Clinical trial NCT04690751
Conditions: Healthy
Sponsor: SK Life Science, Inc.
Start date: 2020-12-21; Completion date: 2021-05-17
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate the relative bioavailability, or the degree and rate at which the drug is absorbed by the body of two cenobamate formulations (200 mg Oral Suspension and a 200 mg Oral Tablet) and to assess the effect of food on the oral bioavailability of the 200 mg Oral Suspension. This study will also look at the safety and tolerability of the oral suspension and the oral tablet under both fasted and fed conditions.

Detailed description:
This study is an open-label, randomized, single-dose, single-center, three-period, six-sequence, balanced crossover study in healthy male and female subjects to assess the relative bioavailability of 200 mg of cenobamate given as an oral tablet or oral suspension and to evaluate the effect of food on the bioavailability of a 200 mg dose of cenobamate given as an oral suspension in fasting and fed conditions.

The study consists of a 28-day screening period, followed by single dose administration of cenobamate (tablet or suspension) on Day 1, Day 22, and Day 43, an assessment period of 62 days and a follow-up visit on Day 69. All subjects will be confined to the clinical site from Day -1 (the day before period 1 dosing) until the morning of Day 4, Day 20 (the day of the last PK sampling for period 1) until the morning of Day 25, and Day 41 (the day of the last PK sampling for period 2) until the morning of Day 46. Outpatient visits will be performed regularly until the 456-hour PK sampling for each period. The follow-up visit will occur on Day 69 (±1 day).

Arms: arm 1: Treatment A: Oral Dose of cenobamate administered as a single 200 mg tablet under fasted conditions arm 2: Treatment B: Oral Dose of cenobamate administered as a single 200 mg/20 mL suspension under fasted conditions arm 3: Treatment C: Oral Dose of cenobamate administered at a single 200 mg/20 mL suspension under fed conditions
Interventions: intervention 1: Cenobamate 200Mg Tab Fasted intervention 2: Cenobamate Oral Suspension Fed intervention 3: Cenobomate Oral Suspension Fasted
Intervention descriptions: intervention 1: Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the treatment of partial onset seizures (POS) in adult patients. intervention 2: Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the treatment of partial onset seizures (POS) in adult patients. intervention 3: Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the treatment of partial onset seizures (POS) in adult patients.

Protocol documents:
Prot_000.pdf: 
YKP3089 
 
Protocol No. YKP3089C037 
 
1 
 
 
  
 
1. 
TITLE PAGE 
YKP3089 
CLINICAL STUDY PROTOCOL 
 
RELATIVE BIOAVAILABILITY OF A SINGLE 200 MG 
DOSE OF CENOBAMATE (YKP3089) GIVEN AS AN 
ORAL TABLET OR AS AN ORAL SUSPENSION AND 
THE EFFECT OF FOOD ON A SINGLE 200 MG DOSE 
OF CENOBAMATE GIVEN AS AN ORAL SUSPENSION 
 
SK Life Science, Inc. Study Number: YKP3089C037 
IND Number: IND076809 
 
Sponsor: 
SK Life Science, Inc. 
461 From Road, 5th floor 
Paramus  
NJ 07652 
USA 
Original Date 
21 October 2020 
Version Number 
 Amendment 1, Version 2.0 
Version Date 
30 November 2020 
Previous Version 
21 October 2020 
 
CONFIDENTIAL 
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. 
 
 




YKP3089 
 
Protocol No. YKP3089C037 
 
3 
 
 
  
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for cenobamate (YKP3089). I have read the 
YKP3089C037 Protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
Ahad Sabet, MD, CPI 
Principal Investigator/Research Physician, EDS 
PRA Health Sciences 
Medical Director – EDC SLC 
Phone: (801) 904-4638, VNET: # 124.4638 
Fax: (801) 261-3341 
Mobile Phone: (314) 973-6949 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
 
 
 
 
 
 
 
Date 
 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
4 
 
 
  
 
AMENDMENT 1 SUMMARY OF CHANGES  
 
Section 
Previous Version’s text/ 
Content 
Amended Text/ Content 
Rationale/ 
Description 
Synopsis  
Healthy Male or female 
subjects of 18 to 50 years of 
age (inclusive) 
Male or female subjects of 18 to 
50 years of age (inclusive), at the 
time of screening 
Deleted and 
added text for 
clarification  
Synopsis  
Inclusion criteria number 2 
was skipped ending in 
number 9 
Updated numbering so that 
number 2 was not skipped ending 
in number 8 
Need for 
sequential 
numbering 
Synopsis 
Inclusion 7:  
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 
Inclusion 6 (was Inclusion 7): 
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. 
Removed 
redundant 
language and 
need for sponsor 
agreement as 
normal ranges are 
already agreed 
upon prior to 
study start 
Synopsis 
Inclusion 9:  
Females 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 as 
per Principal Investigator’s 
judgment  
Inclusion 8 (was Inclusion 9): 
Females 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., 
bilateral tubal ligation or bilateral 
salpingectomy or hysterectomy), 
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  
Removed 
procedures that 
may necessitate 
the use of HRT 
(HRT is not 
allowed in this 
study as a 
concomitant 
medication) 


YKP3089 
 
Protocol No. YKP3089C037 
 
5 
 
 
  
 
Table 4: Schedule 
of Assessments 
Amended Table formatting to 
properly align visits with days 
they are occurring on 
Formatting was 
off in previous 
protocol 
Table 4: Schedule 
of Assessments 
 
Added C-SSRS at Baseline 
(screening) 
And C-SSRS “Since Last Visit” 
to: 
Screening Day -28 
Admit Day -1 
Admit Day 41 
Admit Day 62 
And Follow up Visit Day 69 
The C-SSRS is a 
commonly 
requested test 
from IRBs 
Table 4: Schedule 
of Assessments 
Inclusion/Exclusion row 
has a superscript a 
Moved superscript a to Eligibility 
Confirmation assessment on Day 
-1 
Clarification on 
when a review of 
the 
inclusion/exclusio
n is to occur in 
light of eligibility 
confirmation 
Table 4: Schedule 
of Assessments 
Randomization at Day -1 
Randomization removed from 
Day-1 and added to Day 1 
Clarification on 
timing of 
randomization 
Table 4: Schedule 
of Assessments 
 
Removed Tympanic Temperature 
from schedule of Assessments 
Temperature will 
be taken in 
accordance with 
site SOPs as part 
of vitals 
Table 4: Schedule 
of Assessments 
12-Lead ECG Day1  
12-Lead ECG Removed from 
Day 1 and added to Day-1 
12-Lead ECG will 
only be conducted 
at screening and 
baseline 
Table 4: Schedule 
of Assessments 
Removed the duplicated word 
“Note:” from the footnotes 
Removed 
redundant 
wording 
Table 4: Schedule 
of Assessments 
Note under table 
Added “C-SSRS = Columbia 
Suicide Severity Rating Scale” to 
notes under table 
Needed to add 
definition of C-
SSRS 


YKP3089 
 
Protocol No. YKP3089C037 
 
6 
 
 
  
 
Table 4: Schedule 
of Assessments 
Added Footnote b: Baseline 
“Baseline/Screening” version of 
C-SSRS will be used 
Needed to add 
type of C-SSRS 
to be conducted at 
baseline 
Table 4: Schedule 
of Assessments 
Added Footnote c: “Since Last 
Visit” version of C-SSRS will be 
used 
Needed to add 
type of C-SSRS 
to be conducted at 
times outside of 
baseline 
Table 4: Schedule 
of Assessments 
Added Footnote d: 
“Randomization to occur prior to 
dosing on Day 1” 
Clarification on 
when 
randomization 
will occur 
Table 4: Schedule 
of Assessments 
The following footnotes were 
adjusted: 
b  e 
c  f 
d  g 
e  h 
f  i 
Adjusted to make 
room for 
additional 
footnotes 
7.1.1.1. 
“Screening assessments will 
be comprised of relevant 
medical history, 
demographics (including 
the assessments of body 
height, weight, BMI, 
smoking status, and alcohol 
history), serum pregnancy 
test, serum FSH, clinical 
labs, serology tests (HIV 
and Hep B/C), urine drug 
screening, breath alcohol, 
tympanic temperature, 
physical examination, vital 
signs, 12-lead ECG, 
concomitant therapy, and 
review of 
inclusion/exclusion criteria” 
“Screening assessments will be 
comprised of relevant medical 
history, demographics (including 
the assessments of body height, 
weight, BMI, smoking status, and 
alcohol history), serum pregnancy 
test, serum FSH, clinical labs, 
serology tests (HIV and Hep 
B/C), urine drug screening, breath 
alcohol, a complete physical 
examination, vital signs, 12-lead 
ECG, concomitant medications, 
C-SSRS and review of 
inclusion/exclusion criteria” 
Added type of 
physical 
examination and 
C-SSRS to 
harmonize with 
the Schedule of 
Assessments 
7.1.1.2. 
Confirmation of eligibility 
(including a review of the 
inclusion/exclusion 
criteria), 
height/weight/BMI, urine 
pregnancy, clinical labs, 
urine drug screen, breath 
Confirmation of eligibility 
(including a review of the 
inclusion/exclusion criteria), 
height/weight/BMI, urine 
pregnancy, clinical labs, urine 
drug screen, breath alcohol, 12-
lead ECG, CSSR-S, and 
Added 12-lead 
ECG and CSSR-S 
to harmonize with 
Schedule of 
Assessments 


