according to the study 
drug actually received.  
All summaries of safety 
will be referenced using 
the Safety set. 
Safety 
Population: All 
subjects who were 
randomized and 
received at least 1 
dose of study drug.  
 
Revised the 
definition for the 
clarification 
11.2. Analysis 
Populations 
PK set: All subjects who 
satisfied the PK 
evaluation criteria and 
dosed with the study drug 
without any major 
protocol violations and 
with sufficient PK 
profiles 
PK population: 
All subjects who 
received at least 1 
dose of study drug 
and have sufficient 
PK data without 
any major protocol 
deviations. 
Revised the 
definition for the 
clarification 
11.4.2.2. 
Demographics and 
Baseline 
Characteristics 
Demographic, 
background, and baseline 
characteristics will be 
summarized for the FA 
set and will include (but 
are not limited to) subject 
disposition, 
demographics, baseline 
characteristics, medical 
history, and prior 
medications.  Continuous 
variables will be 
summarized by 
descriptive summary 
statistics and categorical 
variables by frequency 
tables. 
Demographic, 
parameters and 
baseline 
characteristics will 
be summarized for 
the Safety 
Population.  
Continuous 
variables will be 
summarized by 
descriptive 
summary statistics 
and categorical 
variables by the 
number and 
percentage of 
participants. 
 
To clarify, the 
following changes 
were made: 
1. Replaced the 
word 
“background” 
with 
“parameters”; 
2. Corrected the 
redundant 
phrases; 
3. Replaced the 
“frequency 
tables” with 
“number and 
percentage of 
participants”; 
4. Deleted the 
redundant 
statement as 
shown 

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11.4.2.3. Medical 
History 
N.A. 
Medical history 
encompassing 
abnormalities and 
surgeries reported 
before the 
Screening visit will 
be coded using the 
Medical Dictionary 
for Regulatory 
Activities 
(MedDRA), 
version 19.0 or 
newer. 
Added a new 
section 11.4.2.3. 
in order to 
improve the 
statistical analysis 
plan 
11.4.2.4. Prior and 
Concomitant 
Medications 
…regardless of whether 
medication end date is 
missing or not. 
…regardless of whether 
medication start date is 
missing or not.  Note that 
medication that started 
prior to initial dosing of 
the study drug and 
continued after initial 
dosing will be 
summarized as prior 
medication and separately 
as concomitant 
medication.  
…regardless of the 
medication end 
date. …regardless 
of the medication 
start date.  The 
prior and 
concomitant 
medications will be 
summarized 
separately.  
Grammar 
correction and 
clarification  
11.4.4.4. Vital 
Signs 
systolic and diastolic 
blood pressure (mmHg) 
systolic and 
diastolic blood 
pressure (mmHg) 
measurements (in 
supine and 
standing in the 
same sequence in 
each subject, in 
order to allow 
orthostatic 
measurements) 
Added the 
orthostatic 
measurements 
with vital sign 
assessments per 
FDA 
recommendation 

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12.2.2. Subject 
Information and 
Informed Consent 
N.A. 
A subject 
identification 
number (subject 
ID) will be 
assigned to each 
subject at the time 
that informed 
consent is 
obtained; this 
subject ID will be 
used throughout 
the study. 
Added the new 
text to clarify as 
shown 
Amendment 2 
Section 
Old text / Content 
Amended text / 
Content 
Rationale / 
Description 
9.4.2. Allocation of 
Subject Numbers 
Randomized subjects will 
be assigned with a 4-digit 
randomization number in 
the order in which they 
are enrolled.  The first 
digit of the randomization 
number will refer to the 
Cohort number.  For 
example, subjects in 
Cohort 1 will have the 
randomization numbers 
1xxx; subjects in Cohort 
2 will have the 
randomization numbers 
2xxx.  In a case where a 
subject needs to be 
replaced, the last 2 digits 
of the randomization 
number for replacement 
participants will be 
identical to those of the 
original participant’s 
randomization number.  
The second digit, 
however, will be replaced 
with a 2.  For example, if 
 Randomized 
subjects will be 
assigned with a 6-
digit randomization 
number in the 
order in which they 
are enrolled.  The 
first digit of the 
randomization 
number will refer 
to the part A or B 
(1 or 2). The 
second and third 
digits will refer to 
the Cohort number.  
For example, 
subjects in Cohort 
1 of part A will 
have the 
randomization 
numbers 101xxx; 
subjects in Cohort 
2 of part A will 
have the 
randomization 
numbers 102xxx.  
Changed 4-digit 
randomization 
number to 6-digit 
in order to 
accommodate part 
A and part B. 
 
 
 
 
Add one more 
digit to 
accommodate 
more cohorts.  
 
 
 
 
 
 

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the original participant’s 
randomization number is 
1101, then the 
randomization number 
for the replacement 
participant will be 1201. 
Participants who 
prematurely discontinue 
from the study may be 
replaced at the sponsor’s 
discretion. 
In a case where a 
subject needs to be 
replaced, the last 2 
digits of the 
randomization 
number for 
replacement 
participants will be 
identical to those 
of the original 
participant’s 
randomization 
number.  The 
fourth digit, 
however, will be 
replaced with a 2.  
For example, if the 
original 
participant’s 
randomization 
number is 110101, 
then the 
randomization 
number for the 
replacement 
participant will be 
110201. 
Participants who 
prematurely 
discontinue from 
the study may be 
replaced at the 
sponsor’s 
discretion.  
 
 

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Amendment 3 
Section 
Old text / Content 
Amended text / Content 
Rationale / 
Description 
2.0. Schedule of 
Assessments: 
Table 1  
N.A. 
Added Pregnancy Test 
(Serum) at screening and 
admission (Day -1). Adjusted 
footnote letters. 
Revised 
schedule of 
assessments to 
add pregnancy 
test to gender 
effect cohort. 
Added a 
footnote for 
clarification. 
8.1. Inclusion 
Criteria 
1.  Male subjects of 
18 to 50 years of 
age (inclusive).  
 
1. Male subjects of 18 to 
50 years of age 
(inclusive) except for 
the gender effect 
cohort.  
 
 
Revised to 
clarify the 
gender effect 
cohort will 
enroll healthy 
female 
subjects of 
non-
childbearing 
potential. 
8.1. Inclusion 
Criteria 
8. For Part A 
(gender effect 
cohort): Female 
of non-
childbearing 
potential (18 to 
50 years of age 
(inclusive)), 
who have 
undergone a 
sterilization 
procedure at 
8. For Part A (gender 
effect cohort): Female 
of non-childbearing 
potential (18 to 50 
years of age 
(inclusive)), who have 
undergone a 
sterilization procedure 
at least 6 months prior 
to dosing with official 
documentation (e.g., 
hysteroscopic 
Added 
pregnancy test 
for screening 
and admission 
(Day -1). 

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least 6 months 
prior to dosing 
with official 
documentation 
(e.g., 
hysteroscopic 
sterilization, 
bilateral tubal 
ligation or 
bilateral 
salpingectomy, 
hysterectomy, 
or bilateral 
oophorectomy), 
or be 
postmenopausal 
with 
amenorrhea for 
at least 1 year 
prior to dosing 
and follicle-
stimulating 
hormone (FSH) 
serum levels 
consistent with 
postmenopausal 
status as per 
Principal 
Investigator’s 
judgment 
 
sterilization, bilateral 
tubal ligation or 
bilateral 
salpingectomy, 
hysterectomy, or 
bilateral 
oophorectomy), or be 
postmenopausal with 
amenorrhea for at 
least 1 year prior to 
dosing, a follicle-
stimulating hormone 
(FSH) serum levels 
consistent with 
postmenopausal status 
and serum pregnancy 
test at screening and 
upon admission with a 
negative result as per 
Principal 
Investigator’s 
judgment 
 
 
9.4.2 Allocation 
of 
Randomization 
Numbers 
Allocation of 
Subject Numbers 
Allocation of 
Randomization Numbers 
Revised to 
correct 
wording  

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1. 
PROTOCOL SYNOPSIS 
Title A Phase 1, Randomized, Double-Blinded, Single-Dose Escalation Study 
Followed by a Multiple-Dose Escalation Study of SKL24741 in Healthy 
Subjects 
  
Clinical Phase Phase 1 
  
Objectives Part A (single dose administration) 
Primary:  
• 
To evaluate the safety and tolerability of single oral ascending 
doses of SKL24741 capsule(s) administered to healthy male 
subjects 
Secondary:  
• 
To evaluate the pharmacokinetics (PK) of SKL24741 (R-
enantiomer), SKL24742 (S-enantiomer) (if appropriate), and its 
possible metabolites (if deemed necessary) following 
administration of single oral ascending doses of SKL24741 
capsule(s) administered to healthy male subjects 
• 
To assess the food effect on the PK of SKL24741 and SKL24742 
(if appropriate) following administration of a single oral dose of 
SKL24741 capsule(s) administered to healthy male subjects 
• 
To assess the gender effect on the PK of SKL24741 and SKL24742 
(if appropriate) following administration of a single oral dose of 
SKL24741 capsule(s) administered to healthy female subjects 
 
Part B (multiple dose administration) 
Primary:  
• 
To evaluate safety and tolerability of multiple oral ascending doses 
of SKL24741 capsule(s) administered for 14 days to healthy male 
subjects 
Secondary:  
• 
To evaluate the PK of SKL24741, SKL24742 (if appropriate), and 
its possible metabolites (if deemed necessary) following 
administration of multiple oral ascending doses of SKL24741 
capsule(s) administered to healthy male subjects 
  
Endpoints Primary:  
• 
Safety and tolerability will be based on assessment of adverse 
events, clinically significant laboratory assessments, 
electrocardiograms (ECGs), peak expiratory flow rate (PEFR), vital 
signs (blood pressure, heart rate, body temperature, respiratory rate, 

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arterial oxygen saturation (SaO2) (using pulse oximetry)), physical 
examinations, and Columbia-Suicide Severity Rating Scale (C-
SSRS) (Part B only). 
Secondary:  
• 
PK parameters will be calculated for SKL24741 and SKL24742 (if 
appropriate) from plasma and urine PK data. 
Number of 
Subjects 
98 
  
Study Population Healthy male subjects (60 in Part A and 32 in Part B), aged 18 to 50 years 
(inclusive) 
Healthy female subjects (non-childbearing potential) (6 in Part A), aged 18 
to 50 years (inclusive) for gender effect cohort of Part A 
 
Investigational 
Drug 
Active substance: SKL24741  
Activity: An inhibitor of voltage-gated sodium channels and a possible 
activator of Big Potassium channels 
Dosage Form: Capsule 
Route of Administration: Oral 
  
Study Treatment Part 
Doses 
A 
A single oral dose of 10, 25, 50, 100, 200, 300, 400, 600, 800, 
and 1000 mg of SKL24741 or placebo will be administered to 
subjects in the morning of the first day, following an overnight 
(10-hour) fast (all doses) or approximately 30 minutes after 
the start of a high-calorie, high-fat breakfast (Food effect 
cohort). 
B 
Multiple oral administrations of 4 dose levels of SKL24741 or 
placebo administered to male subjects each day for 14 days. 
Dose, dosing regimen, and food status (fasting vs. fed) used in 
Part B will be determined based on the outcome of Part A. 
  
Schedule of Study 
Visits 
Subjects in Part A will remain in the clinic for a 4-night stay (discharged 
on Study Day 4).  Subjects in Part B will remain in the clinic for a 17-night 
stay (discharged on Study Day 17).  There will be one Follow-up visit 14 to 
16 days after the last dosing occasion for all subjects. 
  
Pharmacokinetic 
Evaluations 
Plasma Samples for Bioanalytical (BA) Analysis 
Part A 

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• 
Pre-dose, and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 
60, and 72 hours post-dose following the single dose administration 
Part B 
• 
Study Days 1 and 7: Pre-dose, and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 
12, 16, and 24 hours post-dose.  The 24-hour post-dose blood PK 
samples for Days 1 and 7 should be taken before dosing on Days 2 
and 8, respectively 
• 
Study Days 3 to 6 and 9 to 13: Pre-dose only 
• 
Study Day 14: Pre-dose, and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 
18, 24, 36, 48, 60, and 72 hours post-dose 
  
 Urine Samples for Bioanalytical (BA) Analysis 
Part A 
• 
Pre-dose, and 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72 
hours post-dose following the single dose administration 
• 
No urine collection for PK analysis in the food and gender effect 
cohorts 
Part B 
• 
No urine collection for PK analysis in Part B 
  
Safety Evaluations Adverse events, clinical laboratory assessments, electrocardiograms 
(ECGs), peak expiratory flow rate (PEFR), vital signs (blood pressure, heart 
rate, body temperature, respiratory rate, arterial oxygen saturation (SaO2) 
(using pulse oximetry)), physical examinations, and Columbia-Suicide 
Severity Rating Scale (C-SSRS) (Part B only) 

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2. 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments is provided in Table 1 for Part A (single dose administration) 
and Table 2 for Part B (multiple dose administration).  

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Table 1: 
Schedule of Assessments - Part A (Single Dose Administration) 
Assessment 
Screening 
Admission 
Confinement 
Follow-up 
(14-16 days after 
dosing day) 
 
Study Day 
Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
 15-17 
Admissiona 
 
X 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Confinement 
 
X 
X 
X 
X 
X 
 
Dischargeb 
 
 
 
 
 
X 
 
Outpatient Visit 
X 
 
 
 
 
 
X 
Informed Consentc 
X 
 
 
 
 
 
 
Inclusion and Exclusion 
Criteria Check 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Smoking Screen (cotinine 
urine test) 
X 
X 
 
 
 
 
 
Drugs of Abuse 
(urine)/Alcohol Screen 
(urine and breath)d 
X 
X 
 
 
 
 
 

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Assessment 
Screening 
Admission 
Confinement 
Follow-up 
(14-16 days after 
dosing day) 
 
Study Day 
Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
 15-17 
Physical Examinatione 
Xe 
X 
 
 
 
X 
X 
Prior and Concomitant 
Medication 
Details for all medications will be taken on an ongoing basis from screening to follow-up (FU). 
Height, weight, and BMIf 
X 
 
 
 
 
 
Xf 
Vital Signsg 
X 
X 
Xg 
X 
X 
X 
X 
Peak Expiratory Flow 
Rateh 
 
X 
Xh 
X 
 
 
X 
Safety Single 12-Lead 
ECG 
X 
X 
 
 
X 
X 
X 
Extensive Triplicate 
ECGi 
 
 
Xi 
X 
 
 
 
Serology Tests (HBsAg, 
HCV Ab, HIVAg and 
Ab) 
X 
 
 
 
 
 
 
Hematology, 
Coagulation, and Clinical 
Chemistryj 
X 
X 
 
X 
 
X 
X 
Urinalysisj 
X 
X 
 
 
 
 
X 

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Assessment 
Screening 
Admission 
Confinement 
Follow-up 
(14-16 days after 
dosing day) 
 
Study Day 
Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
 15-17 
Alpha-1-acid 
Glycoprotein 
X 
 
 
 
 
 
 
Total, LDL, and HDL 
Cholesterol 
X 
 
 
 
 
 
 
FSH test – Females onlyk 
X 
 
 
 
 
 
 
Pregnancy Test- Females 
onlyl 
X 
X 
 
 
 
 
 
PK Sampling – Plasmam 
 
 
XError! 
Reference 
source not 
found. 
XError! 
Reference 
source not 
found. 
XError! 
Reference 
source not 
found. 
X 
 
PK Sampling – Urinen 
 
 
XError! 
Reference 
source not 
found. 
XError! 
Reference 
source not 
found. 
XError! 
Reference 
source not 
found. 
X 
 
PGX Sampling – Whole 
bloodo 
 
X 
 
 
 
 
 
Study Drug Dosingp 
 
 
X 
 
 
 
 

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Assessment 
Screening 
Admission 
Confinement 
Follow-up 
(14-16 days after 
dosing day) 
 
Study Day 
Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
 15-17 
Adverse Event 
Assessment and 
Reporting 
Ongoing from the time of signing the Informed Consent Form  
(Non-treatment and Treatment emergent adverse events) 
a Subjects will be admitted to the clinic the day prior to study drug administration. 
b Subjects will be discharged on Study Day 4 after the 72-hour PK sample has been collected and the final assessment has been completed. 
c At screening, a separate informed consent form (ICF) will be used to obtain the subject's consent for the utilization of their DNA for pharmacogenomic (PGX) 
testing. 
d For drugs of abuse/alcohol screen, refer to Section 10.6.2.  At the time of signing the ICF, a negative result from the breath alcohol test is required. 
e Complete physical examination should be performed at screening only. Abbreviated physical examination should be performed at all other marked study days. 
See Section 10.6.3. 
f Height and weight will be collected, and BMI calculated at screening.  Only weight will be collected at FU. 
g Highlighted time points for vital signs (Section 10.6.3) as follows: pre-dose (baseline), 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1.  Vital signs should be 
assessed at all other marked study days.   
h Peak expiratory flow rate will be assessed at admission (Day -1), pre-dose (baseline), 2 and 24 hours post-dose after the single dose, and FU. 
i Extensive triplicate ECGs, except for the food effect cohort, will be obtained to collect continuous 12-lead ECG data from pre-dose until 24 hours post-dose as 
specified.  Three replicates (triplicate) of ECG data will be collected as close as possible from -0.75, -0.5, and -0.25 hours pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 
and 24 hours post-dose after single dose administration.  Subjects should not eat a meal within 1 hour of digital ECG data collection.  See the instruction on 
lunch and dinner time (Section 8.3.1) to avoid any meal intake within 1 hour of the 6-hour and 12-hour post-dose ECG time points. 
j For clinical laboratory assessments, refer to Section 10.6.2. 
k Postmenopausal status for females of non-childbearing potential will be further confirmed with the follicle-stimulating hormone (FSH) serum levels that are 
consistent with postmenopausal status.  Refer to Inclusion Criteria for details (Section 8.1). 
l  Pregnancy test (serum) will be collected at screening and admission (Day -1) to confirm pregnancy status of the gender effect cohort (Section 8.1). 
m  PK blood draw will be performed at pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, and 72 hours post-dose following the single dose 
administration (Section 10.3.1).  See Table 8 for PK time window. 

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n PK urine samples, except for the food and gender effect cohorts, will be collected for each specified time interval: pre-dose and between 0-4, 4-8, 8-12, 12-24, 
24-48, and 48-72 hours post-dose following the single dose administration (Section 10.3.2).  The urine volume at each interval should be recorded as part of PK 
data. 
o PGX samples (whole blood) will only be collected from the subjects who consented for DNA testing. 
p Details regarding study drug administration are provided in Section 9.3. 
BMI: body mass index; ECG: electrocardiogram; FSH: following-stimulating hormone; FU: Follow-up; HbsAg: hepatitis B surface antigen; HCV Ab: hepatitis 
C antibody; HDL: high density lipoprotein; HIV Ab: human immunodeficiency virus antibody; ICF: informed consent form; LDL: low density lipoprotein; PK: 
pharmacokinetic(s); PGX: pharmacogenomic(s).  
 