YKP3089 
 
Protocol No. YKP3089C037 
 
7 
 
 
  
 
alcohol, and concomitant 
medications on Day -1 
concomitant medications on Day 
-1 
7.1.1.2. 
Tympanic temperature, 
physical exam and vital 
signs on Day 1 
Physical exam (symptom 
oriented) and vital signs on Day 1 
Removed 
tympanic 
temperature and 
clarified physical 
exam type to 
harmonize with 
Schedule of 
Assessments 
7.1.1.2. 
Added: “Randomization on Day 1 
prior to dosing” 
Added clarifying 
language for 
randomization 
timing 
7.1.1.2. 
Clinical labs, tympanic 
temperature, vital signs, 12-
lead ECG, and concomitant 
medications on Day 4 
Clinical labs, vital signs, and 
concomitant medications on Day 
4 
Removed 
tympanic 
temperature and 
12-lead ECG to 
harmonize with 
schedule of 
assessments 
7.1.1.2. – 7.1.1.18. AE Monitoring 
AE Monitoring throughout 
Added clarifying 
language about 
timing of 
assessments 
7.1.1.2., 7.1.1.7, 
7.1.1.12. 
“… subjects will be issued a 
hypersensitivity card” 
“… subjects will be issued a 
hypersensitivity safety card” 
Added clarifying 
language to 
harmonize with 
Schedule of 
Assessments 
7.1.1.3. – 7.1.1.6., 
7.1.1.8 – 7.1.1.11., 
7.1.1.13 – 7.1.1.17. 
Urine drug screen, breath 
alcohol, Tympanic 
Temperature, vital signs, 
and concomitant 
medications 
Urine drug screen, breath alcohol, 
vital signs, and concomitant 
medications 
Removed 
tympanic 
temperature as 
this will be done 
as part of vital 
signs 
7.1.1.7., 7.1.1.12. 
Clinical labs, urine drug 
screen, breath alcohol, 
tympanic temperature, 
physical exam, vital signs, 
concomitant medications 
on… 
Clinical labs, urine drug screen, 
breath alcohol, vital signs, C-
SSRS, concomitant medications 
on… 
Removed 
tympanic 
temperature, 
physical exam 
and added C-
SSRS to 
harmonize with 
Schedule of 
Assessments 


YKP3089 
 
Protocol No. YKP3089C037 
 
8 
 
 
  
 
7.1.1.7. 
Blood samples to determine 
plasma drug concentrations 
of cenobamate on Day 20 
for end of Period 1 
sampling and Day 22 to the 
morning of Day 25 for 
beginning of Period 2 
sampling 
Blood sample to determine 
plasma drug concentrations of 
cenobamate on Day 20 for end of 
Period 1 sampling 
And 
Blood sampling to determine 
plasma drug concentrations of 
cenobamate on Day 22 to the 
morning of Day 25 for beginning 
of Period 2 sampling 
Split bullet up to 
clarify timing of 
events 
7.1.1.7. 
Tympanic temperature, 
physical exam and vital 
signs on Day 22 
Physical exam (symptom 
oriented) and vital signs on Day 
22 
Removed 
tympanic 
temperature and 
clarified physical 
exam type to 
harmonize with 
schedule of 
assessments 
7.1.1.7. 
Clinical labs, tympanic 
temperature, vital signs, and 
concomitant medications on 
Day 25 
Clinical labs, vital signs, and 
concomitant medications on Day 
25 
Removed 
tympanic 
temperature as 
this will be done 
as part of vital 
signs 
7.1.1.12. 
Blood samples to determine 
plasma drug concentrations 
of cenobamate on Day 41 
for end of Period 2 
sampling and Day 43 to the 
morning of Day 46 for 
beginning of Period 3 
sampling 
Blood sample to determine 
plasma drug concentrations of 
cenobamate on Day 41 for end of 
Period 2 sampling 
And 
Blood sampling to determine 
plasma drug concentrations of 
cenobamate on Day 43 to the 
morning of Day 46 for beginning 
of Period 3 sampling 
Split bullet up to 
clarify timing of 
events 
7.1.1.18. 
Urine pregnancy, clinical 
labs, tympanic temperature, 
physical exam, vital signs, 
and concomitant 
medications 
Urine pregnancy, clinical labs,  
physical exam (symptom 
oriented), vital signs C-SSRS  and 
concomitant medications 
Removed 
tympanic 
temperature, 
added C-SSRS 
and type of 
physical exam to 
harmonize with 


YKP3089 
 
Protocol No. YKP3089C037 
 
9 
 
 
  
 
schedule of 
assessments 
8.1. 
Male or female subjects of 
18 to 50 years of age 
(inclusive) 
Male or female subjects of 18 to 
50 years of age (inclusive), at the 
time of screening 
Added clarifying 
language as to 
when the age will 
be assessed 
8.1. 
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 
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. 
Removed 
redundant 
language and 
need for sponsor 
agreement as 
normal ranges are 
already agreed 
upon prior to 
study start 
8.1. 
Females 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 as 
per Principal Investigator’s 
judgment 
Females 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., 
bilateral tubal ligation or bilateral 
salpingectomy orhysterectomy), 
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 
Removed 
procedures that 
may necessitate 
the use of HRT 
(HRT is not 
allowed in this 
study as a 
concomitant 
medication) 
8.2. 
Smokers (subjects who 
have smoked within 6 
months at screening or 
those with positive results 
from smoking screening) 
Smokers (subjects who have 
smoked within 6 months at 
screening) 
Updated language 
to build in 
flexibility to 
assess this 
criterion 
8.2. 
Documented congenital QT 
syndrome. Corrected QT 
interval (QTc) using 
Fridericia correction 
History of  Familial Short QT 
syndrome. 
Updated exlusion 
to be more 
appropriate for 
cenobamate 


YKP3089 
 
Protocol No. YKP3089C037 
 
10 
 
 
  
 
(QTcF) at Screening or pre-
dose > 450 ms 
exclusion 
criterion 
9.2. 
Concomitant treatment 
(other than hormonal 
contraceptives for women 
of childbearing potential) is 
not permitted throughout 
the study. 
No medication other than 
the study products and 
hormonal contraception for 
women of childbearing 
potential is allowed during 
the study unless absolutely 
required for treatment of 
AEs. 
The use of any investigational 
drug is prohibited within 30 days 
before the first administration of 
cenobamate. The use of any 
prescription or over-the-counter 
drug (other than hormonal 
contraceptives for women of 
childbearing potential) is 
prohibited within less than 15 
days before the first 
administration of cenobamate, 
with the exception of 
vitamin/mineral supplements and 
the occasional use of 
acetaminophen, which is allowed 
up to 24 hours before dosing in 
any treatment period. 
Updated the 
language to allow 
for the as needed 
administration of 
acetaminophen as 
well as the timing 
of when 
acetaminophen 
can be 
administered 
10.5. 
Study drug will be 
administered orally in either 
tablet or solution 
formulation. 
Study drug will be administered 
orally in either tablet or 
suspension formulation. 
Updated language 
to reflect proper 
dosage form 
12.1. 
Safety assessments will 
include physical 
examination, vital signs, 
safety laboratory tests, 
continuous AE monitoring, 
and concomitant medication 
recording. Additional safety 
measurements may be 
performed at the discretion 
of the Investigator for 
reasons related to subject 
safety. 
Safety assessments will include 
physical examination, vital signs, 
safety laboratory tests, continuous 
AE monitoring, C-SSRS review 
and concomitant medication 
recording. Additional safety 
measurements may be performed 
at the discretion of the 
Investigator for reasons related to 
subject safety. 
Added C-SSRS 
review to 
harmonize with 
updated schedule 
of assessments 
12.1. 
1. Vital signs; 
2. PK blood sampling; 
3. Blood and urine sampling 
for safety laboratory assays; 
4. Physical examination. 
1. Vital signs; 
2. PK blood sampling; 
3. Blood and urine sampling for 
safety laboratory assays; 
4. Symptom oriented physical 
examination. 
Clarified type of 
physical exam 
12.1.3. 
Blood pressure, pulse rate, 
and respiratory rate will be 
measured after being in 
supine position for at least 
10 minutes. 
Blood pressure, pulse rate, and 
respiratory rate will be measured 
after being in supine position for 
at least 5 minutes. 
Updated supine 
position time 
requirement to 
allow for quicker 
assessment 


YKP3089 
 
Protocol No. YKP3089C037 
 
11 
 
 
  
 
12.1.4. 
Added a “Suicidality 
Assessment” section to address 
the added C-SSRS assessment 
Needed to add 
this section to 
harmonize with 
the updated 
schedule of 
assessments 
12.1.7. 
ECG will not be collected. ECG will be collected at 
screening and baseline only. A 
subject must be in the supine 
position for at least 10 mins prior 
to any ECG reading. An ECG 
may be repeated if necessary 
Updated language 
as ECG will in 
fact be collected 
at baseline and 
screening. 
12.1.8.3. 
Urine will not be collected 
in this study outside of 
pregnancy testing. 
Please refer to Table 8 for  
urinalysis assessments to be 
collected throughout the study at 
times specified in Table 4 
Updated language 
as urinalysis will 
be conducted per 
Table 8 and Table 
4 
12.1.8.8. 
Intrauterine device 
(placement at least 3 
months prior to the 
Screening visit) with 
appropriate medical 
documentation; 
Intrauterine device (placement at 
least 3 months prior to the 
Screening visit); 
Removed 
language to 
require 
appropriate 
medical 
documentation to 
add flexibility for 
the source of this 
assessment 
12.5.3. 
During Study Day 1, 
subjects will be provided a 
card with the following 
hypersensitivity information 
and will be instructed to 
carry with them at all times: 
During Study Day 4 (prior to 
discharge from CRU), subjects 
will be provided a card with the 
following hypersensitivity 
information and will be instructed 
to carry with them at all times: 
Updated timing to 
harmonize with 
schedule of 
assessments 
19. 
Cenobamate (YKP3089) 
Investigator’s Brochure, 
September 27, 2019 
(Version 13). 
Cenobamate (YKP3089) 
Investigator’s Brochure, October 
05, 2020 (Version 14). 
Updated to most 
recent version of 
the IB 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
12 
 
 
  
 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Clinical Trial Manager 
Steven Jolly 
SK Life Science, Inc. 
461 From Road, 5th Floor 
Paramus, NJ 07652 
Telephone: +1 (201) 500-6024 
Email: sjolly@sklsi.com 
Responsible Physician 
Marc Kamin, MD 
 
SK Life Science, Inc. 
461 From Road, 5th Floor 
Paramus, NJ 07652 
Telephone: +1 (201) 421-3830 
Mobile: +1 (201) 602-3235 
Email:  mkamin@sklsi.com 
Drug Safety Physician 
Marc Kamin, MD 
 
SK Life Science, Inc. 
461 From Road, 5th Floor 
Paramus, NJ 07652 
Telephone: +1 (201) 421-3830 
Mobile: +1 (201) 602-3235 
Email:  mkamin@sklsi.com 
24-Hour Emergency Contact 
Marc Kamin, MD 
 
SK Life Science, Inc. 
461 From Road, 5th Floor 
Paramus, NJ 07652  
Telephone: +1 (201) 421-3830 
Mobile: +1 (201) 602-3235 
Email: mkamin@sklsi.com 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
13 
 
 
  