 

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SKL24741                                                                     
  
 
 
 
 
 
 
 
 
 
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Table 2: 
Schedule of Assessments - Part B (Multiple Dose Administration) 
Assessment 
Screening 
Admission 
Confinement 
 
Follow-up 
(14 – 16 
days after 
final 
dosing 
day) 
 
Study Day 
Assessment 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 28 to 30 
Admissiona 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dischargeb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed Consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
Exclusion Criteria 
Check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking Screen 
(cotinine urine test)  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of Abuse 
(urine)/Alcohol 
Screen (urine and 
breath)d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Assessment 
Screening 
Admission 
Confinement 
 
Follow-up 
(14 – 16 
days after 
final 
dosing 
day) 
 
Study Day 
Assessment 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 28 to 30 
Physical 
Examinatione 
Xe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Prior and 
Concomitant 
Medication 
Details for all medications will be taken on an ongoing basis from screening to follow-up (FU). 
Height, Weight, 
and BMIf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
Vital Signsg 
X 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
X 
X 
X 
Peak Expiratory 
Flow Rateh 
 
X 
Xh 
X 
 
 
 
 
 
 
 
 
 
 
 
Xh 
X 
 
 
X 
Safety Single 12-
lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Extensive 
Triplicate ECGi 
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
 
 
 
Serology Tests 
(HBsAg, HCV Ab, 
HIVAg and Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
Coagulation, and 
Clinical Chemistryj 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 

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SKL24741                                                                     
  
 
 
 
 
 
 
 
 
 
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Assessment 
Screening 
Admission 
Confinement 
 
Follow-up 
(14 – 16 
days after 
final 
dosing 
day) 
 
Study Day 
Assessment 
-28 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 28 to 30 
Urinalysisj 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Alpha-1-acid 
Glycoprotein 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total, LDL, and 
HDL Cholesterol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
PK Sampling – 
Plasmak 
 
 
Xk 
X 
X 
X 
X 
X 
Xk 
X 
X 
X 
X 
X 
X 
Xk 
Xk 
Xk 
X 
 
PGX Sampling – 
Whole bloodl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Dosingm 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Event 
Assessment and 
Reporting 
Ongoing from the time of signing the Informed Consent Form  
(Non-treatment and Treatment emergent adverse events) 
a Subjects will be admitted to the clinic the day prior to study drug administration. 
b Subjects will be discharged on Study Day 17, after the 72-hour PK sample from the final dose has been collected and the final assessment has been completed. 
c At screening, a separate informed consent form (ICF) will be used to obtain the subject's consent for the utilization of their DNA for pharmacogenomic (PGX) 
testing. 
d For drugs of abuse/alcohol screen, refer to Section 10.6.2.  At the time of signing the ICF, a negative result from the breath alcohol test is required. 

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e Complete physical examination should be performed at screening only. Abbreviated physical examination should be performed at all other marked study days.  
See Section 10.6.3. 
f Height and weight will be collected, and BMI calculated at screening.  Only weight will be collected at FU. 
g Highlighted time points for vital signs (Section 10.6.3) as follows: pre-dose (baseline), 1, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1; pre-dose, and at 2, 6, 
and 8 hours post-dose on Days 2 through 14.  Vital signs should be assessed at all other marked study days. 
h Peak expiratory flow rate will be assessed at admission (Day -1), pre-dose (baseline), 2 and 24 hours post-dose after the first dose (Day 1 dosing) and the last 
dose (Day 14 dosing), and FU. 
i Extensive triplicate ECGs will be obtained to collect continuous 12-lead ECG data from pre-dose until 24 hours post-dose as specified.  Three replicates 
(triplicate) of ECG data will be collected as close as possible from -0.75, -0.5, and -0.25 hours pre-dose, and 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1, 
at pre-dose only on Days 2 through 13, and -0.75, -0.5, and -0.25 hours pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 14.  Subjects should 
not eat a meal within 1 hour of digital ECG data collection.  See the instruction on lunch and dinner time (Section 8.3.1) to avoid any meal intake within 1 hour 
of the 6-hour and 12-hour post-dose ECG time points. 
j Clinical laboratory specimens (Section 10.6.2) will be obtained at pre-dose, if study drug administration occurs on the marked study days. 
k On Days 1 and 7, PK blood draw will be performed at pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post-dose.  The 24-hour post-dose PK 
plasma samples for Days 1 and 7 should be taken before dosing on Days 2 and 8, respectively.  On Days 3 to 6 and 9 to 13, PK blood draw will be performed at 
pre-dose only.  On Day 14, PK blood draw will be performed at pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, and 72 hours post-dose 
following the final dosing (Section 10.3.1).  See Table 8 for PK time window. 
l PGX samples (whole blood) will only be collected from the subjects who consented for DNA testing. 
m Details regarding study drug administration are provided in Section 9.3. 
BMI: body mass index; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; FU: Follow-up; HbsAg: hepatitis B surface antigen; HCV 
Ab: hepatitis C antibody; HDL: high density lipoprotein; HIV Ab: human immunodeficiency virus antibody; ICF: informed consent form; LDL: low density 
lipoprotein; PK: pharmacokinetic(s); PGX: pharmacogenomic(s).  
 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENTS ................................................................................... 4 
Amendment 1 ............................................................................................................... 4 
Amendment 2 ............................................................................................................. 15 
Amendment 3 ............................................................................................................. 17 
1. 
PROTOCOL SYNOPSIS ....................................................................... 19 
2. 
SCHEDULE OF ASSESSMENTS......................................................... 22 
TABLE OF CONTENTS ........................................................................................... 31 
LIST OF TABLES ..................................................................................................... 36 
LIST OF FIGURES ................................................................................................... 37 
3. 
LIST OF ABBREVIATIONS................................................................. 38 
4. 
INTRODUCTION .................................................................................. 43 
4.1. 
Background ............................................................................................. 43 
4.1.1. 
Nonclinical Experience ........................................................................... 44 
4.1.1.1. 
Pharmacology ......................................................................................... 44 
4.1.1.2. 
Pharmacokinetics .................................................................................... 46 
4.1.1.3. 
Nonclinical safety ................................................................................... 48 
4.1.2. 
Clinical Experience ................................................................................. 50 
4.2. 
Rationale for Present Study .................................................................... 50 
4.2.1. 
Study Design Rationale .......................................................................... 50 
4.2.2. 
Dosing Rationale .................................................................................... 51 
5. 
STUDY OBJECTIVES .......................................................................... 54 
6. 
STUDY ENDPOINTS ............................................................................ 55 
6.1. 
Primary Endpoint .................................................................................... 55 
6.2. 
Secondary Endpoints .............................................................................. 55 
7. 
STUDY DESIGN ................................................................................... 56 
7.1. 
Overview of Study Design ...................................................................... 56 
7.2. 
Dosing strategy ....................................................................................... 58 
7.3. 
Dose Escalation Criteria ......................................................................... 59 
8. 
SELECTION OF STUDY POPULATION ............................................ 61 
8.1. 
Inclusion Criteria .................................................................................... 61 
8.2. 
Exclusion Criteria ................................................................................... 61 

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8.3. 
Life Style Guidelines .............................................................................. 63 
8.3.1. 
Meals and Dietary Restrictions ............................................................... 63 
8.3.2. 
Alcohol, Caffeine, and Tobacco ............................................................. 63 
8.3.3. 
Activity ................................................................................................... 63 
8.4. 
Removal of Subjects in the Study ........................................................... 63 
8.5. 
Replacement of Subjects ......................................................................... 64 
9. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT ........... 65 
9.1. 
Identification of Investigational Product ................................................ 65 
9.2. 
Preparation and Dispensing .................................................................... 65 
9.3. 
Administration ........................................................................................ 65 
9.4. 
Method of Assigning Subjects to Treatment Groups ............................. 66 
9.4.1. 
Randomization ........................................................................................ 66 
9.4.2. 
Allocation of Randomization Numbers .................................................. 67 
9.5. 
Packaging and Labeling .......................................................................... 67 
9.6. 
Study Drug Supply, Storage, and Handling ............................................ 67 
9.7. 
Drug Accountability ............................................................................... 68 
9.8. 
Disposal or Retention of Unused Drug ................................................... 68 
9.9. 
Compliance ............................................................................................. 68 
9.10. 
Blinding and Unblinding ........................................................................ 68 
9.10.1. 
Blinding .................................................................................................. 69 
9.10.2. 
Unblinding .............................................................................................. 69 
9.11. 
Prior and Concomitant Medications ....................................................... 70 
9.11.1. 
Prohibited and Prior Medications ........................................................... 70 
9.11.2. 
Concomitant Medications ....................................................................... 70 
10. 
ASSESSMENTS..................................................................................... 71 
10.1. 
Timing of Assessments ........................................................................... 71 
10.2. 
Subject and Disease Characteristics ....................................................... 71 
10.3. 
Pharmacokinetics .................................................................................... 71 
10.3.1. 
Blood Sampling ...................................................................................... 71 
10.3.2. 
Urine Sampling ....................................................................................... 72 
10.3.3. 
Sample Collection, Processing and Handling for PK Assessment ......... 72 
10.3.3.1. 
Blood Sample Processing ....................................................................... 72 

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10.3.3.2. 
Urine Sample Processing ........................................................................ 72 
10.3.4. 
Bioanalysis .............................................................................................. 73 
10.4. 
Pharmacogenomics ................................................................................. 73 
10.4.1. 
Blood collection for PGX samples ......................................................... 73 
10.5. 
Efficacy ................................................................................................... 73 
10.6. 
Safety ...................................................................................................... 73 
10.6.1. 
Adverse Events ....................................................................................... 74 
10.6.2. 
Clinical Laboratory Assessments ........................................................... 74 
10.6.3. 
Physical Examinations and Vital Signs .................................................. 77 
10.6.4. 
Electrocardiograms ................................................................................. 77 
10.6.4.1. 
Safety 12-Lead ECGs ............................................................................. 78 
10.6.4.2. 
Extensive Triplicate ECGs ..................................................................... 78 
10.6.5. 
Columbia-Suicide Severity Rating Scale ................................................ 79 
10.6.6. 
Peak Expiratory Flow Rate (PEFR) Measurement ................................. 79 
10.6.7. 
Contraception and Pregnancy ................................................................. 79 
10.6.7.1. 
Contraception .......................................................................................... 79 
10.6.7.2. 
Pregnancy ............................................................................................... 80 
11. 
STATISTICAL AND ANALYTICAL PLANS ..................................... 81 
11.1. 
Sample Size and Power .......................................................................... 81 
11.2. 
Analysis Populations .............................................................................. 81 
11.3. 
Clinical Pharmacology Analysis............................................................. 81 
11.3.1. 
Pharmacokinetic Analysis ...................................................................... 81 
11.4. 
Statistical Analysis .................................................................................. 82 
11.4.1. 
General Considerations ........................................................................... 82 
11.4.2. 
Background Characteristics .................................................................... 82 
11.4.2.1. 
Subject Disposition ................................................................................. 82 
11.4.2.2. 
Demographics and Baseline Characteristics ........................................... 82 
11.4.2.3. 
Medical History ...................................................................................... 82 
11.4.2.4. 
Prior and Concomitant Medications ....................................................... 83 
11.4.2.5. 
Study Drug Exposure .............................................................................. 83 
11.4.2.6. 
Study Drug Compliance ......................................................................... 83 
11.4.3. 
Efficacy Analysis .................................................................................... 83 

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11.4.4. 
Safety Analysis ....................................................................................... 83 
11.4.4.1. 
Adverse Events ....................................................................................... 84 
11.4.4.2. 
Clinical Laboratory Assessments ........................................................... 84 
11.4.4.3. 
Electrocardiogram ................................................................................... 85 
11.4.4.4. 
Vital Signs .............................................................................................. 85 
11.4.4.5. 
Physical Examination ............................................................................. 85 
11.4.4.6. 
Peak Expiratory Flow Rate ..................................................................... 85 
11.4.4.7. 
Columbia-Suicide Severity Rating Scale (Part B only) .......................... 86 
11.4.4.8. 
Other Safety Analysis ............................................................................. 86 
11.4.5. 
Other Analysis ........................................................................................ 86 
11.4.6. 
Interim and Independent Data Monitoring Committee Analyses ........... 86 
11.4.6.1. 
Interim Analysis ...................................................................................... 86 
11.4.6.2. 
Independent Data Monitoring Committee Analysis ............................... 86 
12. 
PROCEDURAL, ETHICAL, REGULATORY, AND 
ADMINISTRATIVE CONSIDERATIONS .......................................... 87 
12.1. 
Adverse Event ......................................................................................... 87 
12.1.1. 
Definition ................................................................................................ 87 
12.1.1.1. 
Severity Assessment ............................................................................... 88 
12.1.1.2. 
Causality Assessment ............................................................................. 89 
12.1.2. 
Routine Reporting ................................................................................... 89 
12.1.3. 
Serious Adverse Reporting ..................................................................... 90 
12.1.4. 
Laboratory Results as Adverse Events ................................................... 91 
12.2. 
Administrative Requirements ................................................................. 92 
12.2.1. 
Ethical Considerations ............................................................................ 92 
12.2.2. 
Subject Information and Informed Consent ........................................... 92 
12.2.3. 
Investigator Compliance ......................................................................... 93 
12.2.4. 
Access to Records ................................................................................... 93 
12.2.5. 
Subject Privacy ....................................................................................... 93 
12.2.6. 
Record Retention .................................................................................... 93 
12.2.7. 
Study Termination .................................................................................. 94 
12.3. 
Data Quality Assurance .......................................................................... 94 
12.4. 
Monitoring .............................................................................................. 94 

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12.5. 
Electronic Data Capture .......................................................................... 95 
12.6. 
Report and Publications .......................................................................... 95 
12.6.1. 
Publication of Study Results ................................................................... 95 
12.6.2. 
Clinical Study Report ............................................................................. 96 
13. 
REFERENCES ....................................................................................... 97 
APPENDIX A. CALCULATION OF BODY MASS INDEX ............................... 98 
APPENDIX B. PRIOR AND CONCOMITANT MEDICATIONS AND OTHER 
STUDY RESTRICTIONS ...................................................................... 99 
APPENDIX C. SUMMARY OF CHANGES TO PROTOCOL .......................... 100 
APPENDIX D. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(BASELINE/SCREENING) ................................................................. 101 
APPENDIX E. COLUMBIA-SUICIDE SEVERITY RATING SCALE (SINCE 
LAST VISIT) ........................................................................................ 104 
 
 

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LIST OF TABLES 
Table 1: 
Schedule of Assessments - Part A (Single Dose Administration) .......... 23 
Table 2: 
Schedule of Assessments - Part B (Multiple Dose Administration) ....... 27 
Table 3: 
Summary of NOAELs, systemic exposure at the NOAEL dose levels, 
MRSD and human starting dose ............................................................. 52 
Table 4: 
Study Design ........................................................................................... 56 
Table 5: 
Sentinel Dosing Strategy ........................................................................ 59 
Table 6: 
Dose Stopping Rules (Part A and Part B) ............................................... 60 
Table 7: 
Study Treatment ...................................................................................... 65 
Table 8: 
Acceptable Windows for PK Blood Sampling (Part A and Part B) ....... 71 
Table 9: 
Acceptable Windows for PK Urine Sampling (Part A - SAD only) ...... 72 
Table 10: Clinical Laboratory Assessments ........................................................... 74 
Table 11: General Descriptions of Severity Scale .................................................. 88 
Table 12: Definitions of Causality Assessment ...................................................... 89 
Table 13: Contact Information for IQVIA .............................................................. 91 
Table 14: Contact Information for Sponsor Medical Monitor ................................ 91 

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LIST OF FIGURES 
Figure 1: 
Schematic of study design ...................................................................... 51 
 
 

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3. 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
5-HT 
Serotonin 5-hydroxytryptamin 
ADD 
After-discharge durations 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse event 
AEDs 
Antiepileptic drugs 
ALT 
Alkaline transaminase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase  
AR 
Accumulation ratio 
AUC 
Area under the concentration-time curve  
AUC24hr 
Area under the concentration-time curve from time zero to 24 hours post-dose 
AUC∞  
Area under the concentration-time curve from 0 to infinity 
AUCt  
Area under the concentration-time curve from 0 to t 
AUCτ 
Area under the concentration-time curve over the dosing interval 
BA 
Bioanalytical 
BCRP 
Breast cancer resistance protein 
BK 
Big Potassium 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
BSA 
Body surface area 
CHO 
Chinese hamster ovary 
CL 
Total clearance 
CL/F 
Apparent clearance 
CLR 
Renal clearance 
Cmax 
Maximum concentration 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CPAP 
Clinical pharmacology analysis plan 
CRO 
Contract research organization 

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Abbreviation 
Term 
CRF 
Case report form 
CRU 
Clinical research unit 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
Case Study Report 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DMCM 
Methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate hydrochloride  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED50 
Half-maximal effective dose 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EEG 
Electroencephalography 
EMA 
European Medicines Agency 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FIH 
First-in-human 
fe 
Fraction of drug dose excreted in urine 
Frel 
Relative bioavailability 
FU 
Follow-up 
GABA 
Gamma-aminobutyric acid 
Gamma-GT 
Glutamyl transpeptidase 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMS 
Generalized myoclonic seizures 
GTCS 
Generalized tonic-clonic seizures 
HBsAg 
Hepatitis B surface antigen 
HCN 
Hyperpolarization-activated cAMP-regulated cation 
HCV 
Hepatitis C virus 

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Abbreviation 
Term 
HCV Ab 
Hepatitis C antibody 
HDL 
High density lipoprotein  
HED 
Human equivalent dose 
HEK 
Human embryonic kidney 
hERG 
Human ether-à-go-go related gene 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV Ab 
Human immunodeficiency virus antibody 
HIV Ag 
Human immunodeficiency virus antigen 
hNav 
Human voltage-gated sodium channels 
hDAT 
Human dopamine transporter 
hNET 
Human norepinephrine transporter 
HR 
Heart rate 
IC50 
Half-maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IP 
Intraperitoneal 
IRB 
Institutional Review Board 
IV 
Intravenous 
K2EDTA 
Di-potassium ethylenediaminetetraacetic acid 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactic dehydrogenase 
LDL 
Low density lipoprotein  
LMA 
Locomotor activity 
MAD 
Multiple ascending dose(s) 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MES 
Maximal electroshock seizure 

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Abbreviation 
Term 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose 
Nav 
Voltage-gated sodium channels 
NCA 
Non-compartmental analysis 
NMDA 
N-methyl-D-aspartate 
NOAEL 
No observed adverse effect level 
NOEL 
No observed effect level 
NTD50 
Median neurotoxic dose 
PBR 
Peripheral benzodiazepine receptor 
PEFR 
Peak expiratory flow rate  
P-gp 
P-glycoprotein 
PGX 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time; Preferred Term 
PT INR 
Prothrombin time (PT) international normalized ratio (INR) 
PTZ 
Pentylenetetrazol 
QA 
Quality assurance 
QC 
Quality control 
Racc 
Accumulation ratio 
RBC 
Red blood cell 
rPOS 
Refractory partial-onset seizures 
SAD 
Single ascending dose(s) 
SAE 
Serious adverse event 
SaO2 
Arterial oxygen saturation 
SAP 
Statistical analysis plan 
SAR 
Suspected adverse reaction 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SI 
International System of Units 
SKLSI 
SK Life Science, Inc. 
SOC 
System Organ Class 

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Abbreviation 
Term 
SOP 
Standard operating procedure 
SRS 
Spontaneous recurrent seizures 
τ 
Dosing interval 
t½  
Half-life 
TCA 
Tricyclic antidepressant 
tmax 
Time to maximum concentration 
TK 
Toxicokinetic(s) 
US 
United States 
Vd/F 
Apparent volume of distribution 
WBC 
White blood cell 
WHO-DD 
World Health Organization-Drug Dictionary 
 

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4. 
INTRODUCTION 
4.1. 
Background 
Epilepsy is a neurological disorder that is characterized by an enduring predisposition to 
generate epileptic seizures and the associated cognitive, psychological and social 
consequences (Fisher et al., 2014).  An epileptic seizure has a transient behavioral change 
that might be objective signs or subjective symptoms (such as loss of awareness, stiffening, 
jerking, a sensation that rises from the abdomen to the chest, a smell of burnt rubber or déjà 
vu), caused by abnormal excessive or synchronous neuronal activity in the brain (Devinsky et 
al., 2018).  Epilepsy is one of the most common neurologic conditions.  Almost 10% of 
people will experience a seizure during their lifetime (Hauser and Beghi, 2008).  Epilepsy is 
the third leading contributor to the global burden of disease for neurological disorders and 
affects 65 million people worldwide (Ngugi et al., 2010).  About one-third of patients have 
refractory epilepsy (i.e., seizures not controlled by two or more antiepileptic medications or 
other therapies).  Approximately 75% of epilepsy begins during childhood, reflecting the 
heightened susceptibility of the developing brain to seizures (Stafstrom and Carmant, 2015).  
Although the cause of epilepsy in many patients is unknown, seizures can be the result of 
almost any insult that disturbs brain function.  These insults include acquired causes (for 
example, after stroke or traumatic brain injury), infectious diseases (such as 
neurocysticercosis), autoimmune diseases, and genetic mutations.  To date, over 500 genes 
associated with epilepsy have been identified (Devinsky et al., 2018). 
Epilepsy is classified in terms of epilepsy syndromes and seizure types.  The latter is 
determined by the electroencephalography (EEG) patterns observed when the seizure is 
occurring and by the clinical seizure characteristics.  Examples of seizure types include 
absence seizures (previously known as petit mal), simple partial seizures (previously known 
as focal motor or aura), complex partial seizures (previously known as psychomotor or 
temporal lobe) and generalized tonic-clonic seizures (also known as grand mal) (Meinardi et 
al., 1985).  
Once seizure types are identified, this information determines the epilepsy syndrome in 
conjunction with information about cause, age of onset, and interictal EEG abnormalities.  
Epilepsy can be basically classified as idiopathic (no apparent structural injury, probable 
genetic cause) or symptomatic (structural brain abnormality of known or unknown cause).  
Further differentiation can be made on whether the seizures begin in a focal region (partial 
epilepsy) or begin diffusely (generalized epilepsy).  Idiopathic generalized epilepsy is the 
most common childhood epilepsy; absence, myoclonic, and generalized tonic-clonic seizures 
may also be seen.  In adults, symptomatic partial epilepsy is most common and may cause 
simple partial, complex partial, or generalized tonic-clonic seizures (Commission on 
Classification and Terminology of the International League Against Epilepsy, 1981).  
Although the International League Against Epilepsy updated new classification of epilepsy in 
2017, the previous classification method was used to avoid confusion in this summary.   
SKL24741 [(1R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[3-[4-(trifluoromethyl)phenyl]phenyl] 
ethanol] is a novel small molecule that is being developed by SK Life Science, Inc. for the 

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treatment of epilepsy. SKL24741 is intended for oral administration and is a potent inhibitor 
of voltage-gated sodium channels (Nav).  SKL24741 is a chiral compound with an R-
configuration; SKL24741 displays more potent efficacy in a refractory partial-onset seizure 
(rPOS) animal model and a broader safety margin in animal studies compared to the 
(S)-enantiomer (SKL24742). 
The first-line treatment for epilepsy includes antiepileptic drugs (AEDs) of which over 20 
drugs have been approved by the United States Food and Drug Administration (US FDA) 
and the European Medicines Agency (EMA).  However, despite the availability of many 
AEDs, approximately one-third of patients fail to achieve seizure control (Devinsky et al., 
2018).  Therefore, the key unmet needs are: effective drugs for drug-resistant epilepsy, 
improved tolerability of drug treatment, development of individualized treatments based on 
epilepsy syndrome, and disease-modifying therapies.  Based on the results for SKL24741 in 
in vitro studies and animal models of rPOS and other types of epilepsy, this compound has 
the potential to address these unmet needs. 
Further details regarding the SKL24741 studies are discussed in the Investigator’s Brochure. 
4.1.1. 
Nonclinical Experience 
In vitro and in vivo nonclinical studies were conducted to investigate primary and safety 
pharmacology properties; absorption, distribution, metabolism, and excretion (ADME) 
properties, pharmacokinetic drug interactions; and toxicology of SKL24741 according to the 
current regulatory guidance.  All definitive in vitro safety pharmacology and pivotal 
toxicology studies were conducted in compliance with Good Laboratory Practice (GLP) 
regulations.  As with many neurological compounds, SKL24741 has a steep dose response 
with respect to adverse central nervous system (CNS) clinical signs in rats and dogs 
(Section 4.1.1.3). 
4.1.1.1. 
Pharmacology 
A range of in vitro mechanism of action and in vivo efficacy studies have been conducted to 
characterize the primary pharmacodynamics of SKL24741.  In vitro mechanism of action 
studies were conducted with SKL24741, including radioligand binding assays, functional 
assays, and ion channel patch clamp assays to evaluate the selectivity of SKL24741 and the 
potential for off-target effects.  An extensive series of in vitro studies were conducted to 
evaluate the effects on synaptic ion channels, including sodium, calcium, and potassium ion 
channels, as well as its effects on gamma-aminobutyric acid (GABA), N-methyl-D-aspartate 
(NMDA), and hyperpolarization-activated cAMP-regulated cation 1 (HCN1) currents.  
Functional assays evaluating the effects of SKL24741 on serotonin 5-hydroxytryptamine 
(5-HT) receptor subtypes showed that SKL24741 significantly (i.e., ≥50%) inhibited 5-HT2A, 
5-HT2B, 5-HT2C, and 5-HT1D with half-maximal inhibitory concentration (IC50) values of 5.6, 
2.8, 66, and 81 μM, respectively.  In in vitro electrophysiology assays with sodium channels, 
SKL24741 exhibited state-dependent inhibition of the voltage-gated sodium channel (Nav)  
1.6 current amplitude with an IC50 value of 0.47 μM in the inactivated phase.  SKL24741 
also inhibited other subtypes of human voltage-gated sodium channels (hNav) in a state-
dependent manner, including hNav1.1 (IC50=1.7 μM), hNav1.2 (IC50=0.7 μM), hNav1.3 

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(IC50=1.1 μM), hNav1.7 (IC50=0.59 μM), and Nav1.8 (IC50=0.89 μM).  SKL24741 has a 
much higher affinity for the inactivated state rather than the resting state of Nav channels.  A 
higher affinity of SKL24741 for the inactivated state compared to the tonic state of Nav 
channels would contribute towards a preferential selectivity targeting the pathological 
conditions of epilepsy with potentially less adverse side effects (Eijkelkamp et al., 2012).  In 
a kinetic study using human Nav1.6 channels, SKL24741 (1 μM) significantly slowed the 
recovery time from fast inactivation of Nav1.6 channels.  These profiles of SKL24741 on 
voltage-gated sodium channels may contribute to its antiepileptic activity against bursting 
neurons under epileptic conditions.  In a preliminary study, SKL24741 displayed an 
enhancement effect of Big Potassium (BK) channels in stably expressed human embryonic 
kidney (HEK) cell line. 
In vivo pharmacology studies have demonstrated the efficacy of SKL24741 in various rodent 
models of refractory partial-onset seizures (rPOS), generalized tonic-clonic seizures (GTCS), 
and generalized myoclonic seizures (GMS).  SKL24741 demonstrated efficacy in three 
mouse and one rat models of rPOS.  SKL24741 produced a dose-dependent protective effect 
on electroshock-induced seizures in mice following intraperitoneal (IP) and oral 
administration.  Although less potent than SKL24741, (S)-enantiomer chiral compound 
(SKL24742) and the racemate compound (SKL24505) also protected against seizures 
induced by 6-Hz electrical stimulation at 44 mA in a dose-dependent manner in mice.  IP 
administration of SKL24741 also produced a dose-dependent protective effect on amygdala-
kindled seizures in male Wistar rats and significantly reduced both seizure scores and 
electroencephalographic (EEG) after-discharge durations (ADD).  In the pentylenetetrazol 
(PTZ)-induced kindling seizure test in mice, SKL24741 resulted in a significant reduction in 
seizure score by 42.9%.  In a pilocarpine-induced spontaneous recurrent seizure (SRS) 
model, the maximal protection rate for SKL24741 was 50% at the highest dose tested.  In a 
GTCS model using the maximal electroshock seizure (MES) test, SKL24741 produced a 
dose-dependent seizure protection effect in both mice and rats. 
Finally, the efficacy of SKL24741 was further demonstrated in two GMS models in male 
mice.  These models were induced by administration of PTZ, a non-competitive GABAA 
receptor antagonist, or methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate 
hydrochloride (DMCM), which binds specific benzodiazepine binding sites with high 
affinity; both are potent convulsants.  In both models, SKL24741 had dose-dependent 
protective effects.  Overall, SKL24741 displays a broad spectrum of efficacy in antiepileptic 
animal models.  The results of in vivo efficacy studies suggest that, at doses devoid of 
behavioral toxicity, SKL24741 possesses a broad anticonvulsant spectrum in rat and mouse 
seizure models predictive of efficacy against generalized seizures, partial seizures and 
especially rPOS. 
When tested against 112 CNS targets in radioligand binding assays and 34 CNS targets in 
functional assays, SKL24741 (50 μM) showed no significant (i.e., ≥50%) binding affinity for 
receptors and enzymes located in the CNS with the exception of human dopamine D4.2 (66% 
inhibition), rat peripheral benzodiazepine receptor (PBR) (51% inhibition), human sigma 2 
(54% inhibition), human dopamine transporter (hDAT) (63% inhibition), and human 
norepinephrine transporter (hNET) (63% inhibition).  In functional assays, SKL24741 

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showed half-maximal inhibitory concentration (IC50) of 5.6, 2.8, 65.5 and 81 μM for 4 
serotonin receptor subtypes (5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1D). 
In an in vitro human ether-á-go-go related gene (hERG) assay in HEK293 cells, SKL24741 
inhibited hERG potassium channel currents in a concentration-dependent manner, with an 
IC50 of 21.1 µM.  Overall, this result indicates low potency for the hERG channel as there 
was a substantial safety margin based on SKL24741 exposures at efficacious doses in rodent 
seizure models (i.e., Cmax ≈ 2.53 μM; plasma protein binding = 96.2%).  Further evaluations 
using cardiac ion channels to determine cardiovascular risk showed that SKL24741 inhibited 
(concentration-dependent) peak hNav1.5 (IC50=20.2 μM) and late hNav1.5 (IC50=4.91 μM) 
currents in HEK293 cells stably expressing hSCN5A and hCav1.2 currents (IC50=17.2 μM) 
in Chinese hamster ovary (CHO)-K1 cells.  Cardiovascular effects were also evaluated in 
vivo in a GLP study in telemetered male dogs; after single oral doses of SKL24741, there 
were no unscheduled mortalities and no SKL24741-related changes in any of the parameters 
evaluated with the exception of decreased QTc intervals at ≥10 mg/kg from 0.5 to 18 hours 
post-dose (up to -9 msec [-4%]). 
SKL24741-related neurotoxicity was evaluated in non-GLP studies in mice and rats using the 
rotarod test after oral or IP administration.  Following single IP administration of SKL24741 
in mice and rats, the peak toxicity time was 0.5-hour post-dose with a median neurotoxic 
dose (NTD50) of 17.3 mg/kg.  Following single oral administration of SKL24741 in rats, the 
peak toxicity time was 1-hour post-dose with an NTD50 of 177.5 mg/kg.  The effects of 
SKL24741 on locomotor activity (LMA) were evaluated in male rats.  There were no 
significant effects of SKL24741 on LMA up to a single oral administration of 100 mg/kg.  In 
a GLP study, the modified Irwin battery of assessments was used to evaluate the CNS effects 
of SKL24741 administered up to 40 mg/kg in male rats.  Following oral administration, 
decreased extensor thrust and dilated pupils of both eyes were noted in rats administered 
≥30 mg/kg, and moderate grasping loss, moderate piloerection, and lower body temperature 
(up to -1.0°C) were noted in rats administered with 40 mg/kg.  Based on these findings, the 
no observed effect level (NOEL) for neurological function in this oral study was 15 mg/kg. 
In a GLP study, the respiratory effects of SKL24741 were evaluated in male rats using head-
out plethysmography.  SKL24741 had no significant effects on tidal volume. However, there 
was a decrease in respiration rates up to 28 breaths/minute (-22%) and a decrease in minute 
volume up to 62 mL/minute (-28%).  All doses had similar respiratory effects, and no NOEL 
dose was observed.  These observations are considered to be related to the pharmacological 
action of SKL24741, and the temporal response was consistent with the extended exposure 
profile of SKL24741 in rats. 
4.1.1.2. 
Pharmacokinetics 
The pharmacokinetics (PK) of SKL24741 have been studied both in vitro and in vivo.  
Toxicokinetic (TK) evaluations were performed as a part of oral repeated-dose toxicity 
studies in rats and dogs for up to 28 days.  SKL24741 is intended for oral administration, 
therefore its absorption PK properties were evaluated in an in vitro permeability assay and 
following single oral and intravenous (IV) dosing in male mice, rats, and dogs.  Plasma 

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samples were analyzed for SKL24741 levels using high performance liquid chromatography 
coupled with tandem mass spectrometry.   
SKL24741 demonstrated high permeability with efflux ratios of 0.916 to 0.985 in Caco-2 cell 
monolayers.  Assessments with breast cancer resistance protein (BCRP) and P-glycoprotein 
(P-gp) inhibitors indicated that SKL24741 may be a substrate of BCRP and P-gp.  However, 
given the large passive permeability of SKL24741, it is unlikely that the in vivo absorption of 
SKL24741 would be impacted by efflux due to these transporters.   
In single-dose bioavailability and PK studies in male mice, rats, and dogs, SKL24741 was 
administered by IV bolus or oral gavage.  The elimination kinetics of SKL24741 following a 
single IV bolus dose varied slightly across species.  The highest clearance (CL) and shortest 
half-life (t½) were observed in mice, the lowest CL was observed in dogs and the longest t½ 
was observed in rats.  Across species tested in the nonclinical program (mice, rats, dogs), CL 
values were 3- to 4-fold lower than the calculated values of liver plasma flow (i.e., 3.0, 1.8, 
and 1.1 L/hr/kg, respectively) (Davies and Morris, 1993), indicating that SKL24741 was 
cleared slowly from the body.  Volume of distribution was comparable in mice and dogs and 
both were less than that observed in rats; Such data also indicated SKL24741 distributed 
outside of the central compartment.  For fed and fasted rats given SKL24741 orally, the 
exposures were similar between the two feeding states. The relative bioavailability (Frel) of 
SKL24741 after oral administration in mice, fed and fasted rats, and dogs was high 
(Frel82.9%).  Based on a single-dose radiolabeled PK study, male and female rats had 
similar exposures, indicating no sex differences following both IV and oral doses. 
TK parameters were evaluated in non-GLP and GLP oral toxicity studies of up to 28-day 
duration.  In general, sex differences in SKL24741 exposure, in terms of Cmax and area under 
the concentration-time curve from time zero to 24 hours post-dose (AUC24hr), were less than 
2-fold in both rats and dogs, indicating no gender differences.  In both species, exposure 
tended to increase with increasing dose levels, but dose-proportionality varied depending on 
species and dose levels.  No accumulation was observed in rats and dogs following 28 days 
of oral administration. 
SKL24741 was highly bound to plasma proteins across species (mouse: 98%, rat: 96%; 
rabbit: 96%; dog: 98%; monkey: 97%; and human: 96%; all values are approximate means).  
Blood-to-plasma concentration ratios were approximately 0.8 to 1.0 for all species and 
concentrations, indicating SKL24741 primarily partitioned into the plasma.  In a quantitative 
whole-body autoradiography study with [14C]-SKL24741 in rats, [14C]-SKL24741 was 
widely distributed to most tissues.  Although tissue concentrations of radioactivity were still 
detectable in all tissues at 72 hours post-dose, concentrations decreased steadily between 120 
through 672 hours post-dose with most tissues at below the limit of quantitation (BLQ) by 
672 hours post-dose.  Tissue-to-blood exposure ratios in the cerebellum were 2.3 to 3.8-fold 
indicating [14C]-SKL24741 partitioned into the brain tissue regardless of sex or rat strain 
(same trend noted in other brain regions).  The concentration of radioactivity in pigmented 
tissues, specifically the uveal tract, had greater exposures than those observed for all other 
tissues, suggesting an apparent association of [14C]-SKL24741 with tissues containing 
melanin. 