 
2. 
SYNOPSIS 
Name of Sponsor/Company: SK Life Science, Inc. 
Name of Investigational Product: Cenobamate (YKP3089) 
Name of Active Ingredient: [(1R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate 
Protocol Number: YKP3089C037 
Phase: 1 
Country: USA 
Title of Study: Relative Bioavailability of a Single 200 mg Dose of Cenobamate Given as an Oral 
Tablet or as an Oral Suspension and the Effect of Food on a Single 200 mg Dose of Cenobamate 
Given as an Oral Suspension 
Study center(s): PRA Health Sciences, 1255 East 3900 South Salt Lake City, UT 84124 
Principal Investigator: Ahad Sabet, MD 
Studied Period (years): 2021 
Estimated date first patient enrolled: 11 January 2021 
Estimated date last patient completed: 21 March 2021 
Objectives:  
Primary:  
1. The relative bioavailability of 200 mg of cenobamate given as an oral tablet vs 200 mg of 
cenobamate given as an oral suspension in fasting condition and;  
2. The effect of food on the bioavailability of a 200 mg oral dose of cenobamate given as a 
suspension 
Secondary:  
• 
The secondary objective of this study is to assess the safety and tolerability of a single 
200 mg dose of cenobamate given as either an oral tablet in fasting condition or an oral 
suspension in fasting and fed conditions 
Study Design:  
• 
This study is an open-label, randomized, single-dose, single-center, three-period, six-
sequence, balanced crossover study in healthy male and female subjects to assess the 
relative bioavailability of 200 mg of  cenobamate given as an oral tablet or oral 
suspension and to evaluate the effect of food on the bioavailability of a 200 mg dose of 
cenobamate given as an oral suspension in fasting and fed conditions. 
Endpoints: 
Primary Endpoints:   
Pharmacokinetic assessment for cenobamate in plasma 
• 
Cmax: Maximum observed plasma concentration 
• 
tmax: Time to reach Cmax  
• 
AUClast: AUC from the time of dosing to the time of the last measurable concentration 
• 
AUC∞: AUC from time 0 extrapolated to infinity 


YKP3089 
 
Protocol No. YKP3089C037 
 
14 
 
 
  
 
Secondary Endpoints:  
Safety and Tolerability 
• 
Adverse events (AEs) 
• 
Safety laboratory tests (including clinical chemistry, hematology, coagulation and 
urinalysis) 
• 
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature) 
• 
Physical examination 
Further Endpoints: 
Pharmacokinetic assessment for cenobamate in plasma 
• 
AUC%extrap: Percentage of the AUC that was extrapolated 
• 
Clast: Last quantifiable concentration 
• 
t½: Terminal half-life 
• 
CL/F: Oral clearance 
• 
λz: Terminal rate constant 
• 
Vz/F: Apparent volume of distribution during terminal phase 
Number of Subjects: 24  
Subjects will be balanced amongst gender and ethnic groups to the extent possible. A subject who 
prematurely ends the study and who received treatment may be replaced. In case of discontinuation 
related to an adverse event, the replacement will be discussed between the Investigator and SKLSI. 
Main Inclusion Criteria:  
1. Male or female subjects of 18 to 50 years of age (inclusive), at the time of screening 
2. Able to read, understand, sign, and date a written informed consent form (ICF) before study 
participation at screening 
3. Agree to use effective methods of contraception as described in Section 12.1.7.8 and 
Section 12.1.7.9. 
4. Body mass index (BMI) between 18.5 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. 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. 
7. Able to understand and comply with protocol requirements and instructions and likely to 
complete the study as planned 
8. Females 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., bilateral tubal ligation or bilateral salpingectomy or hysterectomy), or be 


YKP3089 
 
Protocol No. YKP3089C037 
 
15 
 
 
  
 
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 
Investigational product, dosage and mode of administration:  
• 
Active Substance: Cenobamate (YKP3089) 
• 
Activity: Reducer of repetitive neuronal firing by enhancing the fast and slow 
inactivation of sodium channels and by inhibiting the persistent component of the sodium 
current. A positive allosteric modulator of six subtypes of the γ-aminobutyric acid 
(GABAA) ion channel. 
• 
Strength: 200 mg oral tablets or 200 mg (10 mg/mL) oral suspension 
• 
Dosage Form: Tablet or Suspension 
• 
Manufacturer (tablets): Manufactured by Patheon, Whitby, Canada for SK Life Science, 
Inc. 
• 
Manufacturer (suspension): Manufactured by CoreRx, Florida, USA for SK Life Science, 
Inc. 
Study Treatment:  
• 
Treatment A: Oral Dose of cenobamate administered as a single 200 mg tablet on Day 1 
under fasted conditions  
• 
Treatment B: Oral Dose of cenobamate administered as a single 200 mg/20 mL 
suspension on Day 1 under fasted conditions 
• 
Treatment C: Oral Dose of cenobamate administered at a single 200 mg/20 mL 
suspension on Day 1 under fed conditions 
Study Population: Healthy Volunteers 
Study Schedule: 
The study consists of a 28-day screening period, followed by single dose administration of 
cenobamate (tablet or suspension) on Day 1, Day 22, and Day 43, an assessment period of 62 days 
and a follow-up visit on Day 69. All subjects will be confined to the clinical site from Day -1 (the day 
before period 1 dosing) until the morning of Day 4, Day 20 (the day of the last PK sampling for 
period 1) until the morning of Day 25, and Day 41 (the day of the last PK sampling for period 2) until 
the morning of Day 46. Outpatient visits will be performed regularly until the 456-hour PK sampling 
for each period (See Table 4). The follow-up visit will occur on Day 69 (±1 day). 
 
Screening:  
All subjects will be screened within 28 days up to 2 days prior to the study drug administration 
 
Admission:  
Admission in the clinical unit will occur in the morning of Day -1 for Period 1, Day 20 for end of 
Period 1 and beginning of Period 2 and Day 41 for end of Period 2 and beginning of Period 3. All 
subjects will be admitted in a fasted state 


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Protocol No. YKP3089C037 
 
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Assessment Period:  
The study drug will be administered in the morning of Day 1, Day 22, and Day 43 for Period 1, 
Period 2, and Period 3, respectively. Study drug will be administered after all pre-dose 
assessments have been completed. The subjects will stay at the clinical site until Day 4, Day 25, 
and Day 46 for Period 1, Period 2, and Period 3, respectively. The subjects will be discharged 
after completion of all scheduled assessments. Outpatient visits will be performed as outlined in 
Table 4.  
 
Follow-up:  
A follow-up visit will be performed on Day 69 (±1 day) 
 
Refer to the Schedule of Assessments (Table 4) for further details. 
Reference therapy, dosage and mode of administration:  
Treatment A: Oral Dose of cenobamate administered as a single 200 mg tablet on Day 1 under fasted 
conditions 
Treatment B: Oral Dose of cenobamate administered as a single 200 mg/20 mL suspension on Day 1 
under fasted conditions 
Treatment C: Oral Dose of cenobamate administered as a single 200 mg/20 mL suspension on Day 1  
under fed conditions 
Evaluation: 
Pharmacokinetics:  
Serial blood samples for PK assessments will be sampled at various time points from Day 1, Day 22, 
and Day 43 starting at pre-dose through 456 hours (20 days) following oral administration of 
cenobamate tablets or suspension (See Table 4). 
The PK samples may be used for additional exploratory PK and/or metabolite analyses. 
Descriptive statistics and graphs will be generated for plasma concentrations and PK parameters for 
each treatment.  
The formulation effect will be tested for: Cenobamate oral suspension administered under fed and 
fasting conditions and cenobamate oral tablet administered under fasting conditions. These analyses 
will be conducted separately on Cmax, AUClast and AUC∞ using a mixed model on the log 
transformed data with treatment, sequence and period as fixed effects and subject within sequence as 
random effect. Geometric mean ratios (GMRs) will be computed for: 
1. Cenobamate oral suspension administered under fasted conditions versus cenobamate oral 
tablet administered under fasting conditions 
2. Cenobamate oral suspension administered under fed conditions versus cenobamate oral 
suspension administered under fasting conditions 
Additionally, for the above comparisons, the corresponding 90% confidence intervals (90% CIs) will 
be calculated. No formulation effect or food interaction will be concluded when the 90% CIs are 
within the reference range [0.80 – 1.25]. For each subject, the Wilcoxon signed-rank test will be used 
to test for differences in tmax. 
 
 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
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Safety:  
Safety data will be summarized with descriptive statistics and frequency tables. AEs will be coded 
using MedDRA. Prior and concomitant medications will be listed using WHO Drug Dictionary 
Enhanced™ (WHO DDE). Data listings and tabulations will be generated for all safety assessments. 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
AMENDMENT 1 SUMMARY OF CHANGES .............................................................................4 
PROCEDURES IN CASE OF EMERGENCY .............................................................................12 
2. 
SYNOPSIS .................................................................................................................13 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Background .................................................................................................................29 
5.1.1. 
Non-Clinical Experience ............................................................................................29 
5.1.2. 
Clinical Human Experience ........................................................................................29 
5.1.2.1. 
Clinical Pharmacokinetics ..........................................................................................29 
5.1.2.2. 
Clinical Safety ............................................................................................................30 
5.2. 
Benefit-Risk Assessment ............................................................................................31 
5.3. 
Rationale for Present Study ........................................................................................32 
5.3.1. 
Study Design Rationale ..............................................................................................32 
5.3.2. 
Anticipated Pharmacokinetic Behavior ......................................................................32 
5.3.2.1. 
Food Effect on Cenobamate Suspension ....................................................................32 
5.3.2.2. 
Relative Bioavailability Between Cenobamate Suspension and Cenobamate 
Tablet ..........................................................................................................................32 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................33 
6.1. 
Primary Objective .......................................................................................................33 
6.2. 
Secondary Objectives .................................................................................................33 
6.3. 
Endpoints ....................................................................................................................33 
6.3.1. 
Primary Endpoints ......................................................................................................33 
6.3.2. 
Secondary Endpoints ..................................................................................................33 
6.3.3. 
Further Endpoints .......................................................................................................33 
7. 
INVESTIGATIONAL PLAN .....................................................................................34 
7.1. 
Overall Study Design ..................................................................................................34 


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7.1.1. 
Visits ...........................................................................................................................40 
7.1.1.1. 
Visit 1 (Screening) ......................................................................................................40 
7.1.1.2. 
Visit 2 (Baseline) (Beginning Day -1) ........................................................................40 
7.1.1.3. 
Visit 3 (Morning of Day 6) .........................................................................................40 
7.1.1.4. 
Visit 4 (Morning of Day 9) .........................................................................................41 
7.1.1.5. 
Visit 5 (Morning of Day 12) .......................................................................................41 
7.1.1.6. 
Visit 6 (Morning of Day 16) .......................................................................................41 
7.1.1.7. 
Visit 7 (Beginning on the Morning of Day 20) ..........................................................41 
7.1.1.8. 
Visit 8 (Morning of Day 27) .......................................................................................42 
7.1.1.9. 
Visit 9 (Morning of Day 30) .......................................................................................42 
7.1.1.10. 
Visit 10 (Morning of Day 33) .....................................................................................42 
7.1.1.11. 
Visit 11 (Morning of Day 37) .....................................................................................42 
7.1.1.12. 
Visit 12 (Beginning on the Morning of Day 41) ........................................................43 
7.1.1.13. 
Visit 13 (Morning of Day 48) .....................................................................................43 
7.1.1.14. 
Visit 14 (Morning of Day 51) .....................................................................................43 
7.1.1.15. 
Visit 15 (Morning of Day 54) .....................................................................................43 
7.1.1.16. 
Visit 16 (Morning of Day 58) .....................................................................................44 
7.1.1.17. 
Visit 17 (Morning of Day 62) .....................................................................................44 
7.1.1.18. 
Visit 18 Follow-Up (Day 69) ......................................................................................44 
7.2. 
Number of Subjects ....................................................................................................44 
7.3. 
Treatment Assignment ................................................................................................44 
7.3.1. 
Methods for Treatment Group Assignment ................................................................45 
7.3.2. 
Allocation of Subject Numbers ..................................................................................45 
7.4. 
Dose Adjustment Criteria ...........................................................................................45 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................45 
7.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................46 
7.5. 
Criteria for Study Termination ...................................................................................46 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................47 
8.1. 
Subject Inclusion Criteria ...........................................................................................47 
8.2. 
Subject Exclusion Criteria ..........................................................................................47 
8.3. 
Subject Withdrawal Criteria .......................................................................................49 
8.3.1. 
Withdrawn Subject Data Collection ...........................................................................49 
8.3.2. 
Lost to Follow-Up.......................................................................................................49 


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8.3.3. 
Replacement of Subjects .............................................................................................50 
9. 
TREATMENT OF SUBJECTS ..................................................................................51 
9.1. 
Description of Study Drug ..........................................................................................51 
9.2. 
Concomitant Medications ...........................................................................................51 
9.2.1. 
Prior Treatments .........................................................................................................51 
9.3. 
Treatment Compliance ................................................................................................52 
9.3.1. 
Lifestyle Guidelines ....................................................................................................52 
9.3.1.1. 
Meals and Dietary Restrictions ...................................................................................52 
9.3.1.2. 
Alcohol, Caffeine, and Tobacco .................................................................................52 
9.3.1.3. 
Physical Activity .........................................................................................................53 
9.4. 
Randomization and Blinding ......................................................................................53 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................54 
10.1. 
Study Drug ..................................................................................................................54 
10.1.1. 
Cenobamate Oral Tablet .............................................................................................54 
10.1.2. 
Cenobamate Oral Suspension .....................................................................................54 
10.2. 
Study Drug Packaging and Labeling ..........................................................................54 
10.3. 
Study Drug Storage .....................................................................................................54 
10.4. 
Study Drug Preparation ..............................................................................................54 
10.5. 
Administration ............................................................................................................55 
10.5.1. 
Timing of Doses in the Study .....................................................................................55 
10.5.1.1. 
Timing of Doses for Treatment A and Treatment B ...................................................55 
10.5.1.2. 
Timing of Doses for Treatment C ...............................................................................55 
10.5.2. 
High-Calorie, High-Fat Meal for Treatment C ...........................................................55 
10.6. 
Study Drug Accountability .........................................................................................56 
10.7. 
Study Drug Handling and Disposal ............................................................................56 
11. 
PHARMACOKINETIC ASSESSMENTS .................................................................57 
11.1. 
Blood Sample Collection ............................................................................................57 
11.2. 
Urine Sample Collection .............................................................................................58 
11.3. 
Sample Analysis .........................................................................................................58 
11.3.1. 
Sample Processing and Handling for PK Assessment ................................................58 
11.3.2. 
Bioanalysis ..................................................................................................................58 
11.3.3. 
Exploratory Pharmacogenomic Assessments .............................................................58 
12. 
ASSESSMENT OF SAFETY .....................................................................................59 


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12.1. 
Safety Parameters .......................................................................................................59 
12.1.1. 
Adverse Events ...........................................................................................................59 
12.1.2. 
Demographic/Medical History ...................................................................................60 
12.1.3. 
Vital Signs ..................................................................................................................60 
12.1.4. 
Suicidality Assessment ...............................................................................................60 
12.1.5. 
Weight and Height ......................................................................................................60 
12.1.6. 
Physical Examination .................................................................................................60 
12.1.7. 
Electrocardiogram (ECG) ...........................................................................................61 
12.1.8. 
Laboratory Assessments .............................................................................................61 
12.1.8.1. 
Hematology .................................................................................................................62 
12.1.8.2. 
Blood Chemistry .........................................................................................................62 
12.1.8.3. 
Urinalysis ....................................................................................................................62 
12.1.8.4. 
Virus Serology ............................................................................................................62 
12.1.8.5. 
Drug Screen ................................................................................................................63 
12.1.8.6. 
Additional Tests ..........................................................................................................63 
12.1.8.7. 
Pregnancy ...................................................................................................................63 
12.1.8.8. 
Contraception for Female Subjects .............................................................................63 
12.1.8.9. 
Contraception for Male Subjects ................................................................................64 
12.2. 
Adverse and Serious Adverse Events .........................................................................64 
12.2.1. 
Definitions of Adverse Events ....................................................................................65 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................65 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................65 
12.2.1.3. 
Severity Assessment ...................................................................................................66 
12.2.1.4. 
Causality Assessment .................................................................................................67 
12.3. 
Relationship to Study Drug ........................................................................................67 
12.4. 
Recording Adverse Events .........................................................................................68 
12.5. 
Reporting Adverse Events ..........................................................................................68 
12.5.1. 
Routine Reporting .......................................................................................................68 
12.5.2. 
Serious Adverse Reporting .........................................................................................69 
12.5.3. 
Rash/Hypersensitivity/DRESS Syndrome ..................................................................71 
13. 
STATISTICS ..............................................................................................................73 
13.1. 
Statistical and Analytical Plans ..................................................................................73 
13.1.1. 
Sample Size and Power ..............................................................................................73 


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13.1.2. 
Analysis Populations ..................................................................................................73 
13.1.3. 
Pharmacokinetic Analysis ..........................................................................................73 
13.1.3.1. 
Pharmacokinetic Parameters .......................................................................................73 
13.1.3.2. 
Formulation and Food Effect Analysis .......................................................................74 
13.1.3.3. 
Analysis on Tmax .........................................................................................................74 
13.1.3.4. 
Summary and Presentation of PK Data and Parameters in the CSR ..........................74 
13.2. 
Other Statistical Analyses ...........................................................................................75 
13.2.1. 
Efficacy Analysis ........................................................................................................75 
13.2.2. 
Safety Analysis ...........................................................................................................75 
13.2.3. 
Adverse Events ...........................................................................................................75 
13.2.4. 
Clinical Laboratory Assessments ...............................................................................75 
13.2.5. 
Vital Signs ..................................................................................................................75 
13.2.6. 
Physical Examinations ................................................................................................75 
13.2.7. 
Demographic Data ......................................................................................................75 
13.2.8. 
Baseline Characteristics and Other Data ....................................................................76 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................77 
14.1. 
Study Monitoring ........................................................................................................77 
14.2. 
Audits and Inspections ................................................................................................77 
14.2.1. 
Electronic Data Capture (EDC) ..................................................................................77 
14.2.2. 
Case Report Forms .....................................................................................................78 
14.3. 
Institutional Review Board (IRB) ...............................................................................78 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 
16. 
ETHICS ......................................................................................................................80 
16.1. 
Ethics Review .............................................................................................................80 
16.2. 
Ethical Conduct of the Study ......................................................................................80 
16.2.1. 
Subject Information and Informed Consent ...............................................................80 
16.2.2. 
Investigator Compliance .............................................................................................80 
16.2.3. 
Access to Records .......................................................................................................81 
16.2.4. 
Subject Privacy ...........................................................................................................81 
16.3. 
Written Informed Consent ..........................................................................................81 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................82 
17.1. 
Inspection of Records .................................................................................................82 
17.2. 
Retention of Records ..................................................................................................82 


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17.2.1. 
Screening ....................................................................................................................82 
17.2.2. 
Data Quality Assurance ..............................................................................................82 
17.2.3. 
Investigator Documentation Responsibilities .............................................................83 
18. 
PUBLICATION POLICY ..........................................................................................84 
18.1. 
Publication of Study Results .......................................................................................84 
18.2. 
Clinical Study Report .................................................................................................84 
19. 
LIST OF REFERENCES ............................................................................................85 
20. 
APPENDICES ............................................................................................................86 
 
 
. 