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In vitro metabolism studies indicated that SKL24741 had high metabolic stability in rat, 
rabbit, dog, monkey and human microsomes, and moderate metabolic stability in mouse 
microsomes.  In hepatocytes, SKL24741 showed high metabolic stability in rats and rabbits 
and moderate stability in mice, dogs, humans, and monkeys.  In a separate hepatocyte assay, 
SKL24741 showed notably greater metabolism in monkeys, compared to other species.  A 
total of six SKL24741 metabolites were found following incubation with mouse, rat, rabbit, 
dog, monkey, and human hepatocytes.  Similar metabolic profiles were observed in 
hepatocytes from rats, rabbits, dogs, and humans, with no unique human metabolites.  
Metabolite M1 was not observed in monkey hepatocytes but was seen in human hepatocytes 
and all other species.  SKL24741 showed low potential for covalent binding to liver proteins 
and low potential to form reactive metabolites that could bind to liver proteins.  At a 
concentration up to 100 μM, SKL24741 had no inhibitory effect on cytochrome P450 (CYP) 
2B6, CYP2C8, CYP2D6, and CYP3A4 (i.e., IC50 >100 μM for isozymes).  The IC50 values 
CYP1A2, CYP2C9, and CYP2C19 were 21.1 μM, 99 μM, and 58.7 μM, respectively.  
Excretion of SKL24741 was evaluated following single oral administration of 
[14C]-SKL24741 in rats.  The primary route of elimination of radioactivity was in the feces, 
with high levels being recovered in the bile of cannulated rats, suggesting that hepatic 
clearance and biliary excretion play an important role in the elimination of [14C]-SKL24741. 
4.1.1.3. 
Nonclinical safety 
Nonclinical toxicology studies have been conducted in Sprague-Dawley rats and Beagle dogs 
to support oral administration of SKL24741 in humans.  In vitro metabolite profiling data 
supported the selection of rats and dogs as the rodent and non-rodent toxicology species.  All 
pivotal studies were performed in compliance with GLP regulations (21 Code of Federal 
Regulations (CFR) 58).  All doses were given once daily via oral administration to support 
clinical dosing. 
In a non-GLP study in male and female rats, single administration of ≥120 mg/kg SKL24741 
resulted in severe clinical signs of hypoactivity and ataxia with low body carriage and/or 
lateral recumbency and led to the unscheduled euthanasia of the 120 and 200 mg/kg animals.  
Administration of 40 or 80 mg/kg SKL24741 resulted in animals that were ataxic or had low 
body carriage, but fully recovered by Day 2.  Administration of 80 mg/kg also led to 
decreased body weight gain and food consumption.  As clinical signs and body weight 
effects for 80 mg/kg were generally tolerable, the maximum tolerated dose (MTD) following 
single oral administration in rats was 80 mg/kg.   
In a non-GLP 7-day repeat-dose toxicity and TK study, male and female rats were 
administered doses of 0, 20, 40, or 80 mg/kg/day SKL24741.  Due to severe clinical signs of 
hypoactivity and ataxia with low body carriage and/or sternal or lateral recumbence, all 
animals (main and TK animals) dosed at 80 mg/kg/day were euthanized on Day 1 within 3 
hours post-dose.  Treatment-related clinical signs of hypoactivity, ataxia, hunched posture, 
piloerection, thin appearance, or limited use of hind limbs were noted for most animals 
administered 40 mg/kg/day beginning on Day 5.  Treatment-related weight loss and 
decreased food consumption were also observed at this dose level following the first few 
doses of SKL24741.  SKL24741-related reduced reticulocytes and increased cholesterol were 

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observed in all animals administered 40 mg/kg/day.  Based on these findings, the 7-day MTD 
in rats was 40 mg/kg/day (Day 7 Cmax and AUC24hr values of 7.40 µg/mL and 111 µg*h/mL, 
respectively, in males and 12.5 µg/mL and 269 µg*h/mL, respectively, in females). 
In a GLP 28-day repeat-dose study toxicity and TK study, male and female rats were 
administered 0, 15, 30, or 40 mg/kg/day SKL24741.  No unscheduled mortalities were 
observed.  Clinical observations were dose-responsive and included transient ataxia and 
hypoactivity for both sexes administered ≥30 mg/kg/day and low body carriage for animals 
administered 40 mg/kg/day.  Isolated incidences of hunched appearance and lateral 
recumbency were also observed at 40 mg/kg/day.  Clinical signs were considered adverse at 
40 mg/kg/day due to the nature and severity of the observations.  Dose-dependent decrease in 
body weight, correlating with decreased food consumption, was observed at ≥30 mg/kg/day; 
however, these observations were not considered adverse due to their transient nature and 
reversibility.  Clinical chemistry changes included mild, reversible, higher cholesterol 
concentration in males and females administered ≥15 mg/kg/day and ≥30 mg/kg/day, 
respectively, which were not considered adverse.  SKL24741-related increased liver weights 
were observed in males administered ≥30 mg/kg/day and females administered ≥15 
mg/kg/day.  Microscopic liver findings of minimal centrilobular hepatocyte hypertrophy 
were observed in males and females administered ≥30 mg/kg/day.  These findings were 
consistent with potential microsomal enzyme induction in the liver, an adaptive response, and 
were considered non-adverse due to their minimal severity and partial recovery following the 
2-week recovery phase. Based on FDA recommendation, a NOAEL of 15 mg/kg/day was 
considered for calculating the starting dose (mean combined sex Cmax values was 3.32 µg/mL 
and AUC24hr 61.2 µg*h/mL). 
In a non-GLP toxicity study, male and female dogs were administered a single dose of 20, 
60, 100, or 300 mg/kg SKL24741.  At doses ≥100 mg/kg, clinical signs of lateral (only 
300 mg/kg female) and sternal recumbency, ataxia, hypoactivity, emesis, and/or foamy white 
vomitus, and excessive salivation were observed.  Decreased food consumption was noted in 
animals administered ≥60 mg/kg with full recovery before the next dosing occasion.  The 
MTD following single oral administration in dogs was 100 mg/kg. 
In a non-GLP 7-day repeat-dose toxicity and TK study, male and female dogs were 
administered 50/10, or 100/30 mg/kg/day SKL24741.  Animals were initially administered 
50 or 100 mg/kg/day.  For the 100 mg/kg/day animals, the moribund condition of one male 
and one female on Day 3 resulted in the unscheduled euthanasia of these two animals.  
Together with clinical observations of body tremors, rigidity, decreased responsiveness, 
motor impairment, hypoactivity, ataxia, emesis and vomitus, and excessive salivation in the 
other animals dosed at 50 and 100 mg/kg/day, all surviving 50 and 100 mg/kg/day animals 
had a 9-day non-dosing period followed by dose level reduction to 10 and 30 mg/kg/day, 
respectively.  Clinical signs at these reduced dose levels were limited to a single incidence of 
emesis and vomitus in one female administered 30 mg/kg/day.  SKL24741-related excessive 
salivation was noted after dosing at ≥10 mg/kg/day.  SKL24741-related changes in absolute 
and/or relative organ weights were noted in animals administered ≥50/10 mg/kg/day, 
including the adrenals, epididymis, heart, kidney, liver, ovaries, pituitary, prostate, spleen, 
testes, thymus, thyroid, and uterus/cervix.  Based on these findings, the 7-day MTD for 

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SKL24741 in dogs was 30 mg/kg/day (Day 7 mean combined sex Cmax and AUC24hr values of 
3.20 µg/mL and 32.2 µg*h/mL, respectively). 
In a GLP 28-day repeat-dose toxicity and TK study, male and female dogs were administered 
0, 10, 20, or 40 mg/kg/day SKL24741.  Clinical observations included ataxia and/or 
hypoactivity, emesis and/or vomitus, and excessive salivation in animals administered ≥10 
mg/kg/day; intermittent tremors in animals administered ≥20 mg/kg/day; decreased 
reactivity, retching, and clear oral discharge in animals administered 40 mg/kg/day; and 
sternal recumbency on a single day in one animal administered 10 mg/kg/day.  Severity and 
frequency of clinical findings increased in a dose-proportional manner; however, the clinical 
observations were not severe enough to be considered adverse and showed evidence of 
reversibility during the 2-week recovery phase.  Based on FDA recommendation, a NOAEL 
of 10 mg/kg/day was considered for calculating the starting dose (mean combined sex Cmax 
values was 2.61 µg/mL and AUC24hr 21.7 µg*h/mL). 
SKL24741 did not show any genotoxic potential in a GLP bacterial reverse mutation (Ames) 
assay or in a GLP in vitro human lymphocyte micronucleus assay.  After oral administration 
up to 40 mg/kg SKL24741 to male Sprague-Dawley rats, there was no increase in 
micronucleated polychromatic erythrocytes.  Additionally, SKL24741 absorption data 
indicated that SKL24741 was not sufficiently photoreactive to result in direct phototoxicity 
in humans.  
4.1.2. 
Clinical Experience 
SKL24741 has not been studied in humans. 
4.2. 
Rationale for Present Study 
The rationale for developing SKL24741 is based on the nonclinical evidence indicating that 
SKL24741 is a potent inhibitor of voltage-gated sodium channels and a possible activator of 
Big Potassium (BK) channels.  SKL24741 was shown to have a broad anticonvulsant 
spectrum in rat and mouse seizure models predictive of efficacy against epilepsy, including 
generalized seizures, partial seizures and especially rPOS (Section 4.1.1.1). 
To date, nonclinical safety and pharmacokinetic findings indicate that SKL24741 has a 
favorable safety profile (Section 4.1.1.3) and dose-dependent drug exposure 
(Section 4.1.1.2). 
This single and multiple ascending dose study is designed to evaluate the safety, tolerability, 
and PK of SKL24741 administered orally to healthy adult subjects.   
4.2.1. 
Study Design Rationale 
A schematic of the proposed study design is presented below in Figure 1.  
The study includes a sequential cohort design that is intended to optimize subject safety and 
assess tolerability, safety, and PK of SKL24741.  In the single-dose escalation part of the 
study (Part A), tolerability, safety, and PK of SKL24741 will be assessed in healthy male 
subjects under fasting condition.  At an appropriate dose based on PK results, one dose 

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cohort will be repeated with the subjects under fed condition, in order to evaluate the 
magnitude of the food effect on the disposition of SKL24741.  To assess the gender effect on 
the disposition of SKL24741, female subjects will be treated at one dose level under fasting 
condition. 
Figure 1: 
Schematic of study design 
 
The multiple dose portion of the study (Part B) will evaluate the tolerability, safety, and PK 
of SKL24741 after 14 days of dosing in healthy male subjects.  Doses, dosing regimen, and 
food status (fasting vs. fed) used in Part B will be determined based on the outcome of 
Part A.  The selection of the first dose level of SKL24741 in Part B will be determined based 
on safety and PK information from Part A. 
During Part A and Part B, a sentinel dosing strategy will be used (Section 7.2).  Safety 
reviews will be performed prior to dose escalation from one cohort to another (dose level 
increase).  Dose escalation criteria and dose stopping rules (Section 7.3) will be applicable at 
any time. 
4.2.2. 
Dosing Rationale 
As this study is the first-in-human (FIH) study, the initial dose of SKL24741 has been 
conservatively selected according to the United States Food and Drug Administration (FDA) 
guidance document entitled “Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers” (FDA Guidance for Industry, 2005). 
The dose levels planned for the Phase 1 clinical trial are based on the overall safety and 
tolerability profile of SKL24741 established in the nonclinical program.  In the GLP 28-day 
oral toxicity studies, the FDA-recommended no observed adverse effect level (NOAEL) 
doses of 15 mg/kg/day for rats and 10 mg/kg/day for dogs were used for the human starting 
dose calculations.  Based on the results of the SKL24741 toxicology studies, rats were 

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considered the most sensitive species. On a body surface area (BSA) basis, human equivalent 
dose (HED) in rats is 15 mg/kg/day ÷ 6.2 = 2.42 mg/kg/day; HED based on the NOAEL in 
dogs is 10 mg/kg/day ÷ 1.8 = 5.56 mg/kg/day.  By applying a 10-fold safety factor to the 
HED of 2.42 mg/kg/day for rat NOAEL, the maximum recommended starting dose (MRSD) 
for a Phase 1 clinical study in healthy volunteer is 0.242 mg/kg (or 14.5 mg based on an 
assumed human weight of 60 kg [calculation = 2.42 mg/kg/day ÷ 10 (safety factor) × 60 kg]). 
Table 3 provides an overview of the NOAELs from the 28-day GLP repeated-dose 
toxicology studies and the systemic exposures at the NOAEL dose levels.  The HED, MRSD, 
and calculated human starting dose are also presented. 
Table 3: 
Summary of NOAELs, systemic exposure at the NOAEL dose levels, 
MRSD and human starting dose 
Study No. / 
Species 
NOAEL 
(mg/kg/day) 
AUC at 
NOAEL 
Day 28 
(μg*hr/mL) 
Cmax at 
NOAEL 
Day 28 
(μg/mL) 
Scaling 
Factor 
HED 
(mg/kg) 
MRSD (10X Safety Margin 
= HED÷10)  
(mg)  
(60-kg human weight) 
22T0022 / 
Rat 
15* 
 
61.2 
 
3.32 
 
6.2 
 
2.42 
 
14.5 
 
22T0023 / 
Dog 
10* 
 
21.7 
 
2.61 
 
1.8 
 
5.56 
 
33.3 
 
AUC = area under the concentration-time curve; Cmax = maximum concentration; HED = human equivalent 
doses; MRSD = maximum recommended starting dose; NOAEL = no observed adverse effect level. 
*NOAELs based on FDA recommendation  
Based on these data from the most sensitive species (rat), the MRSD is approximately 14.5 
mg with a 10-fold safety factor applied to the HED (HED ÷ 10).  However, a larger safety 
factor of approximately 15 was applied to the HED (HED ÷15) due to steep dose-toxicity 
profile in rats and dogs (Section 4.1.1).  Therefore, the starting dose of this FIH clinical study 
will be a single oral dose of 10 mg of SKL24741.  With this starting dose, a safety factor 
would be approximately 33 from the HED derived from the dog. 
The first cohort of the single ascending dose (SAD) study will receive a single dose at the 
Dose 1 level (i.e., 10 mg) and subsequent cohorts will receive doses up to 1000 mg (as a 
single dose) based on the prediction from allometric scaling and in silico assessment.  
However, dose levels of SKL24741 will be adjusted if needed based on plasma exposure, 
safety and tolerability observed at each dose level during the study. 
The single-dose escalation scheme (Part A) is designed to explore a range of doses up to the 
plasma exposure observed at the NOAEL of 10 mg/kg/day in dogs (Day 28 mean combined 
sex Cmax and AUC values of 2.61 µg/mL and 21.7 µg*hr/mL, respectively; Table 3) if the 
safety and tolerability allow reaching this plasma exposure.  A few additional single dose 
levels beyond the dog NOAEL exposures may be considered if the safety and tolerability 
warrant a higher dose of SKL24741.  However, the dose escalation increment will not exceed 
1.5-fold between each dose level due to the steep dose response observed in toxicology 
species (Section 4.1.1).  The institutional review board (IRB) will be notified prior to 
initiating these additional cohorts.  In any case, the plasma exposure in humans will not 

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exceed the exposure observed at the NOAEL of 15 mg/kg/day in rats (Day 28 mean 
combined sex Cmax and AUC values of 3.32 µg/mL and 61.2 µg*hr/mL, respectively). 
After the first dose level, if drug exposure in humans differ from what is expected from 
nonclinical studies, the dose-escalation scheme may be re-evaluated.  The dose level selected 
to assess the preliminary food and gender effects may also be re-evaluated.  Any changes to 
the dose escalation scheme will be reviewed and approved by the Sponsor and submitted to 
the IRB. 

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5. 
STUDY OBJECTIVES 
Part A 
Primary:  
• To evaluate the safety and tolerability of single oral ascending doses of SKL24741 
capsule(s) administered to healthy male subjects 
Secondary:  
• To evaluate the PK of SKL24741 (R-enantiomer), SKL24742 (S-enantiomer) (if 
appropriate), and its possible metabolites (if deemed necessary) following 
administration of single oral ascending doses of SKL24741 capsule(s) administered to 
healthy male subjects 
• To assess the food effect on the PK of SKL24741 and SKL24742 (if appropriate) 
following administration of a single oral dose of SKL24741 capsule(s) administered 
to healthy male subjects 
• To assess the gender effect on the PK of SKL24741 and SKL24742 (if appropriate) 
following administration of a single oral dose of SKL24741 capsule(s) administered 
to healthy female subjects 
Part B 
Primary:  
• To evaluate safety and tolerability of multiple oral ascending doses of SKL24741 
capsule(s) administered for 14 days to healthy male subjects 
Secondary:  
• To evaluate the PK of SKL24741, SKL24742 (if appropriate), and its possible 
metabolites (if deemed necessary) following administration of multiple oral 
ascending doses of SKL24741 capsule(s) administered to healthy male subjects 

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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint 
Safety and tolerability will be based on assessment of adverse events, clinically significant 
laboratory assessments, electrocardiograms (ECGs), vital signs (blood pressure, heart rate, 
body temperature, respiratory rate, arterial oxygen saturation (SaO2) (using pulse oximetry)), 
physical examinations, peak expiratory flow rate (PEFR), and Columbia-Suicide Severity 
Rating Scale (C-SSRS) (Part B only). 
6.2. 
Secondary Endpoints 
PK parameters will be calculated for SKL24741 and SKL24742 (if appropriate) from plasma 
and urine PK data. 

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7. 
STUDY DESIGN 
7.1. 
Overview of Study Design 
This is a two-part, double-blinded, randomized study of SKL24741.  The schematic of study 
design is shown in Figure 1.  Table 4 further outlines the study design. 
Part A is a single-dose escalation study in healthy male subjects, except for the gender effect 
cohort in healthy female subjects.  It is expected that a total of 66 subjects (60 male and 6 
female subjects) will be enrolled in Part A.  Each subject will be given a single oral dose of 
study drug capsule (SKL24741 or placebo) on one occasion.  There will be 6 new subjects at 
each dose level (4 subjects randomized to SKL24741 and 2 to placebo) during single-dose 
escalation.  Study drug will be administered under fasting condition, except for one cohort 
utilized for the food effect assessment at one of the dose levels.   
To evaluate the magnitude of the food effect on the disposition of SKL24741, a cohort of 
subjects will receive a second dose of study drug under fed condition (Period 2) at an 
appropriate dose level based on PK results.  After completing Period 1 (fasting) as part of 
single dose escalation, these subjects will return to the clinical research unit (CRU) for a 
second confinement to receive a second single dose (same dose level) of study drug under 
fed condition.  A washout period of at least 14 days is planned between fasting and fed 
cohorts (i.e., between Period 1 and Period 2).  As subjects complete the Follow-up visit of 
Period 1 and then return to the CRU for re-admission (Day -1 of Period 2), the same study 
procedures will apply again (including Day -1 procedures) in order to initiate Period 2. 
To assess the gender effect on the disposition of SKL24741, a set of 6 female subjects of 
non-childbearing potential will be treated at one dose level under fasting condition. 
At each dose level, except for the food and gender effect cohorts, a sentinel dosing strategy 
will be used as described in Section 7.2. 
Part B is a multiple-dose escalation study in 32 healthy male subjects.  Doses, dosing 
regimen, and food status (fasting vs. fed) used in Part B will be determined based on the 
outcome of Part A.  Dosing will extend over a 14-day period at each dose level.  Four dose 
levels will be assessed, and subjects will be randomized into one of the four dose levels.  
Each dosing cohort will have 8 new subjects (6 subjects randomized to SKL24741 and 2 to 
placebo) dosed each day for 14 days (Table 4).  Daily dose level in Part B will not exceed the 
maximum dose level used in Part A.   
At each dose level, a sentinel dosing strategy will be used as described in Section 7.2.   
Table 4: 
Study Design 
Part A: Single Ascending Doses (SAD) 
Total Number of 
Subjects 
Randomized Stratification 
(Active/Placebo) 
Number of Subjects 
per Cohort 
Food Status 
(Fasting/Fed) 
60 Male Subjects 
10 mg SKL24741/Placebo 
4 SKL24741/ 
2 Placebo 
Fasting 