YKP3089 
 
Protocol No. YKP3089C037 
 
24 
 
 
  
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information .................................................................................12 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................26 
Table 3: 
Randomized and Balanced Crossover Design ............................................................34 
Table 4: 
Schedule of Assessments ............................................................................................37 
Table 5: 
Investigational Product ...............................................................................................51 
Table 6: 
Acceptable Time Windows for PK Blood Sampling ..................................................57 
Table 7: 
Blood Volume to be Collected per Subject for Drug Plasma Concentration 
Analysis After a Single Dose of Cenobamate (456 Hours) ........................................57 
Table 8: 
Clinical Laboratory Tests ...........................................................................................61 
Table 9: 
Blood Volume to be Withdrawn During the Conduct of the Study ...........................62 
Table 10: General Descriptions of Severity Scale ......................................................................66 
Table 11: Definitions of Causality Assessment ..........................................................................67 
Table 12: Contact Information for IQVIA ..................................................................................70 
Table 13: Contact Information for Sponsor Medical Monitor ....................................................70 
Table 14: Contact Information for PRA Principal Investigator ..................................................70 
Table 15: Serious Adverse Event Reporting Requirement .........................................................70 
Table 16: Primary Pharmacokinetic Parameters .........................................................................74 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
25 
 
 
  
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................36 
 


YKP3089 
 
Protocol No. YKP3089C037 
 
26 
 
 
  
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ANOVA 
Analysis of Variance 
AUC 
Area under the concentration-time curve 
AUC24h 
AUC from the time of dosing to the time of the last 
observation (24 h post-dose) 
AUC∞ 
AUC from time 0 extrapolated to infinity 
AUClast 
AUC from the time of dosing to the time of the last 
measurable concentration 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL/F 
Oral clearance 
CLcr 
Renal creatinine clearance 
Cmax 
Maximum observed plasma concentration 
CNS 
Central Nervous System 
CPAP 
Clinical Pharmacology Analysis Plan 
CPK 
Creatine Phosphokinase 
CPMP 
Committee for Proprietary Medicinal Products; 
Current name: Committee for Medicinal Products for 
Human Use (CHMP) 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interactions 


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Protocol No. YKP3089C037 
 
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Table 2: 
Abbreviations and Specialist Terms  (Continued) 
Abbreviation or Specialist Term 
Explanation 
DNA 
Deoxyribonucleic Acid 
DRESS 
Drug Reaction with Eosinophilia and Systemic Symptoms 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GABA 
Gamma-aminobutyric Acid 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LC-MS/MS 
Liquid Chromatography with Tandem Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
POS 
Partial Onset Seizures 


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Table 2: 
Abbreviations and Specialist Terms  (Continued) 
Abbreviation or Specialist Term 
Explanation 
PT 
Prothrombin Time; Preferred Term 
QA 
Quality Assurance 
QC 
Quality Control 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia correction  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SD 
Standard Deviation 
SI 
International System of units 
SKLSI 
SK Life Science, Inc. 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal half-life 
TEAE 
Treatment-Emergent Adverse Event 
tmax  
Time at maximum concentration 
UGT 
Uridine 5'-diphospho-glucuronosyltransferase 
ULN 
Upper Limit of Normal 
US 
United States 
USCS 
United States Customary System 
Vz/F 
Apparent volume of distribution during terminal phase 
λz 
Terminal rate constant 
 


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Protocol No. YKP3089C037 
 
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5. 
INTRODUCTION 
5.1. 
Background 
Cenobamate (YKP3089) is a small molecule approved in the United States (US) for the 
treatment of partial onset seizures (POS) in adult patients. 
Refer to the most recent version of the Investigator’s Brochure (IB)1 of cenobamate for more 
details.  
5.1.1. 
Non-Clinical Experience 
Non-clinical testing of cenobamate suggests a broad spectrum of antiepileptic effects, as well as 
therapeutic potential for treatment of neuropathic pain, and possible future investigations for 
treatment of anxiety. In in vitro electrophysiology assays, cenobamate was shown to be an 
inhibitor of the fast and slow inactivated state and persistent current of sodium channels and to 
be a positive allosteric modulator of 6 GABAA ion channel subtypes (α1β2γ2, α2β3γ2, α3β3γ2, 
α4β3γ2, α5β3γ2 and α6β3γ2). 
Cenobamate has been assessed in a large number of safety pharmacology and toxicology studies 
including single-dose toxicity, repeat-dose toxicity, cardiotoxicity, genetic toxicity, reproductive 
toxicity, and carcinogenicity in animals. Safety pharmacology studies showed that the doses that 
produced beneficial central nervous system (CNS) effects of cenobamate in animal models do 
not result in obvious negative effects on the CNS. No evidence of cardiovascular effects was 
observed by telemetric electrocardiography in male monkeys. There was no carcinogenic 
potential for cenobamate in transgenic rasH2 mice or Sprague Dawley rats. 
Cenobamate is extensively metabolized. The primary metabolic pathways are by glucuronidation 
via UGT2B7 and to a lesser extent by UGT2B4, and by oxidation via CYP2E1, CYP2A6, 
CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5. 
5.1.2. 
Clinical Human Experience 
To date, approximately 2500 subjects have been exposed to cenobamate in the clinical 
development program. For further details about the completed and ongoing clinical studies, 
please refer to the most recent version of the Investigator Brochure1.  
5.1.2.1. 
Clinical Pharmacokinetics 
In humans, the pharmacokinetics (PK) of cenobamate has been studied after both single dose and 
multiple dosing in healthy subjects. The PK of cenobamate in plasma appears to be non-
proportional after single oral doses ranging from 5 to 750 mg and multiple dosing ranging from 
50 to 500 mg/day. Maximum plasma concentration of cenobamate was generally observed 
between 1- and 4-hours post dosing and a longer terminal half-life was observed as the 
cenobamate dose was increased (approximately 30 hours at 5-10 mg to approximately 76 hours 
at 750 mg). Steady state is generally achieved after 2 weeks of treatment with once daily dosing 
of cenobamate, and the accumulation of cenobamate in plasma over the 50-300 mg dose range 
was approximately 5-fold based on total exposure (AUC).2 
Cenobamate is extensively metabolized and primarily eliminated in the urine (88% of the dose).3 
The disposition of cenobamate following tablet administration is not affected by food. The intra-


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subject variability of cenobamate in healthy subjects is relatively low (about 14% for Cmax and 4-
5% for AUCs). No pharmacokinetic difference was observed for cenobamate between Japanese 
and non-Japanese healthy subjects. 
Multiple drug-drug interaction (DDI) studies were performed in healthy subjects. The 
coadministration of carbamazepine, divalproex and oral contraceptives did not significantly 
modify the PK of cenobamate whereas the coadministration of phenobarbital and phenytoin 
significantly decreased cenobamate plasma exposure (AUC) by approximately 15% and 28%, 
respectively. The coadministration of cenobamate significantly decreased carbamazepine plasma 
exposure (AUC) by approximately 25-35%, and increased phenobarbital and phenytoin plasma 
exposures (AUC) by approximately 37% and 84%, respectively. The coadministration of 
cenobamate with oral contraceptives did not significantly modify ethinylestradiol plasma 
exposure (AUC) but increased slightly the exposure to norethindrone by approximately 37% for 
cenobamate oral doses up to 100 mg/day. 
After the administration of a CYP450 probe cocktail with cenobamate in healthy subjects, the 
results showed that a 200 mg daily dose of cenobamate induced the activity of CYP2B6 and 
inhibited the activity of CYP2C19. For CYP3A, cenobamate exhibited a limited induction at 100 
mg/day whereas a more marked induction was observed at 200 mg/day. No significant effect of 
cenobamate was observed on CYP2C9 activity at 200 mg/day. 
The effect of renal impairment on the PK of cenobamate led to an increase in plasma exposure to 
cenobamate by 1.4-fold and 1.5-fold in mild and moderate renal impaired subjects, respectively. 
The effect of hepatic impairment on the PK of cenobamate led to an increase in plasma exposure 
to cenobamate by 1.9-fold and 2.3-fold in mild and moderate hepatic impaired subjects, 
respectively. No clinical meaningful effect of sex or age is expected on the PK of cenobamate. 
5.1.2.2. 
Clinical Safety 
Cenobamate at oral doses of 100 mg and 200 mg/day was generally well tolerated with a 
predictable and consistent adverse event (AE) profile. Cenobamate at a dose of 400 mg/day 
required more frequent dose reductions because of CNS related AEs and resulted in a higher 
frequency of discontinuations due to AEs. The median of the modal dose in the 400 mg arm of 
Study YKP3089C017 was 300 mg/day. Adverse events (AEs) resolved upon discontinuation of 
cenobamate. 
The most common adverse events (AEs) reported with cenobamate in adults were mild to 
moderate in severity. CNS-related AEs were dose dependent, with higher incidence reported at 
higher doses. Adverse reactions due to cenobamate may include somnolence, dizziness, fatigue, 
headache, diplopia, nausea, nystagmus, balance disorder, and gait ataxia. These adverse reactions 
were mild to moderate in severity and resolved spontaneously upon discontinuation of treatment. 
SAEs considered at least possibly related to cenobamate included drug reaction with eosinophilia 
and systemic reaction, dizziness, vertigo, ataxia, dysarthria, nystagmus (2 subjects), and suicidal 
ideation (2 subjects). A complete list of all SAEs during the cenobamate development program is 
available in the IB.1 The SAEs reported with cenobamate reflect an expected pattern with 
therapy with multiple AEDs. 
In subjects taking cenobamate, the most common serious AEs (SAEs) were CNS related such as 
hospitalization for seizures, ataxia and dizziness particularly at higher dosages. These serious 


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adverse events have been readily clinically identifiable. The general nature of these SAEs 
reflects an expected pattern in subjects with epilepsy. 
Adverse events (AEs) of special interest that emerged during the cenobamate development 
program include rash and hypersensitivity reactions (including three cases of DRESS syndrome) 
with elevations of hepatic enzymes. Drug-induced hypersensitivity reactions with or without 
multi organ involvement (allergic reactions which may be fatal) including DRESS syndrome 
have been seen in patients taking cenobamate. DRESS which has occurred in <0.5% of clinical 
trial participants taking cenobamate stands for Drug Reaction (or Rash) with Eosinophilia and 
Systemic Symptoms. This condition occurs usually in the first 8 weeks after initiation of 
treatment and rarely happens afterwards. In a large open label safety trial of 1339 subjects 
exposed to cenobamate at an initial dose of 12.5mg/day and titrated every two weeks to a 
maximum dose of 400mg /day no cases of DRESS were identified. 
Although two cases of highly elevated hepatic enzymes were identified, there were no cases that 
met the criteria for Hy’s Law and review of the cenobamate safety database revealed that the 
incidence of 3X upper limit of normal (ULN) elevation of alanine aminotransferase (ALT) did not 
meet the criteria for the Rezulin Rule. One of the subjects with highly elevated hepatic enzymes 
died of multi-organ failure with pancreatic, cardiac and pulmonary failure approximately one 
year after starting cenobamate and one month after initiating eslicarbazepine. Final diagnosis 
was sepsis. The other case had elevated hepatic enzymes in conjunction with DRESS syndrome. 
Hepatic enzymes are carefully monitored in all clinical trials. 
It is known that antiepileptic drugs increase the risk of suicidal thoughts or behavior in patients 
taking these drugs for any indication. Although isolated reports of suicidal thoughts and behavior 
have been reported in studies with cenobamate, the relationship between them and cenobamate 
has not been confirmed. Patients treated in cenobamate studies are monitored for the emergence 
or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood 
or behavior. 
A complete list of all SAEs during the cenobamate development program is included in the 
current version of the IB1. The general nature of these SAEs reflects an expected pattern in 
subjects with epilepsy. 
5.2. 
Benefit-Risk Assessment 
This Phase 1 study in healthy volunteers has no direct benefit to the participating subjects. 
The results of two adequate and well-controlled studies demonstrated that 100, 200 and 400 
mg/day of cenobamate are effective for the treatment of partial onset seizures. The most common 
AEs were nervous system and gastrointestinal disorders. Adverse events were consistent, 
predictable, and dose related. The primary safety issue identified was DRESS syndrome. Using a 
low starting dose and titration every two weeks appears to have mitigated this issue. 
Additionally, DRESS has not been reported in any cenobamate single dose study to date. These 
safety issues are readily identifiable with a predictable course and resolved with discontinuation 
of cenobamate. Safety profile of cenobamate is comparable with other drugs in this class. 
Considering the measures taken to minimize risks to patients participating in clinical trials, the 
potential risks identified in association with cenobamate are justified by the anticipated benefits 
that may be afforded to patients with partial onset epilepsy. 


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Any subject who reports a rash or has a developing cutaneous reaction should be carefully 
evaluated for a drug hypersensitivity syndrome. The evaluation should include hematology and 
chemistry blood tests. If a subject reports a rash by telephone, an unscheduled visit should be 
performed as soon as possible. Investigators and coordinators must remind study subjects about 
the possibility of allergic reaction including rash. 
Hepatic enzymes will be carefully monitored to detect any potential liver toxicity. 
The subjects in this clinical study will receive single oral doses of 200 mg of cenobamate at 3 
occasions in fasting or fed conditions administered as either a tablet or suspension formulation. 
Thus, the overall risk to the subjects enrolled in this study is deemed acceptable. Nevertheless, 
the subjects will be closely monitored using frequent clinical laboratory investigations and a 
continuous observation of their well-being. 
5.3. 
Rationale for Present Study 
5.3.1. 
Study Design Rationale 
A new oral suspension formulation of cenobamate has recently been developed and will be used 
to support the cenobamate pediatric clinical program. Since a suspension formulation has not 
been used in any clinical trials to date, the pharmacokinetics (PK) of the suspension formulation 
will be investigated and compared to tablet formulation. The relative BA assessment between 
these 2 formulations will be performed using a single 200 mg dose of cenobamate. Additionally, 
a food effect on the PK of the suspension formulation will be evaluated in this study. These 2 
assessments with the suspension formulation will provide the needed information to use 
appropriately the oral suspension formulation in future clinical studies conducted in pediatric 
populations. 
5.3.2. 
Anticipated Pharmacokinetic Behavior 
5.3.2.1. 
Food Effect on Cenobamate Suspension 
A previous clinical study conducted in healthy volunteers assessing the relative bioavailability of 
an oral tablet formulation of cenobamate administered in fasting and fed conditions showed no 
statistically significant difference in the pharmacokinetics of cenobamate between the fed and 
fasted populations. As such, it is expected that the disposition of cenobamate will be comparable 
with the suspension formulation. 
5.3.2.2. 
Relative Bioavailability Between Cenobamate Suspension and Cenobamate 
Tablet 
The disposition of cenobamate has been previously studied after the administration of different 
oral formulations (capsule and tablet). No statistically significant differences were observed in 
the pharmacokinetics of cenobamate between these formulations. However, an oral suspension 
of cenobamate has not been tested in clinical studies to date. Therefore, the disposition of 
cenobamate as an oral liquid formulation is unknown. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objectives of this study are to assess (1) the relative bioavailability of 200 mg of 
cenobamate given as an oral tablet vs 200 mg of cenobamate given as an oral suspension in 
fasting condition and (2) the effect of food on the bioavailability of a 200 mg oral dose of 
cenobamate given as a suspension. 
6.2. 
Secondary Objectives 
The secondary objective of this study is to assess the safety and tolerability of a single 200 mg 
dose of cenobamate given as either an oral tablet in fasting condition or an oral suspension in 
fasting and fed conditions. 
6.3. 
Endpoints 
6.3.1. 
Primary Endpoints 
The following primary cenobamate PK endpoints will be determined for each subject as the data 
permits: 
• AUC∞: The AUC from time 0 extrapolated to infinity  
• AUClast: AUC from time of dosing to the time of the last measurable concentration, 
and  
• Cmax: Maximum plasma concentration 
6.3.2. 
Secondary Endpoints 
The following secondary safety endpoints will be collected for each subject: 
• Physical examination (PE) 
• Adverse events (AEs) 
• Vital signs 
• Clinical laboratory safety tests including hematology 
6.3.3. 
Further Endpoints 
The following additional PK endpoints will be determined for each subject as the data permits: 
• t½: Terminal half-life 
• tmax: Time to maximum cenobamate plasma concentration 
• CL/F: Oral clearance 
• λz: Terminal rate constant 
• Vz/F: Apparent volume of distribution during terminal phase 
• Clast: Last observed cenobamate plasma concentration 
Additional PK parameters may be calculated as deemed appropriate. A complete list of all PK 
parameters will be provided in the Clinical Pharmacology Analysis Plan (CPAP). 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is an open-label, randomized, single-dose, single-center, three-period, six-sequence, 
balanced crossover study in which healthy subjects, balanced amongst gender and ethnic groups 
to the extent possible, will receive either a single oral 200 mg dose of cenobamate given as a 
tablet under fasted conditions (Treatment A), a single oral 200 mg dose of cenobamate given as 
an oral suspension under fasted conditions (Treatment B), or a single oral 200 mg dose of 
cenobamate given as an oral suspension under fed conditions (Treatment C). All subjects will be 
screened to ensure that inclusion and exclusion criteria are met. The study will be explained to 
each subject prior to providing written informed consent. 
The study will consist of a screening period followed by a dosing period where each subject will 
be randomized into one of six sequences in Table 3. 
Table 3: 
Randomized and Balanced Crossover Design 
 
Treatment Sequence 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
C 
B 
A 
5 
A 
C 
B 
6 
B 
A 
C 
 
The study will be conducted in three periods each with single dose followed by a 21-day washout 
during which PK samples will be taken. The study periods will be conducted as follows: 
Period 1 
• Day -1 to Day 4 (morning) – Subject Confinement 
• Day 1 – Dosing 
• Day 6 (morning) – Subjects return to clinic for 120-hour PK sample and medical 
check 
• Day 9 (morning) – Subject to return to clinic for 192-hour PK sample and medical 
check 
• Day 12 (morning) – Subject to return to clinic for 264-hour PK sample and medical 
check 
• Day 16 (morning) – Subject to return to clinic for 360-hour PK sample and medical 
check 
• Day 20 (morning) – Subject to return to clinic for 456-hour PK sample and medical 
check and begin confinement for Period 2 


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Period 2 
• Day 20 to Day 25 (morning) – Subject Confinement 
• Day 22 – Pre-dose PK Sample and Dosing 
• Day 27 (morning) – Subjects return to clinic for 120-hour PK sample and medical 
check 
• Day 30 (morning) – Subject to return to clinic for 192-hour PK sample and medical 
check 
• Day 33 (morning) – Subject to return to clinic for 264-hour PK sample and medical 
check 
• Day 37 (morning) – Subject to return to clinic for 360-hour PK sample and medical 
check 
• Day 41 (morning) – Subject to return to clinic for 456-hour PK sample and medical 
check and begin confinement for Period 3 
Period 3 
• Day 41 to Day 46 (morning) – Subject Confinement 
• Day 43 – Pre-dose PK Sample and Dosing 
• Day 48 (morning) – Subjects return to clinic for 120-hour PK sample and medical 
check 
• Day 51 (morning) – Subject to return to clinic for 192-hour PK sample and medical 
check 
• Day 54 (morning) – Subject to return to clinic for 264-hour PK sample and medical 
check 
• Day 58 (morning) – Subject to return to clinic for 360-hour PK sample and medical 
check 
• Day 62 (morning) – Subject to return to clinic for 456-hour PK sample and medical 
check 
Follow-Up 
• Day 69 ± 1 day (morning) – Subject to return to clinic for follow-up visit 
The study design is outlined in Figure 1. 


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Figure 1: 
Study Design   
 
 
 
 
 
 


YKP3089 
 
Protocol No. YKP3089C037 
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Table 4: Schedule of Assessments 
 
 
Assessment 
Screening 
Base 
Treatment Period 
FU 
Visit(s) 
1 
2,7,12j 
3,8, 
13 
4,9, 
14 
5,10, 
15 
6,11, 
16 
7,12, 
17i 
18 
Study  
Day(s) 
-28 to  
-2 
-1 
1,22,43 
2,23, 
44 
3,24, 
45 
4,25, 
46 
6,27, 
48 
9,30, 
51 
12,33, 
54 
16,37, 
58 
20,41, 
62 
69 
(±1) 
Post-Dose  
Time (hr) 
-- 
-- 
0 
0.5 
1 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
14 
18 
24 
36 
48 
72 
120 
192 
264 
360 
456 
504 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Confirmation 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
Xb 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Xc 
Dispense Safety 
Card 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Randomizationd 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/ BMI 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancye 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSHe,f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol No. YKP3089C037 
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Assessment 
Screening 
Base 
Treatment Period 
FU 
Visit(s) 
1 
2,7,12j 
3,8, 
13 
4,9, 
14 
5,10, 
15 
6,11, 
16 
7,12, 
17i 
18 
Study  
Day(s) 
-28 to  
-2 
-1 
1,22,43 
2,23, 
44 
3,24, 
45 
4,25, 
46 
6,27, 
48 
9,30, 
51 
12,33, 
54 
16,37, 
58 
20,41, 
62 
69 
(±1) 
Post-Dose  
Time (hr) 
-- 
-- 
0 
0.5 
1 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
14 
18 
24 
36 
48 
72 
120 
192 
264 
360 
456 
504 
Clinical Laboratory 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
HIV, Hep B/C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Breath Alcohol 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Physical Examg 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signsh 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
AE Monitoring 
 