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25 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
50 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
100 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
200 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
300 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
400 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
600 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
800 mg SKL24741/Placebo  
4 SKL24741/ 
2 Placebo 
Fasting 
1000 mg SKL24741/Placebo  4 SKL24741/ 
2 Placebo 
Fasting 
Part A: Food Effect Assessment 
Total Number of 
Subjects 
Dose 
Number of Subjects 
per Cohort 
Food Status 
(Fasting/Fed) 
6 Male Subjects* 
Based on the outcome of 
Part A 
6 SKL24741 
Fed 
Part A: Gender Effect Assessment 
Total Number of 
Subjects 
Dose 
Number of Subjects 
per Cohort 
Food Status 
(Fasting/Fed) 
6 Female Subjects 
(non-childbearing 
potential) 
Based on the outcome of 
Part A  
6 SKL24741 
Fasting 
Note:  
• 
All doses are in a capsule formulation. 
• 
Subjects will remain in the clinic for a 4-night stay (discharged on Study Day 4). 
• 
A sentinel dosing strategy (Section 7.2) will be used for all cohorts, except for food and gender 
effect cohorts, in Part A. 
* Refer to Section 7.1 regarding the subjects returning to the CRU for the food effect assessment. 
Part B: Multiple Ascending Doses (MAD) 

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Total Number of 
Subjects 
Randomized Stratification 
(Active/Placebo) 
Number of Subjects 
per Cohort 
Food Status 
(Fasting/Fed) 
32 Male Subjects 
SKL24741 Dose 1/Placebo 
6 SKL24741/2 
Placebo 
Based on the 
outcome of 
Part A 
SKL24741 Dose 2/Placebo 
6 SKL24741/2 
Placebo 
Based on the 
outcome of 
Part A 
SKL24741 Dose 3/Placebo 
6 SKL24741/2 
Placebo 
Based on the 
outcome of 
Part A 
SKL24741 Dose 4/Placebo 
6 SKL24741/2 
Placebo 
Based on the 
outcome of 
Part A 
Note:  
• 
All doses are in a capsule formulation. 
• 
Each cohort of 8 subjects will receive the study drug each day for 14 days.  Subjects will remain 
in the clinic for a 17-night stay (discharged on Study Day 17). 
• 
Doses, dosing regimen, and food status (fasting vs. fed) used in Part B will be determined based 
on the outcome of Part A. 
• 
A sentinel dosing strategy (Section 7.2) will be used for all cohorts in Part B. 
A cohort of female subjects will be added to Part A for the preliminary gender effect 
assessment as shown in Table 4.  These female subjects will need to be of non-childbearing 
potential, have undergone a sterilization procedure at least 6 months prior to dosing with 
official documentation (e.g., hysteroscopic sterilization, bilateral tubal ligation or bilateral 
salpingectomy, hysterectomy, or bilateral oophorectomy), or be postmenopausal with 
amenorrhea for at least 1 year prior to dosing and follicle-stimulating hormone (FSH) serum 
levels consistent with postmenopausal status as per Principal Investigator’s judgment. 
7.2. 
Dosing strategy 
A sentinel dosing strategy will be used in both Part A (SAD) and Part B (MAD), except for 
the food and gender effect cohorts.  The investigator and the Sponsor will assess safety and 
tolerability data and determine whether it is acceptable to continue dosing (within cohorts) or 
to dose escalate (between cohorts).  
Table 5 summarizes the sentinel dosing strategy as the following.  The first 2 subjects (1 on 
SKL24741 and 1 on placebo) within each cohort may be dosed at the same time.  
Randomization will ensure that one of these 2 subjects (sentinel subjects) receives placebo.  
If the doses are safe and tolerated, as determined by the investigator and the Sponsor, dosing 
of the remaining subjects will occur after the observation period as specified in Table 5.  

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Table 5: 
Sentinel Dosing Strategy 
Dose level  
(Part A and Part B) 
Observation Period and Safety Review 
First dose level 
1) Two sentinel subjects (1 on SKL24741 and 1 on placebo) 
2) 14-day observation period after dosing the first subject with 
SKL24741 
3) The investigator and the Sponsor review all available blinded safety 
data at the end of observation period. 
4) The remaining subjects dosed within the cohort 
Second dose level and 
higher 
1) Two sentinel subjects (1 on SKL24741 and 1 on placebo) 
2) 7-day observation period after dosing the first subject with SKL24741 
3) The investigator and the Sponsor review all available blinded safety 
data at the end of observation period. 
4) The remaining subjects dosed within the cohort 
Dose escalation between the cohorts (dose increase) will only proceed if the safety and 
tolerability of the previous dose(s) are acceptable as judged by the investigator and the 
Sponsor.  If available/needed, PK analysis results will also be considered.  The investigator 
and the Sponsor may adjust the observation period based on the disposition of SKL24741.   
The initiation and the final choice of the dose level for the food and gender effect cohorts 
(single dose administration) will not be performed until the PK and safety/tolerability are 
considered to be acceptable for the dose level provided under fasting condition and in healthy 
male subjects, respectively (Part A, single dose administration) (Figure 1 and Section 7.1). 
The investigator and the Sponsor will take all precautions necessary for studies at an early 
stage in the development of a new chemical entity.  Dose escalation criteria and dose 
stopping rules (Section 7.3) will be applicable at any time.  
7.3. 
Dose Escalation Criteria 
The investigator and the Sponsor will review all available blinded safety (and applicable PK) 
data in a blinding fashion at the end of each dose group before deciding to escalate to the 
next dose level.  Dose escalation decision will be jointly made by the investigator and the 
Sponsor.  The dose level may be adjusted from the protocol planned dose, if deemed 
necessary.   
The investigator will stop dose escalation or recommend modification of the dose escalation 
if in his/her judgment, and in consultation with the Sponsor, such action is medically prudent 
to protect safety of the subjects. 
Study drug administration and dose escalation will be discontinued if, within a cohort, 2 or 
more subjects (for Part A) or 3 or more subjects (for Part B) experience a laboratory 

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abnormality or significant clinical event (severe or life-threatening), considered by the 
investigator to be related or possibly related to the study drug. 
The initiation and the final choice of the first dose level of Part B (multiple dose 
administration) will not be performed until the PK, safety, and tolerability at such 
corresponding dose level after single dose administration (Part A) are assessed and 
considered to be acceptable.   
Dose escalation in Part A and Part B will be stopped based on the dose stopping rules.  The 
situations where the dose stopping rules apply are outlined in Table 6.  If one of the 
following situations occurs, dose will not be escalated.   
Table 6: 
Dose Stopping Rules (Part A and Part B) 
Situation 1 PK futility where the magnitude of plasma exposure (AUC) of SKL24741 
increase is disproportionate and not considered meaningful regarding the 
dose increase. 
Situation 2 Safety/tolerability profile does not warrant a higher dose to be investigated. 
Situation 3 The plasma exposure of SKL2474 exceeds the dose range justified in the 
dosing rationale (Section 4.2.2). 
 
   

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8. 
SELECTION OF STUDY POPULATION 
Subjects must meet all inclusion and exclusion criteria.   
8.1. 
Inclusion Criteria 
1. Male subjects of 18 to 50 years of age (inclusive) except for the gender effect cohort.  
2. Able to read, understand, sign, and date a written informed consent form (ICF) before 
study participation at screening 
3. Agree to use 2 highly effective methods of contraception, including at least one 
barrier method (Section 10.6.7 for details) 
4. Body mass index (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening 
5. Judged to be in good health on the basis of medical history, physical examination, and 
routine laboratory measurements (i.e., without clinically relevant pathology) 
6. Normal electrocardiogram (ECG) (12-lead), arterial blood pressure, and heart rate 
within the normal range of the study center or considered not clinically significant by 
the investigator and in agreement with the Sponsor 
7. Able to understand and comply with protocol requirements and instructions and likely 
to complete the study as planned 
8. For Part A (gender effect cohort): Female of non-childbearing potential (18 to 50 
years of age (inclusive)), who have undergone a sterilization procedure at least 6 
months prior to dosing with official documentation (e.g., hysteroscopic sterilization, 
bilateral tubal ligation or bilateral salpingectomy, hysterectomy, or bilateral 
oophorectomy), or be postmenopausal with amenorrhea for at least 1 year prior to 
dosing and follicle-stimulating hormone (FSH) serum levels consistent with 
postmenopausal status and serum pregnancy test at screening and upon admission 
with a negative result as per Principal Investigator’s judgment 
8.2. 
Exclusion Criteria 
1. History of any illness or condition that, in the opinion of the investigator, might 
confound the results of the study or pose an additional risk in administering study 
drug to the subjects 
2. Smokers (subjects who have smoked within 6 months at screening or those with 
positive results from smoking screening)  
3. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with 
pharmacokinetics of the trial medication (except appendectomy and simple hernia 
repair). 
4. Regular treatment with prescription medications.  Subjects should have ended any 
prescription medications at least 14 days before the first dosing of the study drug.  
Potential subjects should only stop any prescribed medication at the direction of a 
physician. 

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5. Regular treatment with nonprescription medications.  Subjects should have ended any 
nonprescription medications at least 14 days before the first dosing of the study drug.  
Potential subjects should consult a physician before stopping any regular treatment 
with nonprescription medication. 
6. Consumption of herbal medications, dietary supplements, and specific fruit products.  
Subjects should have stopped consumption of herbal medications or dietary 
supplements (e.g., St.  John’s Wort, ginkgo biloba, and garlic supplements), vitamins, 
and grapefruit or grapefruit juice, or Seville oranges at least 14 days before the first 
dosing of study drug. 
7. History of drug or alcohol abuse or addiction within 2 years before the start of study 
drug dosing, or a positive test results for alcohol or drugs of abuse, such as 
amphetamine, barbiturate, benzodiazepine, cocaine, methadone, opiates, oxycodone, 
phencyclidine, propoxyphene, cannabinoid (THC), MDMA (Ecstasy), methaqualone, 
and tricyclic antidepressant (TCA). 
8. Regular consumption of more than 2 units of alcoholic beverages per day or more 
than 14 units per week (1 unit of alcohol equals 1 pint [473 mL] of beer or lager, 
1 glass [125 mL] of wine, 25 mL shot of 40% spirit) before screening.  Subjects may 
not consume any alcohol from 72 hours before the first dosing of study drug through 
the completion of the last PK sampling. 
9. Consumption of an average of more than 5 servings (8 ounces per serving) per day of 
coffee, cola, or other caffeinated beverage before screening.  Subjects may not 
consume any caffeinated beverages from 48 hours prior to dosing until the collection 
of the last PK sample.   
10. Participation in a clinical study involving administration of either an investigational 
or a marketed drug within 2 months or 7 half-lives (whichever is longer) before 
screening. 
11. Blood donation or a significant loss of blood within 60 days of the start of study drug 
dosing or donation of more than 1 unit of plasma within 7 days before screening. 
12. Positive result at screening for any of the following infectious disease tests: hepatitis 
B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), human 
immunodeficiency virus antigen and antibody (HIV Ag, HIV Ab) 
13. Illness within 5 days before the start of study drug dosing (“illness” is defined as an 
acute [serious or non-serious] condition [e.g., the flu or the common cold]) 
14. History of any known relevant allergy/hypersensitivity (including allergy to the trial 
medication or its excipients) 
15. Subject who is judged not eligible for study participation by investigator 

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8.3. 
Life Style Guidelines 
8.3.1. 
Meals and Dietary Restrictions 
Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus fruits (e.g., 
Seville oranges, and pomelos) from 14 days prior to the first dose (Exclusion criteria 
(Section 8.2) and Appendix B) of study medication until the Follow-up visit. 
Clinical Chemistry Assessments: 
• Clinical laboratory specimens are to be collected under fasting condition.  
Subjects should not take food or fluids, except of water, for at least 6 hours prior 
to specimen collection (Section 10.6.2). 
Dosing Days: 
• Food and fluid intake restrictions associated with study drug administration are 
described in Section 9.3. 
• Meal intake should be avoided within 1 hour of ECG data collection during the 
extensive triplicate 12-lead ECG. 
• Lunch will be provided approximately 4 to 5 hours after dosing.   
• Dinner will be provided approximately 9 to 10 hours after dosing. 
• An evening snack will be permitted. 
8.3.2. 
Alcohol, Caffeine, and Tobacco 
• Alcohol, caffeine, and tobacco restrictions are specified in exclusion criteria 
(Section 8.2).  Subjects may undergo an alcohol test at the discretion of the 
investigator. 
A table of study restrictions is provided in Appendix B. 
8.3.3. 
Activity 
Subjects will abstain from strenuous exercise (e.g., heavy lifting, weight training or aerobics) 
for at least 48 hours prior to each blood collection for clinical laboratory tests.  Walking at a 
normal pace will be permitted. 
8.4. 
Removal of Subjects in the Study 
A subject may be discontinued from the study at any time if the subject, investigator, or 
Sponsor determines that it is not in the best interest of the subject to continue participation.  
A subject who prematurely discontinues treatment will be asked to return for a Follow-up 
visit at 14 to 16 days following administration of the last dose of study drug.   
Subjects will be discontinued from the study if: 
• they develop a medical condition that requires concomitant therapy with a 
prohibited medication, 

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• they develop a serious or life-threatening adverse reaction that places them at 
immediate risk, 
• they develop severe nausea or vomiting, 
• their female partner becomes pregnant or if the subject/partner is noncompliant 
with contraception requirements, 
• they are noncompliant with study requirements as determined by the investigator, 
• they withdraw consent. 
In the event that a subject chooses to withdraw from the study, the investigator should make 
a reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the 
subject’s rights.   
• If the subject withdraws from the study and also withdraws consent for disclosure 
of future information, no further evaluations should be performed and no 
additional data should be collected.  The Sponsor may retain and continue to use 
any data collected before such withdrawal of consent. 
• If a subject discontinues due to an adverse event or other medical reason, the 
subject must continue to be followed at regular intervals until the adverse event 
normalizes or returns to the subject’s baseline condition.  SK Life Science, Inc.  
and the investigator will agree to an acceptable follow-up schedule for these 
subjects. 
8.5. 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during one of the study drug administration periods 
for reasons unrelated to safety may be replaced in order to have 6 subjects completing each 
dose level in Part A and 8 completing each dose level in Part B.  The numbering of 
replacement subjects is described in Section 9.4.2. 

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9. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
9.1. 
Identification of Investigational Product 
Three different strengths of oral capsule of SKL24741 (i.e., 5, 25 and 100 mg) will be used at 
various dose levels.  For the dose levels at 200 mg or higher, a new oral capsule formulation 
strength may be developed. 
Placebo-matching capsules will be used for both Part A and Part B, except for the food and 
gender effect cohorts.   
9.2. 
Preparation and Dispensing 
Based on the treatment allocation, the appropriate dose of SKL24741 or matching placebo 
will be prepared and dispensed by an unblinded pharmacist at the clinical site. 
9.3. 
Administration 
The study drug (active) and placebo listed in Table 7 will be administered according to the 
randomization scheme.  The doses listed may require adjustment for safety considerations.   
All subjects will be admitted to the clinical research unit (CRU) the day before dosing. 
Table 7: 
Study Treatment 
Part 
Doses 
A 
A single oral dose of 10, 25, 50, 100, 200, 300, 400 mg, 600 mg, 800 mg, and 1000 
mg of SKL24741 or placebo will be administered to subjects in the morning of the 
first day, following an overnight (10 hour) fast (all doses) or approximately 30 
minutes after the start of a high-calorie, high-fat breakfast (Food effect cohort). 
B 
Multiple oral administrations of 4 dose levels of SKL24741 or placebo administered 
to male subjects each day for 14 days.  Doses, dosing regimens, and food status 
(fasting vs. fed) used in Part B will be determined based on the outcome of Part A. 
The study drug will be administered as an oral capsule formulation given with water 
(approximately 240 mL), as described in the Pharmacy Manual.  An unblinded pharmacist 
will be responsible for providing SKL24741 or placebo in appropriate containers for each 
subject, as per the randomization scheme, to the blinded study personnel for administration. 
Study drug will be administered according to the following guidelines. 
Part A - Single Dose Administration:  
A single oral dose of study drug will be administered to subjects in the morning after a 10-
hour overnight fast.  Subjects will also be instructed not to drink fluids over a period 
extending from 2 hours prior to 2 hours after study drug administration, except for water used 
for the study drug administration. 
Part A - Food Effect Cohort Only 
Subjects will receive a high-calorie, high-fat breakfast as follows: 

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• FDA-recommended breakfast consisting of 2 eggs fried in butter, 2 strips of bacon, 2 
slices of toast (30 gram) with 2 pats of butter, 4 ounces of hash brown potatoes, and 
240 mL (8 fluid ounces) of whole milk (total calories are approximately 1000 kcal; 
50% from fat, approximately 55 grams of fat).  
• Study drug will be administered to subjects assigned to the non-fasting regimen 
approximately 30 minutes after the start of a high-fat, high-calorie breakfast. 
• The meal will be taken about 30 minutes prior to the study drug administration. 
• The meal will be eaten in 30 minutes or less. 
• No fluids except those required for breakfast and dose administration will be allowed 
for two hours before and two hours after dose administration.   
Part B – Multiple Dose Administration:  
Subjects will be dosed each day for 14 days.  Doses, dosing regimen, and food status (fasting 
vs. fed) will be based on the outcome of Part A.   
In both Part A and Part B, study drug administration instructions are as follows: 
• Study drug will be administered only after the indwelling catheter is placed (if 
applicable) and after pre-dose vital signs, peak expiratory flow rate (PEFR), and 
ECG are performed, 
• In Part B, study drug will be given at approximately the same time (within a 1-
hour window) on each dosing occasion, 
• Study drug will be given as an oral capsule.  Subjects will receive the study drug 
in an upright position.  Subjects will be instructed not to lie down for 4 hours after 
taking the study drug, with the exception of study-specific events or assessments 
(sitting in an upright or reclining position [at least 45 degrees] is acceptable), 
• The investigator (or his/her designee) will supervise dosing and conduct a mouth 
inspection of each subject to ensure that the study drug was taken. 
9.4. 
Method of Assigning Subjects to Treatment Groups 
9.4.1. 
Randomization 
The randomization list will be generated by the clinical research organization (vendor) and 
will be provided to the site pharmacist.  The pharmacist will keep the randomization list in a 
secure location.  
Subjects who have completed screening evaluations and are eligible for the study 
participation will be randomized for study drug administration. 
Each randomized subject will be assigned with a unique randomization number. 