 
Continuous Throughout 
Treatment 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sampling 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacogenomic 
Blood Sampling 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Outpatient Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Xi 
X 
Note: C-SSRS= Columbia Suicide Severity Rating Scale; AE = adverse event; BMI = body mass index; ECG = electrocardiogram; FSH = follicle stimulating 
hormone; h = hour; PK = pharmacokinetic 
a Review Inclusion/Exclusion on Day -1 
b Baseline “Baseline/Screening” version of C-SSRS will be used 
c “Since Last Visit” version of the C-SSRS will be used 


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d Randomization to occur prior to dosing on Day 1. 
e Pregnancy testing for female subjects of childbearing potential only; postmenopausal women with last menses less than one year will have a serum pregnancy 
and FSH test during screening only 
f Postmenopausal women only, including women with last menses less than one year 
g Complete physical examination at Screening; Symptom-oriented physical examination on Day 1, Day 22, Day 43 and at follow-up 
h Vital signs (supine systolic and diastolic blood pressure, pulse rate, respiratory rate, and body temperature) measurement in supine position (at least 5 minutes). 
i Note that Visit 17 only is an outpatient visit while Visit 7 and 12 are CRU admission days to bridge between periods 
j Visit 2 is baseline visit Visits 7 and 12 are the start of periods 2 and 3 respectively 
 
 
 
 


YKP3089 
 Protocol No. YKP3089C037 
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7.1.1. 
Visits 
See Table 4 for a detailed list of study assessments by visit 
7.1.1.1. 
Visit 1 (Screening) 
The following will be performed during Visit 1: 
• Subject will be seen in the clinic for a Screening visit within 28 days prior to the first 
dose to assess eligibility for the study 
• Informed consent will be obtained prior to the performance of any study-related 
assessments or procedures 
• The optional pharmacogenomics informed consent should be obtained at this time for 
willing subjects 
• Screening assessments will be comprised of relevant medical history, demographics 
(including the assessments of body height, weight, BMI, smoking status, and alcohol 
history), serum pregnancy test, serum FSH, clinical labs, serology tests (HIV and Hep 
B/C), urine drug screening, breath alcohol, a complete physical examination, vital 
signs, 12-lead ECG, concomitant medications, C-SSRS and review of 
inclusion/exclusion criteria 
7.1.1.2. 
Visit 2 (Baseline) (Beginning Day -1) 
The following will be performed during Visit 2 
• Admission to the CRU on Day -1   
• Pharmacogenomic blood sampling collected on Day -1 (only if consent was obtained) 
• Confirmation of eligibility (including a review of the inclusion/exclusion criteria), 
weight/BMI, urine pregnancy, clinical labs, urine drug screen, breath alcohol, 12-lead 
ECG, CSSR-S, and concomitant medications on Day -1 
• Physical exam (symptom oriented) and vital signs on Day 1 
• Randomization on Day 1 prior to dosing. 
• Dosing of cenobamate per randomized treatment allocation on Day 1 
• Clinical labs, vital signs, and concomitant medications on Day 4 
• Blood samples to determine plasma drug concentrations of cenobamate Day 1 to the 
morning of Day 4 
• AE Monitoring throughout 
• Discharge on the morning of Day 4; upon discharge, subjects will be issued a 
hypersensitivity safety card 
7.1.1.3. 
Visit 3 (Morning of Day 6) 
The following will be performed during Visit 3 


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• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.4. 
Visit 4 (Morning of Day 9) 
The following will be performed during Visit 4 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.5. 
Visit 5 (Morning of Day 12) 
The following will be performed during Visit 5 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.6. 
Visit 6 (Morning of Day 16) 
The following will be performed during Visit 6 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.7. 
Visit 7 (Beginning on the Morning of Day 20) 
The following will be performed during Visit 7 
• Admission to the CRU on Day 20 
• Clinical labs, urine drug screen, breath alcohol, vital signs, C-SSRS, concomitant 
medications on Day 20 
• Blood sample to determine plasma drug concentrations of cenobamate on Day 20 for 
end of Period 1 sampling 
• Dosing of cenobamate per randomized treatment allocation on Day 22 
• Physical exam (symptom oriented) and vital signs on Day 22  


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• Blood sampling to determine plasma drug concentrations of cenobamate on Day 22 to 
the morning of Day 25 for beginning of Period 2 sampling 
• Clinical labs, vital signs, and concomitant medications on Day 25 
• AE Monitoring throughout 
• Discharge on the morning of Day 25; upon discharge, subjects will be issued a 
hypersensitivity safety card 
7.1.1.8. 
Visit 8 (Morning of Day 27) 
The following will be performed during Visit 8 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.9. 
Visit 9 (Morning of Day 30) 
The following will be performed during Visit 9 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.10. Visit 10 (Morning of Day 33) 
The following will be performed during Visit 10 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.11. Visit 11 (Morning of Day 37) 
The following will be performed during Visit 11 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 


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7.1.1.12. Visit 12 (Beginning on the Morning of Day 41) 
The following will be performed during Visit 12 
• Admission to the CRU on Day 41 
• Clinical labs, urine drug screen, breath alcohol, vital signs, C-SSRS, concomitant 
medications on Day 41 
• Blood sample to determine plasma drug concentrations of cenobamate on Day 41 for 
end of Period 2 sampling 
• Physical exam (symptom oriented) and vital signs on Day 43 
• Dosing of cenobamate per randomized treatment allocation on Day 43 
• Blood sampling to determine plasma drug concentrations of cenobamate on Day 43 to 
the morning of Day 46 for beginning of Period 3 sampling 
• Clinical labs, vital signs, and concomitant medications on Day 46 
• AE monitoring throughout 
• Discharge on the morning of Day 46; upon discharge, subjects will be issued a 
hypersensitivity safety card 
7.1.1.13. Visit 13 (Morning of Day 48) 
The following will be performed during Visit 13 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.14. Visit 14 (Morning of Day 51) 
The following will be performed during Visit 14 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.15. Visit 15 (Morning of Day 54) 
The following will be performed during Visit 15 
• Outpatient visit 
• Urine drug screen, breath alcohol, vital signs, and concomitant medications 
• AE Monitoring throughout 


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• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.16. Visit 16 (Morning of Day 58) 
The following will be performed during Visit 16 
• Outpatient visit 
• Urine drug screen, breath alcohol,  vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.17. Visit 17 (Morning of Day 62) 
The following will be performed during Visit 17 
• Outpatient visit 
• Urine drug screen, breath alcohol,  vital signs, and concomitant medications 
• AE Monitoring throughout 
• Blood sample to determine plasma drug concentrations of cenobamate 
7.1.1.18. Visit 18 Follow-Up (Day 69) 
The following will be performed during Visit 18 
• Final outpatient visit 
• Urine pregnancy, clinical labs,  physical exam (symptom oriented), vital signs C-
SSRS  and concomitant medications 
• AE Monitoring throughout 
7.2. 
Number of Subjects 
A total of 24 (4 subjects per sequence) healthy female and male subjects, balanced by gender and 
race/ethnicity to the extent possible, will be included in the study.  
If needed and agreed upon by SKLSI and investigator, replacement subjects will be assigned to 
the same treatment sequence as the subject they are replacing in order to have at least 20 subjects 
completing all three treatments. 
7.3. 
Treatment Assignment 
The study will contain the following treatment groups: 
• Treatment A: 200 mg cenobamate oral tablet under fasting condition 
• Treatment B: 200 mg cenobamate oral suspension under fasting condition 
• Treatment C: 200 mg cenobamate oral suspension under fed condition 


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7.3.1. 
Methods for Treatment Group Assignment 
After obtaining oral and written informed consent, subjects will be screened according to the 
inclusion and exclusion criteria (Section 8.1 and Section 8.2). Prior to dosing on Day 1, subjects 
will be randomized to receive one of three treatment schemes as outlined in Table 3. The 
randomization schedule will be generated by the statistician responsible for this study using 
SAS® software. One copy of the randomization list will be provided to the pharmacist for 
preparation of the appropriate treatment. Subjects withdrawn from the study retain their 
randomization number, if already given. New subjects must always be allotted a new 
randomization number. Once assigned, randomization numbers must not be reused within the 
study site. 
Subjects who drop-out for any reason or withdraw consent prior to dosing will be considered as 
screen failures. Such subjects will not receive a unique subject number. The Investigator will 
keep a screening log of all screen failure subjects, along with the reasons for their screen failure. 
7.3.2. 
Allocation of Subject Numbers 
Once a subject has signed the ICF, that subject will be assigned an 8-digit subject identification 
number (subject ID) e.g. 01001001. The first two digits is for country, the next 3 digits for site, 
and the last 3 digits for subject. Subject numbers will be allocated sequentially in the order in 
which the subjects are screened. Once assigned, subject identification numbers must not be 
reused. The subject number will ensure identification throughout the study.  
Subjects withdrawn from the study will retain their subject identification numbers. Any 
replacement subject will receive the subject number from the subject they are replacing + 100, 
e.g., replacement for 01001003 would have the subject identification number 01001103.  
Subjects who fail screening will be allowed to re-screen only once. The re-screened subject will 
be assigned a new subject number, and the linking information for these two subject numbers 
will be recorded in CRF. 
7.4. 
Dose Adjustment Criteria 
The dose will not be adjusted in this study. 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
The dose of this study will not be adjusted. However, the Investigator may withdraw a subject at 
any time if it is determined that continuing the study would result in a significant safety risk to 
the subject. 
Subjects will be discontinued from the clinical study for any of the following reasons: 
• Females who are pregnant according to a positive pregnancy test, 
• Positive screening of alcohol and/or drugs of abuse, 
• If following the first dose, a subject develops any rash related to the study drug. 
Furthermore, participation in the clinical study could be discontinued by the Investigator in 
charge of the study or by SKLSI for any of the following reasons: 