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9.4.2. 
Allocation of Randomization Numbers 
Subjects fulfilling the eligibility criteria will be randomized to receive their treatment 
according to the randomization list. 
Randomized subjects will be assigned with a 6-digit randomization number in the order in 
which they are enrolled.  The first digit of the randomization number will refer to the part A 
or B (1 or 2). The second and third digits will refer to the Cohort number.  For example, 
subjects in Cohort 1 of part A will have the randomization numbers 101xxx; subjects in 
Cohort 2 of part A will have the randomization numbers 102xxx.  In a case where a subject 
needs to be replaced, the last 2 digits of the randomization number for replacement 
participants will be identical to those of the original participant’s randomization number.  
The fourth digit, however, will be replaced with a 2.  For example, if the original 
participant’s randomization number is 110101, then the randomization number for the 
replacement participant will be 110201. Participants who prematurely discontinue from the 
study may be replaced at the sponsor’s discretion.  
9.5. 
Packaging and Labeling 
For each dose level in the study, SKL24741 study drug and placebo will need to be prepared 
in the pharmacy at the CRU according to detailed instructions provided by SK Life Science, 
Inc.  At the study site, study drug must be kept in a secure, locked area or locked cabinet with 
access restricted to designated study site personnel.  The study drug and placebo will be 
available in 50cc HDPE bottle with induction sealed child resistant cap and are packaged as 
30 count per bottle.  Refer to the Pharmacy Manual for detailed packaging and labeling 
information. 
9.6. 
Study Drug Supply, Storage, and Handling 
SKL24741 study drug will be provided to the site as oral capsule formulation at a dosage of 
5, 25, and 100-mg strength.  If SKL24741 needs to be investigated at the dose levels of 200 
mg or higher, a larger strength of SKL24741 may be developed for such purpose. 
At the study site, study drug must be kept in a secure, locked area or locked cabinet with 
access restricted to designated study site personnel.  Study drug will be stored at room 
temperature in a dry area, protected from light. 
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final Clinical Study Report (CSR). 
Records will be made of the receipt and dispensing of the study drugs supplied.  At the 
conclusion of the study, any unused study drugs will be retained by CRO, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions.  If no supplies remain, this 
fact will be documented in the pharmacy product accountability records. 
All investigational products will be transported, received, stored, and handled strictly in 
accordance with the container or product label, the instructions supplied to the clinical site 
and its designated pharmacy, the site’s standard operating procedures (SOPs), and applicable 
regulations.  Appropriate storage temperature and transportation conditions will be 

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maintained for the investigational product from the point of manufacture until delivery to the 
site.   
The pharmacy staff will examine the shipment to verify that the investigational products 
were received in acceptable condition.  Once inspected, the investigational products will be 
stored in a secure area with access restricted only to authorized staff, under physical 
conditions consistent with the investigational product requirements.  The site pharmacist or 
delegate is responsible for ensuring that all investigational products received at the site is 
inventoried and accounted for throughout the study, according to the applicable regulations 
and the site’s SOPs.  Details of the receipt, storage, dispensing, and destruction will be 
recorded and maintained in the pharmacy log book by the pharmacy staff.   
The Sponsor will provide written instructions regarding the final disposition of the unused 
study treatments.  Copies of the study treatment accountability records will be provided to 
the Sponsor at the completion of the study and will be made available for review by the Site 
Monitor, if applicable, during the course of the study. 
9.7. 
Drug Accountability 
Study drug may be dispensed only under the supervision of the investigator or designee and 
only to study subjects.  The pharmacist or designated site staff will maintain the information 
regarding the date and amount of study drug received and dispensed to the subjects.  These 
materials will be retained at the site according to instructions provided by the Sponsor or 
designee, and until inventoried by the study monitor.  The study monitor will review the 
study drug records and inventory throughout the study. 
9.8. 
Disposal or Retention of Unused Drug 
At the end of the study, SK Life Science, Inc. will provide instructions as to disposal of any 
unused investigational product.  If SK Life Science, Inc. authorizes destruction at the study 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by SK Life Science, Inc.  Destruction must be adequately documented. 
9.9. 
Compliance 
All doses of the study drug will be administered within the CRU under the direct supervision 
of the investigator or designee.  A mouth check will be performed after each study drug 
administration.  
9.10. 
Blinding and Unblinding 
This study will be double-blinded: participating subjects, study personnel, and SK Life 
Science, Inc. personnel will not be aware of which treatment (SKL24741 or a matching 
placebo) has been given to each subject (Section 9.10.1). 

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9.10.1. 
Blinding 
For each part (Part A and Part B) of the study, eligible subjects will be assigned to their 
randomization number linked to the dosing group by an unblinded pharmacist at the clinical 
site.  During the conduct of the study, all study personnel will be blinded to subject treatment 
assignments except for the following individuals: the bioanalytical laboratory (SK Life 
Science, Inc. Toxicology group or designated contract research organization [CRO]), the 
statistician preparing the randomization list (CRO), the dispensing pharmacist and the 
pharmacy QC/quality assurance (QA) personnel, as applicable.  If a subject is unblinded for 
safety-related regulatory reporting reasons (Section 9.10.2), SK Life Science, Inc. will 
become aware of the subject's treatment assignment. 
To maintain the blinding, the study drug will be administered in an appropriate manner 
(amber container, for instance).  The dispensing of the study drug will be carried out by the 
unblinded clinical site personnel in a way that maintains blinding of the study.  The 
unblinded clinical site personnel will not, otherwise, participate in the study and are not 
permitted to reveal any information to the study team, other study personnel and subjects.  
A copy of the randomization assignment list will be made available to the pharmacist to 
allow the dispensing of the investigational product to take place.  This documentation will be 
kept in a secure location until the clinical database has been locked.  One set of sealed 
envelopes containing the randomization list will be available to the Principal Investigator at 
the start of the study. 
9.10.2. 
Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process. 
Unblinding of individual subject’s treatment by the investigator should be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment 
is necessary for clinical management.  In such cases, the investigator must first attempt to 
contact the study Medical Monitor (see relevant telephone contact number provided in 
Section 12.1.3 or separate contact information document), to discuss the need for unblinding.  
In situations in which the investigator has tried, but is unable to reach the study Medical 
Monitor, he/she should use his/her best judgment, based on the nature and urgency of the 
clinical situation, and may proceed with unblinding without having successfully reached and 
discussed the situation with the study Medical Monitor.  In this case, the investigator will 
notify the Sponsor immediately after or as soon as possible. 
Once a subject's treatment assignment has been unblinded, the medical monitor and study 
coordinator should be notified within 24 hours of unblinding of the treatment.  Information 
relating to unblinding (e.g., reason, date) shall be clearly recorded in the subject’s study file, 
as part of relevant standard operating procedures (SOPs).  In addition, the investigator should 
consider whether the clinical event prompting unblinding should be considered a serious 
adverse event (SAE), according to the regulatory definitions or criteria for SAEs, and if so, 
submit an SAE report to SK Life Science, Inc. within 24 hours (Section 12.1). 

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SK Life Science, Inc. retains the right to break the blinding for subjects who experience 
SAEs suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities.  In addition, SK Life Science, Inc. may, 
for matters relating to safety concerns, unblind individual subjects at any time. 
After dosing each cohort, the safety and preliminary PK data will be provided to the Sponsor 
in a blinding fashion.  If needed, preliminary dataset of drug concentration may be disclosed 
in an unblinding fashion to the Sponsor under restricted conditions (e.g., data quality 
control).   
9.11. 
Prior and Concomitant Medications 
A table of prior and concomitant medication restrictions is provided in Appendix B. 
9.11.1. 
Prohibited and Prior Medications 
Subjects should stop taking any prescription, nonprescription, and herbal medications as well 
as any dietary supplements and specific fruit products at least 14 days before the first dose of 
the study drug, per exclusion criterion 6 in Section 8.2.  Potential subjects should only stop 
taking any prescribed medications at the direction of a physician and consult a physician 
before stopping any regular treatment with nonprescription medications. 
If any medication has been taken between the screening and the dose of study drug in Part A, 
and between the screening and the first dose of study drug in Part B, regardless of when 
dosing of the medication ended, the name, dose, route, regimen, start/stop dates, and reason 
for its use will be documented in the subject's electronic case report form (eCRF). 
9.11.2. 
Concomitant Medications 
Subjects will not take any prescription, nonprescription, or herbal medications, dietary 
supplements, or fruit products listed in exclusion criteria (Section 8.2) during the study until 
completion of the Follow-up visit assessments. 
Acetaminophen is an acceptable concomitant medication.  A maximum of 1000 mg within 
24 hours may be prescribed by the investigator or designee when necessary.  Other 
medication to treat adverse events may be prescribed only after consultation with the SK Life 
Science, Inc. Medical Monitor unless the medication is necessary to eliminate an apparent 
immediate hazard to a subject.  The investigator will notify the SK Life Science, Inc.  
Medical Monitor within 24 hours of prescribing medications to treat adverse events, if 
indicated. 
All concomitant medications (including drug name, dose, route, regimen, start/stop dates, and 
reason for its use) administered for the time period from administration of the dose of the 
study drug in Part A or the first dose of study drug in Part B through to the Follow-up visit 
will be documented in the subject’s eCRF.  

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10. 
ASSESSMENTS 
10.1. 
Timing of Assessments 
The timing of assessments is shown in Table 1 and Table 2. 
10.2. 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, 
height, weight, and BMI. 
10.3. 
Pharmacokinetics 
An overview of the schedule of PK assessments is given in Table 1 and Table 2.  
10.3.1. 
Blood Sampling 
Part A 
• Pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, and 72 hours 
post-dose following the single dose administration 
Part B 
• Study Days 1 and 7: Pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours 
post-dose.  The 24-hour post-dose blood PK samples for Days 1 and 7 should be 
taken before dosing on Days 2 and 8, respectively.  
• Study Days 3 to 6 and 9 to 13: Pre-dose only 
• Study Day 14: Pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, 
and 72 hours post-dose 
Directions for blood PK collection and sample shipment will be provided in the Sample 
Handling Guidelines. 
Windows for blood PK sampling are described in Table 8.  PK samples collected outside of 
these windows will be considered protocol deviations. 
Table 8: 
Acceptable Windows for PK Blood Sampling (Part A and Part B) 
Sampling Time 
Acceptable Window 
Pre-dose 
-30 mins before dose or immediately before 
breakfast (if under fed condition) 
0.25 to 1 hour post-dose 
 2 minutes 
2 to 18 hours post-dose 
 10 minutes 
24 to 72 hours post-dose 
 20 minutes 
 
 

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10.3.2. 
Urine Sampling 
Part A 
• Pre-dose and 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72 hours post-
dose following the dose administration. 
• No urine collection for PK analysis in the food and gender effect cohorts 
Part B 
• No urine collection for PK analysis in Part B 
Table 9: 
Acceptable Windows for PK Urine Sampling (Part A - SAD only) 
Sampling Time 
Acceptable Window 
Pre-dose 
-30 mins before dose 
0 to 72 hours post-dose 
± 15 minutes 
10.3.3. 
Sample Collection, Processing and Handling for PK Assessment 
Detailed procedures for the sample collection, processing and handling for PK assessment 
will be provided in a separate document (i.e., Sample Handling Guidelines).  The following 
Sections (Section 10.3.3.1 and Section 10.3.3.2) briefly summarize the sample processing 
and handling for blood and urine. 
The shipment address and assay lab contact information will be provided to the 
investigational site prior to initiation of the trial.  
Blood and urine samples may be used for metabolite and biomarker exploratory analyses.  
Possible results from these exploratory analyses may be reported in standalone report(s) if 
deemed necessary. 
10.3.3.1. Blood Sample Processing  
Blood (whole blood) will be collected via direct venipuncture or by an indwelling catheter at 
each scheduled sample time point.  Blood samples will be collected into blood collection 
tubes containing K2EDTA anticoagulant.  The content of the tube will be mixed gently by 
inverting 6 to 8 times (without shaking), and the sample will be placed in an upright position 
on wet ice until ready for centrifugation.  Blood samples should be processed to harvest 
plasma within 30 minutes of collection.  Blood samples will be centrifuged at 4 oC for 
10 minutes at approximately 2000 xg to separate plasma.  Plasma will be aliquoted into 
labeled cryogenic storage vials, followed by storage at -70 oC in an upright position until 
shipment to the bioanalytical laboratory.  Refer to the Sample Handling Guidelines for 
detailed sample collection, processing and handling. 
10.3.3.2. Urine Sample Processing  
Urine collection for PK analysis at a given time interval should be collected into a urine 
container maintained in ice or refrigerated for the duration of collection.  At the end of each 
collection time interval, the total volume of urine collected over the given time interval 

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should be recorded as part of PK data.  Refer to the Sample Handling Guidelines for detailed 
sample collection, processing and handling.   
10.3.4. 
Bioanalysis 
Concentration of SKL24741 (R-enantiomer) and SKL24742 (S-enantiomer) in plasma and 
urine will be determined using validated liquid chromatography-mass spectrometry/mass 
spectrometry (LC-MS/MS) methods.  
Residual and/or backup plasma and/or urine samples may be assessed for additional 
SKL24741 metabolites and/or other exploratory assessments, if deemed necessary.  If 
performed, data from these assessments will be documented separately in standalone 
report(s). 
10.4. 
Pharmacogenomics 
Pharmacogenomic (PGX) investigations explore the role of genetic variation in determining 
an individual’s response to drugs.  A separate informed consent for genotyping will be 
obtained from each subject prior to sampling.  These PGX investigations allow evaluation of 
genes coding for proteins that are involved in the absorption, distribution, metabolism and 
excretion (ADME) of drugs.  The gene sequences to be determined include known and likely 
functional variations of key ADME genes and incorporate more than 90% of ADME-related 
genetic markers identified by the PharmaADME group (weblink.pharmaadme.org).  The 
pharmacogenomic data may be included in the final study report, if deemed necessary.  
10.4.1. 
Blood collection for PGX samples 
Blood (whole blood) will be collected into blood collection tubes containing K2EDTA 
anticoagulant at the pre-dose stage (prior to any drug administration) from each subject who 
consented for genotyping.  The content of the tube will be mixed gently by inverting 6 to 8 
times (without shaking), and the sample will be stored in its original sample tube in an 
upright position until shipment to the pharmacogenomic laboratory or biorepository.  Whole 
blood will be stored at -70oC for the subsequent DNA extraction and genotyping.  Refer to 
Sample Handling Guidelines for detailed sample collection, processing and handling. 
10.5. 
Efficacy 
Not applicable. 
10.6. 
Safety 
Safety evaluations will include clinical laboratory assessments, vital signs, physical 
examinations, ECGs, peak expiratory flow rate (PEFR), Columbia-Suicide Severity Rating 
Scale (C-SSRS) (Part B only), and reporting of adverse events.  The SK Life Science, Inc. 
Medical Monitor will review these parameters on an ongoing basis during the study, in order 
to evaluate the safety of study drug dosing. 
Physical examination information collected at screening will be captured for inclusion into 
the clinical database.  Any untoward findings identified during physical examinations will be 

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captured as adverse events, if those findings meet the definition of an adverse event.  
Demographic data collected at screening will be included in the clinical database. 
10.6.1. 
Adverse Events 
Adverse events (serious and non-serious) will be assessed, documented, and reported in 
accordance with International Conference on Harmonization Good Clinical Practice 
(ICH-GCP).  Section 12.1 briefly outlines the definitions, collection periods, criteria, and 
procedures for documenting, grading, and reporting of all adverse events.  A separate 
document will be provided for the detailed eCRF completion guidelines for adverse events 
for investigators, and training will be provided. 
10.6.2. 
Clinical Laboratory Assessments 
Clinical laboratory assessments to be conducted in this study are shown in Table 10.  Blood 
and urine specimens will be analyzed at the CRU or its designated laboratory as appropriate.  
Clinical laboratory specimens are to be collected under fasting condition (subjects should not 
take food or fluids, except of water, for at least 6 hours prior to specimen collection).  
The investigator or designee will perform an assessment of all clinical laboratory data for 
clinical significance.  Clinical laboratory parameters will be determined for all subjects using 
the CRU’s or designated laboratory’s routine clinical laboratory methods.  Laboratory test 
results that are abnormal and considered clinically significant must be reported as adverse 
events (Section 12.1.4). 
Monitoring of Laboratory Abnormalities 
In the event of unexplained or unexpected clinically significant laboratory test values, the 
investigator may choose to repeat the test(s) as soon as possible and follow until the results 
have returned to the normal range and/or an adequate explanation for the abnormality is 
found.  The investigator will clearly mark all laboratory test values that are outside the 
normal range on the laboratory reports and will indicate which of these deviations are 
clinically significant.  Any abnormal laboratory result judged by the investigator to be 
clinically significant will be classified as an adverse event and will be recorded on the 
adverse event eCRF.  The investigator will also determine the severity and causality. 
Table 10: 
Clinical Laboratory Assessments 
Hematology 
Leukocytes 
Erythrocytes 
Hemoglobin 
Hematocrit 
Platelets 
Partial automated differential: 
 
lymphocytes 
 
monocytes 
 
eosinophils 

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basophils 
 
neutrophils 
MCV 
MCH 
MCHC 
Coagulation 
PT 
aPTT 
PT INR 
Clinical Chemistry 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Gamma-GT 
AST 
ALT 
LDH 
Creatinine 
Urea 
Total protein 
Glucose 
Inorganic phosphate 
Sodium 
Potassium 
Calcium 
Chloride 
Albumin 
Magnesium 
Urinalysis 
pH 
Color 
Appearance 
Specific gravity 
Glucose 
Ketones 
Protein 
Blood 
Standard microscopy:  

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Casts 
Bacteria 
RBCs 
WBCs 
Smoking Screen (Screening and Admission Only)  
Cotinine 
Follicle-Stimulating Hormone (FSH) Test (Screening Only) for Female Subjects for 
Gender Assessment Groupa 
FSH 
Serology (Screening Only) 
HBsAg 
HIV Ag and Ab  
HCV Ab 
Drugs of Abuse / Alcohol Screen (Screening and Admission Only) 
Amphetamine 
Barbiturate 
Benzodiazepine 
Cocaine 
Methadone 
Opiates 
Oxycodone 
Phencyclidine 
Propoxyphene 
Cannabinoid (THC) 
MDMA (Ecstasy) 
Methaqualone 
Ethanol (Alcohol) (Both urine and breath tests) 
Tricyclic Antidepressant (TCA) 
Other Assessments 
Alpha-1-acid glycoprotein 
Total cholesterol 
LDL cholesterol 
HDL cholesterol 
a Postmenopausal status for females of non-childbearing potential will be further confirmed with follicle- 
stimulating hormone (FSH) serum levels that are consistent with postmenopausal status.  Refer to 
Inclusion Criteria for details (Section 8.1). 
ALT: alkaline transaminase; aPTT: activated partial thromboplastin time; AST aspartate transaminase; 
Gamma-GT: glutamyl transpeptidase; FSH, follicle-stimulating hormone (FSH); HbsAg: hepatitis B surface 

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antigen; HCV Ab: hepatitis C antibody; HDL: high density lipoprotein; HIV Ab: human immunodeficiency 
virus antibody; LDH: Lactic dehydrogenase; LDL: low density lipoprotein; MCH: mean corpuscular 
hemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; PT: 
prothrombin time; PT INR: PT international normalized ratio; RBC: red blood cell; TCA: tricyclic 
antidepressant ; THC: cannabinoid; WBC: white blood cell. 
10.6.3. 
Physical Examinations and Vital Signs 
A full physical examination (review of all body systems), an abbreviated (symptom-directed) 
physical examination, and vital sign evaluation will be performed at select study visits, as 
specified in Table 1 and Table 2. 
A full physical examination includes a review of the following systems: head/neck/thyroid, 
eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, 
musculoskeletal, and neurological.  Breast, anorectal, and genital examinations will be 
performed when medically indicated.  For the conduct of the eye examination, the site’s 
standard procedures should be followed. 
Physical examinations are to be performed by the Principal Investigator or designee 
(physician, physician assistant, or nurse practitioner) listed on the Form FDA 1572. 
Vital sign evaluations include blood pressure (systolic and diastolic measurements in supine  
and standing in the same sequence in each subject, in order to allow orthostatic 
measurements), temperature, heart rate, respiratory rate, and arterial oxygen saturation 
(SaO2) (using pulse oximetry).  Additional vital sign assessments may be performed if 
clinically indicated, in the opinion of the investigator.  Clinically significant abnormal 
findings in vital signs and physical examination will be reported as adverse events. 
10.6.4. 
Electrocardiograms 
For study conduct, electrocardiograms (ECGs) will be classified as either safety or triplicate 
ECGs at the time points indicated in Table 1 and Table 2.  Electrocardiograms will be 
recorded using the site’s standard ECG equipment.  All ECGs will be obtained using 
instruments that analyze data using the same algorithms and produce the same data for 
interpretation.  Digital ECGs will be captured and transferred to the designated core 
cardiology laboratory for ECG analysis.  Collection of additional ECGs for routine safety 
monitoring at additional time points or days is at the discretion of the investigator based on 
GCP.  
ECGs will be obtained using a Mortara continuous 12-lead digital ECG recorder.  The ECG 
will include all 12-standard leads and will be recorded at a paper speed of 25 mm/sec.  
Standard ECG parameters will be measured, including heart rate (HR), RR, PR, QT, QTc 
intervals, and QRS duration.  All ECGs should be collected after at least 5 minutes of supine 
rest and prior to blood sample collection.  The device will remain connected to the subject 
during the collection periods as appropriate.  The ECG data will be transmitted wirelessly to 
the Surveyor system, which will extract ECG recordings at the protocol specified time points. 
Triplicate ECGs will be extracted approximately 1 minute apart reviewed and analyzed by 
the central ECG laboratory.  The ECG extractions will be time-matched to the PK samples 
but obtained before the actual sampling time to avoid changes in autonomic tone associated 

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with the psychological aspects of blood collection as well as the reduction in blood volume 
subsequent to blood collection.  The continuous ECG data will be sent to the central ECG 
laboratory for a high-resolution measurement of the cardiac intervals and morphological 
assessment.  The ECG core laboratory staff will be blinded to treatment, time, and study day 
identifiers. 
10.6.4.1. Safety 12-Lead ECGs 
Standard 12-lead ECGs should be performed at the time points indicated in Table 1 and 
Table 2, in addition to any other times, if clinically indicated.  The following guidelines must 
be followed:  
• The subject will be instructed to rest in the supine position for at least 5 minutes 
before having an ECG performed, 
• The ECG will be performed prior to any other procedures that may affect heart 
rate (e.g., blood draws). 
The ECG data traces will be made for safety review by the investigator and maintained with 
source documentation.  Any clinically significant ECG abnormalities at screening will 
exclude the subject’s participation in the study.  Thereafter, clinically significant abnormal 
findings will be reported as adverse events. 
To ensure safety of the subjects, the Principal Investigator or designee will make 
comparisons to Day -1 (baseline) measurements.  If the QTc is increased by >60 msec from 
the Day 1 pre-dose value or an absolute QTc value is >500 msec for any scheduled ECG, 
2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 
original measurement.  If either of the QTc values from these repeated ECGs remain above 
the threshold value (>60 msec increase from the Day 1 pre-dose; or is >500 msec), a single 
ECGs must be repeated at least hourly until QTc values from 2 successive ECGs fall below 
the threshold value that triggered the repeat measurement. 
10.6.4.2. Extensive Triplicate ECGs 
Extensive triplicate 12-lead ECGs, except for the food effect cohort, will be obtained to 
collect continuous 12-lead ECG data from pre-dose until 24 hours post-dose at the specified 
time points (Table 1 and Table 2).  Triplicate 10-second, 12-lead ECG recordings (digital 
ECGs) will be obtained within a 5-minute time window around the targeted time points 
outlined in the Schedule of Assessments described in Table 1 for Part A (single dose 
administration) and Table 2 for Part B (multiple dose administration).  During the extensive 
triplicate 12-lead ECG assessment, meal intake should be avoided within 1 hour of ECG data 
collection.  
Timing and recording technique for ECGs will be standardized for all subjects.  Subjects will 
be required to lie quietly in a supine position with minimal movement and minimal exposure 
to noise and other environmental stimuli for at least 5 minutes before the ECG time point in 
order to allow for quality ECG data.  All ECG data should occur in a 5-minute time window 
around the targeted time.  If digital ECGs are artifactual and of poor quality, analyzable 10-

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second ECGs will be repeated as close as possible to targeted time points.  Actual time of the 
ECG recording will be used for the analysis. 
The triplicate 10-second, 12-lead ECG time points post-dose are guided by PK animal data 
and are based around the estimated Tmax.  The time points may be changed depending on PK 
information obtained during the study from previous cohorts. 
10.6.5. 
Columbia-Suicide Severity Rating Scale  
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a brief questionnaire that provides 
for the identification, quantification, and standardized assessment of the occurrences and 
severity of suicidal ideation and behavior.  The C-SSRS will be assessed only after multiple 
dose administration (Part B).  The “Baseline (Lifetime/Recent)” version of the C-SSRS will 
be assessed at screening (Appendix C).  The C-SSRS “Since Last Visit” version will be 
assessed on other study days (Appendix D). 
10.6.6. 
Peak Expiratory Flow Rate (PEFR) Measurement 
Peak expiratory flow rate (PEFR) will be measured within a 30-minute time window around 
the targeted time points as outlined in the Schedule of Assessments in Table 1 for Part A 
(single dose administration) and Table 2 for Part B (multiple dose administration).  The peak 
expiratory flow rate (PEFR, also known as a peak flow) is the maximum rate that a person 
can exhale during a short maximal expiratory effort after a full inspiration.  Measurements 
will be performed in an upright position, with lips tightly closed around the mouth piece of 
the peak flow meter and blowing out as hard and as fast as possible into the meter. 
10.6.7. 
Contraception and Pregnancy 
The effects of SKL24741 on conception, pregnancy, and lactation in humans are not known.  
SKL24741 did not show any genotoxic potential in a standard battery of in vitro (Ames, 
human lymphocyte micronucleus) and in vivo (rat bone marrow micronucleus) studies (see 
Investigator’s Brochure). 
10.6.7.1. Contraception 
Subjects who can father a child must agree to use 2 highly effective methods of 
contraception, including at least one barrier method, as follows.  Male subjects must use a 
condom with spermicide and if subject’s female partner is of childbearing potential, she must 
use 1 of the following highly effective methods of contraception: 
• Hormonal contraception, 
• Occlusive cap (cervical cap or diaphragm) with spermicide, 
• Intrauterine device. 
For male subjects with female partner(s) of non-childbearing potential (i.e., post-menopausal 
or post-surgical sterilization) at least 6 months before the first dose of study drug, no 
additional contraception method is required.   

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For all study subjects who can father a child with partners of child-bearing potential, all 
methods of contraception, including abstinence, must be used from the time of consent 
through 90 days after the last dose of study drug.  Subjects whose partners become of child-
bearing potential during the study must agree to the contraceptive requirements. 
10.6.7.2. Pregnancy 
If the female partner of a subject becomes pregnant, the subject must permanently 
discontinue study treatment.  The investigator must notify the Medical Monitor, SK Life 
Science, Inc., and IQVIA by completing the Pregnancy Report form, faxing and emailing the 
form as per the Table of Contact (Table 13 and Table 14), within 24 hours of the site’s 
knowledge of the partner’s pregnancy.  The subject's treatment assignment will be unblinded, 
and if the subject was taking the active drug, the subject's partner will be followed until the 
end of pregnancy (e.g., delivery, miscarriage) and the infant exposed in-utero will be 
followed for 1 year after birth, provided consent is obtained.  An ICF will be provided to 
explain these follow-up activities. Pregnancy does not constitute an adverse event. 

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11. 
STATISTICAL AND ANALYTICAL PLANS 
This section presents a summary of the planned clinical pharmacology and safety analyses 
for this study.  Safety statistical analysis details will be provided in the Statistical Analysis 
Plan (SAP) for this study, and clinical pharmacologic analysis details (including the 
definition of the PK population) will be provided in the Clinical Pharmacology Data Analysis 
Plan (CPAP), both of which will be finalized prior to clinical database lock.  
Final analyses will take place after all subjects have completed the study and all data have 
been entered in the clinical study database. 
11.1. 
Sample Size and Power 
No formal sample size calculations have been performed.  This study utilizes the sample size, 
or the number of subjects, that is commonly employed in early clinical pharmacology 
studies, in order to achieve the study objectives.  Subjects who do not complete all the 
treatments and assessments specified in this protocol may be replaced.   
11.2. 
Analysis Populations 
• Safety Population: All subjects who were randomized and received at least 1 
dose of study drug.   
• PK Population: All subjects who received at least 1 dose of study drug and have 
sufficient PK data without any major protocol deviations.   
All subject (randomized or dosed) data will be presented in the subject data listings. 
11.3. 
Clinical Pharmacology Analysis 
11.3.1. 
Pharmacokinetic Analysis 
The PK analysis of SKL24741 (R-enantiomer) and SKL24742 (S-enantiomer) (if 
appropriate) will be performed using non-compartmental analysis (NCA) method.   
The following PK parameters will be calculated for SKL24741 and SKL24742 (if 
appropriate) for the plasma concentration-time profile: Maximum concentration (Cmax), time 
to maximum concentration (tmax), area under the concentration-time curve (AUC) from 0 to 
infinity (AUC∞), AUC from time 0 to a given time t (AUCt), AUC over the dosing interval 
(AUCτ), apparent clearance (CL/F), apparent volume of distribution (Vd/F), half-life (t½), and 
accumulation ratio (Racc).  In addition, the fraction excreted unchanged in the urine (fe) and 
renal clearance (CLR) will be calculated, if deemed appropriate.  If SKL24741 metabolites 
are quantified in this study, appropriate PK parameters will be calculated for metabolites.  
Other PK parameters will be determined, as deemed appropriate.  
A detailed description of the planned PK analysis will be presented in the CPAP.  Statistical 
analyses on PK data may be performed if deemed appropriate. 

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11.4. 
Statistical Analysis 
This section presents a summary of the planned statistical analyses of safety for this study.  
Statistical analysis details will be provided in the SAP for this study, which will be finalized 
prior to clinical database lock. 
11.4.1. 
General Considerations 
The SK Life Science, Inc. Biometrics designated CRO will analyze the safety data derived 
from this study.  Only descriptive analyses will be performed; no statistical hypothesis testing 
will be done.  Continuous variables (e.g., age) and PK parameters will be summarized by 
means of descriptive statistics (e.g., number of subjects (n), arithmetic mean, arithmetic 
standard deviation (SD), standard error of the mean (SEM), coefficient of variation (CV), 
geometric mean, geometric CV, median, first and third quartiles, minimum, and maximum).  
If the measurements in the source (raw) data are integers, then the corresponding mean and 
median will be presented to 1 decimal place and the SD to 2 decimal places; if the 
measurements are obtained to 1 decimal place, then the mean and median will be presented 
to 2 decimal places and the SD to 3 decimal places; and so forth.  Minimum and maximum 
will be displayed as reported in the source (raw) data.  Categorical variables (e.g., presence 
of an adverse event) will be summarized using counts and percentages.  Percentages will be 
presented to 1 decimal place unless otherwise specified.  Statistical analysis results will be 
presented by treatment group and as appropriate.  
All subject data, including derived, will be presented in the subject data listings; listings will 
display all subjects who were randomized and/or dosed with the study drug. 
11.4.2. 
Background Characteristics 
11.4.2.1. Subject Disposition 
The number and percentage of subjects in each disposition category (e.g., randomized,  
completing treatment period, completing the Follow-up visit, and discontinuing study with a 
breakdown of the reasons for discontinuation) will be summarized by the treatment group. 
11.4.2.2. Demographics and Baseline Characteristics 
Demographic, parameters and baseline characteristics will be summarized for the Safety 
Population.  Continuous variables will be summarized by descriptive summary statistics and 
categorical variables by the number and percentage of participants. 
11.4.2.3. Medical History 
Medical history encompassing abnormalities and surgeries reported before the Screening 
visit will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
version 19.0 or newer. 

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11.4.2.4. Prior and Concomitant Medications 
Medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) and summarized by medication class and preferred term for the Safety 
Population as frequency tables in 2 parts: 
• Prior medication: medication received between the Screening visit and the dose of 
study drug in Part A, and between the Screening visit and the first dose of study drug 
in Part B, regardless of when dosing of the medication ended, 
• Concomitant medication: medication received at or after the dose of the study drug 
in Part A or the first dose of study drug in Part B. 
If the medication start date is on or after the date of initial dosing of the study drug, then 
medication will be summarized as concomitant medication regardless of the medication end 
date.  If the medication end date is before the date of initial dosing of the study drug, then 
medication will be summarized as prior medication regardless of the medication start date.  
The prior and concomitant medications will be summarized separately.  
11.4.2.5. Study Drug Exposure 
Exposure to study drug in Part B (multiple dose administration) will be defined as total 
number of days treated with study drug during the study, with total days calculated as last 
day of study drug minus first day of study drug plus 1 day.  
11.4.2.6. Study Drug Compliance 
As the study drug will be administered under direct supervision at the study site, no analysis 
of compliance will be performed. 
11.4.3. 
Efficacy Analysis 
As efficacy is not being measured in this study, no efficacy analysis will be performed. 
11.4.4. 
Safety Analysis 
The overall safety profile of SKL24741, relative to placebo, will be assessed in terms of the 
following safety endpoints: 
• Incidence of treatment-emergent adverse events 
• Clinical laboratory values (hematology, coagulation, clinical chemistry, urinalysis 
and cholesterol) 
• ECG outcomes 
• Vital signs 
• Peak expiratory flow rate (PEFR) 
• Columbia-Suicide Severity Rating Scale (C-SSRS) (Part B only) 

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Statistical analysis details will be provided in the SAP.  Safety analyses will be based on the 
Safety analysis set.  
All safety data will also be presented in individual subject data listings. 
11.4.4.1. Adverse Events 
Adverse events will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of subjects experiencing an adverse event will be 
summarized by the MedDRA system organ class and preferred term, as well as by dose 
received.  Adverse events will be classified as pre-treatment or treatment-emergent. 
Pre-treatment adverse events are defined as adverse events that were reported or worsened 
after signing the ICF up to start of study medication. 
Treatment-emergent adverse events are defined as adverse events that were reported or 
worsened on or after start of study medication through the Follow-up visit. 
Only treatment-emergent adverse events will be summarized in tables.  Treatment-emergent 
adverse events will hereafter be referred to as “adverse events.”  
The incidence of adverse events will be summarized.  Adverse event summaries will include 
the following: 
• All adverse events (regardless of severity or relationship to study drug) 
• SAEs 
• Adverse events by severity 
• Adverse events by relationship to study drug 
• Adverse events leading to discontinuations 
• Adverse events leading to deaths 
Adverse event summaries will be presented by MedDRA System Organ Class and Preferred 
Term.  A subject with multiple occurrences of the same adverse event or a continuing 
adverse event will be counted once, and only the maximum severity level will be presented in 
the severity summaries, and the worst relationship level in the relationship summaries.  
Adverse events will be listed separately for those leading to death, SAEs, dose interruption, 
and permanent discontinuation.  
All adverse events through the Follow-up visit will be listed in an individual subject data 
listing, including pre-treatment adverse events.  
11.4.4.2. Clinical Laboratory Assessments 
All statistical analyses of laboratory values will be performed using International System of 
Units (SI).  Hematology, coagulation, clinical chemistry, urinalysis, and cholesterol panel 
results will be summarized by dose received and by part of the study at each scheduled time 
point. 

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The raw values, changes from baseline, percentage change from baseline (for selected 
laboratory parameters), shifts from baseline (categorical change from baseline), and clinical 
abnormalities will be summarized as appropriate.  Baseline will be defined in the study SAP.  
Clinically significant abnormal findings will be reported as adverse events. 
11.4.4.3. Electrocardiogram 
A summary of raw values and change from baseline values (as specified in the study SAP) 
will be provided by treatment group, dose received, and by part of the study at each 
scheduled visit for the following ECG measurements: heart rate (HR), RR, PR, QT, QTc 
intervals, and QRS duration.  In addition, the number and percentage of subjects by 
maximum on-treatment value of QT/QTc intervals, categorized as 450 msec, >450 msec 
and 480 msec, >480 msec and 500 msec, and >500 msec, as well as maximum 
on-treatment change from baseline value of QT/QTc intervals, categorized as 30 msec, 
>30 msec and 60 msec, and >60 msec, will be provided.  Baseline will be defined in the 
study SAP.  Correction of the QT values will be done using Fridericia formula.  Clinically 
significant abnormal findings will be reported as adverse events. 
11.4.4.4. Vital Signs 
The following vital signs will be summarized by treatment group at each scheduled time 
point: systolic and diastolic blood pressure (mmHg) measurements (in supine and standing in 
the same sequence in each subject, in order to allow orthostatic measurements), body 
temperature (°C), heart rate (beats per minute [bpm]), respiratory rate (breaths per minute), 
and arterial oxygen saturation (SaO2) (using pulse oximetry).  The raw values, changes from 
baseline, percentage change from baseline (for selected parameters), shifts from baseline 
(categorical change from baseline), and clinical abnormalities will be summarized as 
appropriate.  Baseline will be defined in the study SAP.  Clinically significant abnormal 
findings in vital signs will be reported as adverse events. 
11.4.4.5. Physical Examination 
Physical examination findings at screening will be presented as a listing only.  At post-
screening assessments, any untoward findings identified during physical examinations will 
be captured as adverse events, if those findings meet the definition of an adverse event. 
11.4.4.6. Peak Expiratory Flow Rate 
Peak expiratory flow rate (PEFR) results will be summarized by treatment group and by part 
of the study at each scheduled time point. The raw values, changes from baseline, percentage 
change from baseline, shifts from baseline (categorical change from baseline), and clinical 
abnormalities will be summarized as appropriate.  Baseline and unit (e.g., L/min) will be 
defined in the study SAP.  Clinically significant abnormal findings will be reported as 
adverse events. 

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11.4.4.7. Columbia-Suicide Severity Rating Scale (Part B only) 
Columbia-Suicide Severity Rating Scale (C-SSRS) results will be summarized by treatment 
group and by part of the study at each study day of assessment. The raw values, changes 
from baseline, and clinical abnormalities will be summarized as appropriate.  Baseline will 
be defined in the study SAP.  Clinically significant abnormal findings will be reported as 
adverse events. 
11.4.4.8. Other Safety Analysis 
Not applicable. 
11.4.5. 
Other Analysis 
Not applicable. 
11.4.6. 
Interim and Independent Data Monitoring Committee Analyses 
11.4.6.1. Interim Analysis 
Not applicable. 
11.4.6.2. Independent Data Monitoring Committee Analysis 
Not applicable. 

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12. 
PROCEDURAL, ETHICAL, REGULATORY, AND 
ADMINISTRATIVE CONSIDERATIONS 
12.1. 
Adverse Event 
12.1.1. 
Definition  
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
participating in a clinical investigation.  This AE does not necessarily need to have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable and unintended 
sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product, whether or not related to the 
investigational product. 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility 
that the study treatment caused the adverse event.  ‘Reasonable possibility’ means that there 
is evidence to suggest a causal relationship between the study treatment and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a study treatment. 
An AE may be: 
• A new illness, 
• Worsening of a concomitant illness or a baseline event, 
• An effect of the study treatment; it could be an abnormal laboratory value as well 
as a significant shift from baseline within normal range which the Principal 
Investigator or medically qualified designate considers to be clinically important. 
Surgical procedures themselves are not AEs.  They are therapeutic measures for conditions 
that required surgery.  The condition for which the surgery is required is an AE, if it occurs 
or is detected during the treatment period.  Planned surgical measures permitted by the 
clinical study protocol and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the start of study treatment.  In the latter case, the 
condition should be reported as medical history. 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any 
dose: 
• Results in death, 
• Is life-threatening, 
• Requires nonscheduled (not routine or planned) subject hospitalization for ≥ 24 
hours or prolongation of existing hospitalization for ≥ 24 hours,  
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
• Is a congenital anomaly or birth defect, 

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• Is an important medical event defined as an event that does not fit one of the other 
outcomes but may jeopardize the subject and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes.  Examples include 
allergic bronchospasm (a serious problem with breathing) requiring treatment in 
an emergency room, serious blood dyscrasias (blood disorders), or 
seizure/convulsion that does not result in hospitalization.  The development of 
drug dependence or drug abuse would be other examples of important medical 
events. 
• All AEs that do not meet any of the criteria for seriousness should be regarded as 
non-serious AEs 
• A pre-existing condition is one that is present at the start of the study.  A pre-
existing condition should be recorded as an AE if the frequency, intensity, or the 
character of the condition worsens during the study period. 
• At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an AE must also be recorded and documented as an AE. 
12.1.1.1. Severity Assessment 
The investigator or the designated person will provide an assessment of the severity of each 
AE by recording a severity rating on the appropriate AE reporting page of the subject’s CRF.  
In classification of AEs, the term “severe” is not the same as “serious”.  Severity is a 
description of the intensity of a specific event.  The term “serious” relates to a subject/event 
outcome or action criteria, usually associated with events that pose a threat to a subject’s life 
or functioning. 
All adverse events will be graded according to the severity scale below.  General descriptions 
of each severity grade may be found in Table 11. 
Table 11: 
General Descriptions of Severity Scale 
Severity Scale 
General Descriptions 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; The AE is easily tolerated and does not interfere with 
daily activities. 
Moderate 
Minimal, local or noninvasive intervention indicated; The AE interferes with 
daily activities, but the subject is still able to function. 
Severe 
Not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; The AE is incapacitating and requires 
medical intervention. 
Every effort will be made to obtain an adequate evaluation of the severity. 

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12.1.1.2. Causality Assessment 
An assessment should be made of the causal relationship of the adverse event to the study 
treatment, i.e., according to the following definitions in Table 12. 
Table 12: 
Definitions of Causality Assessment 
Causality 
Assessment 
Definitions 
Unrelated 
The event is occurring before dosing 
The event is definitely produced by the subject’s clinical state or by other modes of 
therapy administered to subject 
Remote 
The event does not follow a reasonable (poor) temporal relationship with drug 
treatment 
And/or the event is readily explained by the subject’s clinical state or by other 
modes of therapy administered to subject 
Possible 
Reasonable temporal relationship with drug treatment 
But the event could have been produced by the subject’s clinical state or by other 
modes of therapy administered to subject 
Probable 
Reasonable temporal relationship with drug treatment, abates upon discontinuation 
of drug 
And/or event cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
Definite 
Distinct temporal relationship with drug treatment, abates upon discontinuation of 
drug (de-challenge) and is confirmed by reappearance of the reaction on repeat 
exposure (re-challenge) 
Adverse events must be followed until resolution by the Principal Investigator.  Resolution is 
defined as the return to baseline status or stabilization of the condition with the expectation 
that it will remain chronic.  Adverse events that are not serious and are ongoing at the 
subject’s last visit will be followed for a maximum of 30 days.  Serious adverse events that 
are not resolved or stabilized during this time period will be followed until resolution or 
stabilization. 
12.1.2. 
Routine Reporting 
For the purposes of this study, the period of observation of adverse events for each subject 
extends from the signing of the informed consent form until their last visit including the 
follow-up visit or early termination, whichever is longer.   
All events reported by the subject, observed by the clinical staff (events, such as abnormal, 
clinically significant findings from physical examinations, ECG tracings, laboratory 
assessments, and vital sign measurements), or elicited by general questioning will be 
recorded in the Institution’s source document and reported as an adverse event and captured 
in the adverse events CRF.  If necessary, every effort will be made to obtain an adequate 

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follow-up of the subjects.  Should any subject choose to withdraw early from the study, they 
will be advised of the safety precautions to be taken. 
Early Termination and End of Study (EOS) visit assessments should be performed, including 
the following: medical history, vital signs, physical exam, safety and clinical laboratory tests, 
ECG, peak expiratory flow rate (PEFR), Columbia-Suicide Severity Rating Scale (C-SSRS), 
and adverse event/concomitant monitoring. 
Subjects will be questioned on their health status at the beginning of each visit and before 
their departure from the clinical site.  Open-ended questions will be asked. 
Classification will be performed by System Organ Class (SOC) and Preferred Term (PT) 
using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) at the 
start of the study. 
In general, AEs occurring secondary to other events (e.g., clinical sequelae or a cascade of 
events) should be identified by their primary cause.  For example, if severe vomiting is 
known to result in dehydration, it is sufficient to record only vomiting as SAE or AE in the 
CRF.  However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF.   
12.1.3. 
Serious Adverse Reporting 
The investigator or any other study center personnel’s knowledge will notify any SAEs 
including fatal or life-threatening to SK Life Science, Inc. (SKLSI) and their designee 
IQVIA on an SAE report form, without regard to causality, within 24 hours after becoming 
aware of its occurrence.  
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the 
investigational product.  Information not available at the time of the initial report (e.g., an 
end date for the AE, laboratory values received after the report, or hospital discharge 
summary) must be documented and an updated SAE report form should be forwarded to the 
Sponsor and their designee IQVIA within 24 hours of new/updated information.  All follow-
up information must be reported as soon as the relevant information is available.  The 
notification of all SAE’s should be directed to the following Sponsor representatives 
(Table 13 and Table 14). 

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Table 13: 
Contact Information for IQVIA 
Name 
IQVIA 
Email 
QPV_SKLSI_SafetyMailbox@quintiles.com  
Telephone 
+1 (855) 564-2229 
Fax 
+1 (855) 638-1674 
Table 14: 
Contact Information for Sponsor Medical Monitor 
Name 
Jimmy Schiemann 
Email 
jschiemann@sklsi.com 
Telephone 
+1 (404) 509-4293 
Fax 
+1 (201) 421-3884 
At the time of the initial SAE report, the investigator should provide as much of the 
following information as possible: 
• Study identifier  
• Study site 
• Subject number  
• A description of the event 
• Date of onset 
• Current Status  
• Whether study drug was discontinued  
• The reason why the event is classified as serious 
• Investigator’s assessment of the association between the event and study drug 
The Sponsor will be responsible for evaluating the events for expedited reporting, and for 
reporting them to the applicable regulatory agencies. 
If reports of any new and unexpected AEs become available to the Sponsor during the 
clinical portion of this study (related or not to the present study), the Sponsor has to advise 
the clinical site, through its Principal Investigator, of those events.  
12.1.4. 
Laboratory Results as Adverse Events 
The determination of whether laboratory test results are clinically significant should be made 
by a physician or by a clinical study staff member (listed on Form FDA 1572) who is 
qualified to review and assess laboratory tests.  This determination is important, as a 
clinically significant laboratory abnormality must be associated with an adverse event, either 
directly or indirectly as explained below.  

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The criteria for determining whether an abnormal laboratory test finding should be clinically 
significant are as follows: 
Test result is associated with clinical signs or symptoms.  If the signs or symptoms are 
related to a diagnosis that has already been documented as an adverse event, the lab 
abnormality itself generally does not have to be reported as an additional adverse event (e.g., 
hyperglycemia with an adverse event of new-onset diabetes; if diabetes is documented as an 
adverse event, hyperglycemia does not need to be documented separately as it is a common 
finding as part of the diabetes diagnosis). 
Test result requires additional diagnostic testing or medical/surgical intervention. 
Test result leads to a change in study drug dosing or to discontinuation from the study. 
Test result is considered by the investigator to be an adverse event (i.e., any new unfavorable 
sign/symptom, or previous condition that has increased in severity or frequency during the 
study).   
Laboratory abnormalities that are associated with a chronic, stable medical condition (e.g., 
slightly elevated ALT in a subject with hepatitis C that is unchanged or decreased from 
baseline) do not have to be considered clinically significant, but this judgment is left to the 
investigator. 
Note that repeating a test to confirm an abnormal result, in the absence of any of the above, 
does not mean that a lab must be clinically significant.  An abnormal result that is found to be 
in error is not clinically significant and should not be reported as an adverse event. 
12.2. 
Administrative Requirements 
12.2.1. 
Ethical Considerations 
The study will be conducted in accordance with the current ICH-GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and according to 
local regulations.  The IRB will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of the subjects.  The study will be conducted at 
the site where IRB approval has been obtained.  The protocol, Investigator’s Brochure, ICF, 
advertisements (if applicable), written information given to the subjects (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB by the investigator or the Sponsor, as allowable by local regulations. 
12.2.2. 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject prior to study participation.  The method of obtaining and documenting the informed 
consent and the contents of the consent will comply with ICH-GCP and all applicable 
regulatory requirement(s) and will be subject to approval by SK Life Science, Inc. 
A subject identification number (subject ID) will be assigned to each subject at the time that 
informed consent is obtained; this subject ID will be used throughout the study. 
 

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12.2.3. 
Investigator Compliance 
No modifications to the protocol will be made without the approval of SK Life Science, Inc.  
Changes that significantly affect the safety of the subjects, the scope of the investigation, or 
the scientific quality of the study will require IRB notification prior to implementation, 
except where the modification is necessary to eliminate an apparent immediate hazard to 
human subjects.  SK Life Science, Inc. will submit all protocol modifications to the required 
regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the 
protocol, the investigator will contact SK Life Science, Inc. to discuss the planned course of 
action.  If possible, contact should be made prior to the implementation of any changes.  Any 
departures from protocol must be fully documented in the source documentation and in a 
protocol deviation log.  
12.2.4. 
Access to Records 
The investigator must make the source documents of subjects enrolled in this study available 
for inspection by SK Life Science, Inc. or its representative at the time of each monitoring 
visit.  The records must also be available for inspection, verification, and copying, as 
required by regulations, by officials of the regulatory health authorities (FDA and others).  
The investigator must comply with applicable privacy and security laws for use and 
disclosure of information related to this research set forth in this protocol.  
12.2.5. 
Subject Privacy 
To maintain subject confidentiality, all eCRFs, study reports, and communications relating to 
the study will identify subjects by assigned subject numbers.  As required by federal 
regulations, the investigator will allow SK Life Science, Inc. and/or its representative’s 
access to all pertinent medical records in order to allow for the verification of data gathered 
in the eCRFs and for the review of the data collection process.  The FDA (or other regulatory 
authority) may also request access to all study records, including source documentation for 
inspection. 
As applicable, in accordance with the Health Insurance Portability and Accountability Act of 
1996 (HIPAA) and associated privacy regulations, a subject authorization to use personally 
identifiable health information may be required from each subject prior to research activities.  
This authorization document must clearly specify what parties will have access to a subject’s 
personal health information, for what purpose and for how long. 
12.2.6. 
Record Retention 
The investigator will maintain all study records according to ICH-GCP and/or applicable 
local regulatory requirement(s), whichever is longest.  If the investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility and SK Life Science, Inc. must be notified.  

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12.2.7. 
Study Termination 
SK Life Science, Inc. may terminate the study at any time.  For reasonable cause, either the 
investigator or the IRB may terminate the study as well.  Conditions that may warrant 
termination include, but are not limited to: 
• subject or investigator noncompliance 
• unsatisfactory subject enrollment 
• lack of adherence to protocol procedures 
• lack of evaluable and/or complete data 
• potentially unacceptable risk to study subjects 
• decision to modify drug development plan 
• decision by the FDA or other regulatory authority 
Written notification that includes the reason for the protocol termination is required. 
12.3. 
Data Quality Assurance 
SK Life Science, Inc. or its designated representative will conduct a study site visit to verify 
the qualifications of each investigator, inspect trial site facilities, and inform the investigator 
of responsibilities and procedures for ensuring adequate and correct study 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.  Study data for each enrolled subject will be entered into an eCRF by site 
personnel using a secure, validated web-based electronic data capture (EDC) application 
(Section 12.5).  
Study monitors will discuss instances of missing or uninterpretable data with the investigator 
for resolution.  Any changes to study data will be made to the eCRF and documented via a 
database query.  An audit trail for all changes will be maintained within the clinical database. 
Study monitors will discuss instances of missing or uninterpretable data with the investigator 
for resolution.  Any changes to study data will be made to the eCRF and documented via an 
electronic audit trail associated with the affected eCRF. 
12.4. 
Monitoring 
Monitoring and auditing procedures developed or approved by SK Life Science, Inc. will be 
followed, in order to comply with GCP guidelines.  On-site checking of the eCRFs for 
completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed. 
The study will be monitored by SK Life Science, Inc. or its designee.  Monitoring will be 
done by personal visits from a representative of the Sponsor (site monitor) who will review 
the eCRFs and source documents.  The site monitor will ensure that the investigation is 
conducted according to protocol design and regulatory requirements. 

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12.5. 
Electronic Data Capture 
The Sponsor or designee will ensure secure access to and training on the EDC application, 
sufficient to permit site personnel to enter or correct information in the eCRFs for the 
subjects for which they are responsible.  
The eCRFs will be completed for each study subject.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
eCRF.  Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, 
adverse events, other observations, and subject status. 
The investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected.  An explanation should be provided for all missing data. 
The audit trail entry will show the user’s identification information, and the date and time of 
the correction.  Investigators must provide through the EDC application formal approval of 
all the information in the eCRFs and changes to the eCRFs to endorse the final submitted 
data for the subjects for which they are responsible.  
The Sponsor or designee will retain the eCRF data and corresponding audit trails.  A copy of 
the final archival eCRF in the form of a CD or other electronic media will be placed in the 
investigator’s study file. 
12.6. 
Report and Publications 
12.6.1. 
Publication of Study Results 
Any and all scientific, commercial, and technical information disclosed by SK Life Science, 
Inc. in this protocol or elsewhere should be considered confidential and proprietary property 
of SK Life Science, Inc.  The investigator shall hold such information in confidence and shall 
not disclose the information to any third party except to such of the investigator’s employees 
and staff as have been made aware that the information is confidential and who are bound to 
treat it as such and to whom disclosure is necessary, in order to evaluate that information.  
The investigator shall not use such information for any purpose other than for determining 
mutual interest in performing the study and, if the parties decide to proceed with the study, 
for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be 
used by SK Life Science, Inc. in connection with the development of the study drug and 
therefore may be disclosed as required to other clinical investigators, the US FDA, and to 
other government agencies.  The investigator also understands that, in order to allow for the 
use of the information derived from the clinical study, the investigator has the obligation to 
provide SK Life Science, Inc. with complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between SK Life Science, Inc. and the 
investigator and/or the investigator’s institution. 

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12.6.2. 
Clinical Study Report  
A clinical study report that is written in accordance with ICH Guideline E3 will be submitted 
in accordance with local regulations. 

 
 
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13. 
REFERENCES 
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE Official 
Report: A practical clinical definition of epilepsy. Epilepsia, 2014; 55: 475–482.  
Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. Epilepsy. Nat Rev 
Dis Primers. 2018; 4:18024. 
Hauser WA, Beghi E. First seizure definitions and worldwide incidence and mortality. Epilepsia 
2008; 49(Suppl 1):8–12. 
Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton, C. R. Estimation of the burden of 
active and life-time epilepsy: a meta-analytic approach. Epilepsia 2010; 51(5):883–890. 
Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientist. Cold Spring 
Harb Perspect Med. 2015; 5(6):a022426. 
Meinardi H, Binnie CD and Meijer JW. Assessment of effects of antiepileptic drugs. 
Electroencephalogr. Clin. Neurophysiol. Suppl., 1985; 37: 201-214. 
Eijkelkamp N, Linley JE, Baker MD, Minett MS, Cregg R, Werdehausen R, et al. Neurological 
perspectives on voltage-gated sodium channel. Brain, 2012; 135(9):2585-2612. 
Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 
1993; 10(7):1093-1095 

 
 
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APPENDIX A. CALCULATION OF BODY MASS INDEX 
The BMI will be calculated during screening to determine a subject’s eligibility, using the 
subject’s height and weight measurements. The equation for calculating BMI is: 
BMI (kg/m2) = Body weight (kg) ÷ Height2 (m2) 
 
 
 

 
 
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APPENDIX B. PRIOR AND CONCOMITANT MEDICATIONS AND 
OTHER STUDY RESTRICTIONS 
Study Restrictions 
Restricted 
Study Period 
Medication/Food/Activity 
Screening 
Dosing and Follow-up 
Prescription medications 
None for 14 days before the first 
dosing  
None through Follow-up visit 
Nonprescription medications 
None for 14 days before the first 
dosing 
None through Follow-up visit, 
except occasional, limited 
acetaminophen 
Vitamins 
None for 14 days before the first 
dosing 
None through Follow-up visit 
Herbal medications 
Grapefruit/grapefruit juice 
Seville (blood) oranges 
None for 14 days before the first 
dosing  
None through Follow-up visit 
Alcoholic beverages 
Not more than 2 units of 
alcoholic beverages per day or 
more than 14 units per weeka 
None within 72 hours of the 
first dose through collection of last 
pharmacokinetic sample  
Coffee, cola, or other 
caffeinated beverage 
Not more than five 8 oz 
servings/day 
None within 48 hours of the first 
dose through collection of last 
pharmacokinetic sample 
Smoking 
Non-smokers onlyb 
Not allowed 
a 1 unit of alcohol equals 1 pint [473 mL] of beer or lager, 1 glass [125 mL] of wine, 25 mL shot of 40% spirit 
b Subjects who have stopped smoking at least 6 months before screening are considered non-smokers 

 
 
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APPENDIX C. SUMMARY OF CHANGES TO PROTOCOL 
None 
 
 
 

 
 
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APPENDIX D. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(BASELINE/SCREENING)  
 

 
 
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APPENDIX E. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(SINCE LAST VISIT) 
 
 

 
 
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