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• Clinically significant abnormality on vital signs, clinical laboratory, or physical 
examination assessments, as assessed by the investigator or designee, 
• Rash or manifestation of hypersensitivity reaction such as lymphadenopathy, fever, or 
facial swelling related to the study drugs, 
• Noncompliance with the protocol requirements (e.g., blood collection deviations 
which may impact the PK profile), 
• The subject is uncooperative during the study, 
• Occurrence of intolerable adverse event (AE), 
• Lost to follow-up, 
• Unanticipated event which could result in an inadequately characterized PK profile, 
such as missed blood draws, AE, or need to use concomitant medications. 
If a subject prematurely discontinues, or is discontinued from the study, the primary reason for 
the discontinuation will be obtained and recorded on the CRF.  
Replacement subjects may be added at SKLSI’s discretion, in agreement with the investigator. 
7.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
There are no pre-defined Pharmacokinetic criteria for adjusting or stopping doses. Subject 
termination will be governed by safety, tolerability and Investigator discretion.  
7.5. 
Criteria for Study Termination 
SK Life Science, Inc. (SKLSI) 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. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Healthy subjects who meet all the inclusion criteria and none of the exclusion criteria will be 
eligible for participation in this study. The study population will consist of a balanced 
representation of genders and ethnic groups to the extent possible.  
Adherence to the study design requirements, including those specified in the schedule of 
assessments (Table 4), is essential and required for study conduct. Continued eligibility will be 
assessed upon entry into the clinic prior to the start of each visit. 
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria. The subject’s selected by the clinical site will be reviewed by SKLSI for 
final approval. The investigator will maintain a screening log in order to record details of all 
screened subjects and to confirm eligibility or record reasons for screening failure, as applicable. 
Subjects may be re-screened only once within an appropriate time window in case of out of range 
results. 
8.1. 
Subject Inclusion Criteria 
3. Male or female subjects of 18 to 50 years of age (inclusive), at the time of screening 
4. Able to read, understand, sign, and date a written informed consent form (ICF) before 
study participation at screening 
5. Agree to use effective methods of contraception as described in Section 12.1.7.8 and 
Section 12.1.7.9. 
6. Body mass index (BMI) between 18.5 and 30.0 kg/m2 (inclusive) at screening 
7. Judged to be in good health on the basis of medical history, physical examination, and 
routine laboratory measurements (i.e., without clinically relevant pathology) 
8. 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. 
9. Able to understand and comply with protocol requirements and instructions and likely to 
complete the study as planned 
10. Females 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., bilateral tubal ligation or bilateral salpingectomy orhysterectomy), 
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 
8.2. 
Subject Exclusion Criteria 
1. Clinically relevant abnormal medical history, abnormal findings on physical examination, 
vital signs, ECG, or laboratory tests at Screening that the Investigator judges as likely to 
interfere with the objectives of the trial or the safety of the volunteer 


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2. Smokers (subjects who have smoked within 6 months at screening)  
3. History of any drug related hypersensitivity reactions as well as severe hypersensitivity 
reactions (like angioedema) or DRESS as evaluated by the Investigator 
4. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with 
pharmacokinetics of the study drug (except appendectomy and simple hernia repair) 
5. Any prescribed or over-the-counter medication taken within 2 weeks prior to start of 
administration of study drug (Day 1) or within 6 times the elimination half-life of the 
medication prior to start of study drug intake (whichever is longer). Occasional use of 
acetaminophen is allowed up until 24 hours before dosing 
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), and grapefruit or 
grapefruit juice, or Seville oranges at least 2 weeks before the first dosing day of study 
drug. Vitamins/mineral supplements are allowed up until 24 hours before dosing 
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   
9. Consumption of an average of more than 5 servings (8 ounces per serving) per day of 
coffee, cola, or other caffeinated or methyl xanthine beverages before screening 
10. Consumption of any caffeine- or methyl xanthine-containing products (e.g., coffee, tea, 
chocolate, or soda) or alcoholic beverages within 48 hours prior to Day 1 of each period 
and until the end of each PK sampling period  
11. 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 
12. 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 
13. 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) 
14. 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]) 
15. History of any known relevant allergy/hypersensitivity (including allergy to the trial 
medication or its excipients) 
16. Subject who is judged not eligible for study participation by Investigator 


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17. History of  Familial Short QT syndrome.  
8.3. 
Subject Withdrawal Criteria 
Any subject may be withdrawn from the study at the discretion of the Investigator. The subject is 
also free to terminate his/her participation at any time. However, if the subject has been dosed 
with study medication, it is recommended to ask the subject to remain in contact with the center, 
and the investigational site should make every effort to convince the subject to return for a safety 
follow-up visit. The Investigator will also undertake to obtain more detailed information about 
any subject lost to follow-up. Subjects withdrawn from the study must not be re-included. 
8.3.1. 
Withdrawn Subject Data Collection 
The principal Investigator and/or designee will document on the termination page of the CRF 
and in the subject’s medical records the primary reason for the subject’s withdrawal as follows: 
• Lost to follow-up: subjects who leave the clinic during the hospitalization period or 
do not attend the following visit. Intensive efforts should be made to locate and recall 
them if possible and, at a minimum, to determine their health status; 
• AE: an AE form must be completed; the type of AE should be specified; 
• Deviation from protocol; 
• Consent withdrawn; 
• Other: if none of the above-mentioned reasons are applicable, then the reason will be 
specified. 
All withdrawals will be reported immediately to SKLSI. For all dropouts, a Follow-up visit will 
be arranged for approximately 21 days after the most recent drug administration and will 
document the progress of their condition. In every case, the CRF must be filled in up to the last 
visit performed. 
8.3.2. 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for scheduled visits and 
is unable to be contacted by the study site. The following actions must be taken if a subject fails 
to return to the clinic for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study; 
• In cases in which the subject is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
subject’s medical record; 


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• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to Follow-up. 
8.3.3. 
Replacement of Subjects 
Subjects who withdraw or are withdrawn during the study for reasons unrelated to safety may be 
replaced in order to have at least 20 evaluable subjects who completed the 3 treatment periods. In 
case of replacement, a subject will be assigned to the same treatment sequence as the 
discontinued subject. 
In case of moderate or severe AE causing the subject to withdraw, a joint decision between 
SKLSI and the Investigator will be taken on the appropriateness of replacing the subject. 
 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Table 5 lists the details of the two cenobamate formulations to be used in this study. 
Table 5: 
Investigational Product 
 
Investigational Product 
Product Name: 
Cenobamate 
Cenobamate 
Activity: 
Reducer of repetitive neuronal firing by enhancing the fast and 
slow inactivation of sodium channels and by inhibiting the 
persistent component of the sodium current. A positive allosteric 
modulator of six subtypes of the γ-aminobutyric acid (GABAA) ion 
channel. 
Dosage Form: 
Tablet 
Liquid Suspension 
Strength: 
200 mg 
10 mg/mL 
Route of Administration 
Oral 
Oral 
Dosage Form 
Film-coated oval (9.5 mm by 20 
mm) light orange tablets 
Suspension 
Manufacturer 
Patheon for SK Life Science, 
Inc 
Manufactured by CoreRx, 
Florida, USA for SK Life 
Science, Inc 
9.2. 
Concomitant Medications 
The use of any investigational drug is prohibited within 30 days before the first administration of 
cenobamate. The use of any prescription or over-the-counter drug (other than hormonal 
contraceptives for women of childbearing potential) is prohibited within less than 15 days before 
the first administration of cenobamate, with the exception of vitamin/mineral supplements and 
the occasional use of acetaminophen, which is allowed up to 24 hours before dosing in any 
treatment period. 
For any subject, if the use of any concomitant treatment becomes necessary (e.g., for the treatment 
of an AE), the treatment must be recorded in the CRF, including the reason for treatment, generic 
name of the drug, dosage, route, and date and time of administration. If a treatment is administered, 
SKLSI’s medical monitor must be promptly notified in order to assess the subject’s eligibility for 
continuing study participation. 
9.2.1. 
Prior Treatments 
Reasonable efforts will be made to determine all relevant treatments received by the subject 
within 3 months before the first administration of cenobamate (within 15 days before the first 
administration of cenobamate for over-the-counter drugs). 
The use of any prescription or over-the-counter drugs (other than hormonal contraceptives for 
women of childbearing potential) as well as herbal medications, dietary supplements and specific 


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fruit products is prohibited within 2 weeks before the first administration of cenobamate, with 
the exception of vitamin/mineral supplements and the occasional use of acetaminophen, which 
are allowed up to 24 hours before dosing. 
All relevant information must be recorded on the subject's CRF. 
9.3. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All study drug administrations will be under the supervision of the Investigator or 
designee; 
• A mouth and hand check for drug product will be carried out for each subject after 
dosing to ensure that all of the dose has been swallowed. 
Subjects who are unable to adhere to the above measures may be removed from the study based 
on the SKLSI’s decision (on a case-by-case basis) and the CRF will be documented accordingly. 
9.3.1. 
Lifestyle Guidelines 
9.3.1.1. 
Meals and Dietary Restrictions 
Subjects will need to stop consuming grapefruit or drink grapefruit-containing products, or 
Seville oranges at least 2 weeks before the first dosing day of study drug. Vitamins/mineral 
supplements are allowed up until 24 hours before dosing, as specified in exclusion criteria 
(Section 8.2). 
9.3.1.1.1. Treatment A and Treatment B Meals and Dietary Restrictions 
On days that a subject will be confined to the CRU for Treatment A and/or Treatment B, an 
overnight fast will be imposed (when needed) so that no food is consumed within at least 10 
hours before cenobamate administration. On days that a subject will be confined to the CRU, 
dinner will be served the day prior to dosing (Day -1, Day 21, or Day 42) ending at least 10 
hours before dosing. The next meal will be a lunch approximately 4 hours after dosing the 
following day followed by a dinner approximately 10 hours after dosing. On subsequent days of 
confinement, a breakfast, lunch and dinner will be provided at appropriate times. 
9.3.1.1.2. Treatment C Meals and Dietary Restrictions 
On days that a subject will be confined to the CRU for Treatment C, dinner will be served the 
day prior to dosing (Day -1, Day 21, or Day 42) approximately 10 hours prior to dosing. On the 
day of dosing (Day 1, Day 22, or Day 43) a high-calorie, high-fat breakfast will be provided 
approximately 30 mins prior to dosing. The breakfast should be consumed with 30 minutes or 
less and Treatment C should be approximately 30 mins after the start of a meal (Section 10.5.2). 
9.3.1.2. 
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. 


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9.3.1.3. 
Physical 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. 
9.4. 
Randomization and Blinding 
This study is an open-label study. 
Prior to dosing on Day 1, subjects will be randomized to receive one of six treatment sequences 
as outlined in Table 3. The randomization list will be generated by the statistician responsible for 
this study using SAS® software. One copy of the randomization list will be provided to the 
pharmacist for preparation of the appropriate treatment. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
Cenobamate Oral Tablet 
The cenobamate oral tablet formulation is an Opadry® II light orange film coated tablet with the 
following inactive excipients: microcrystalline cellulose, lactose monohydrate, sodium starch 
glycolate, colloidal silicon dioxide, and magnesium stearate. 
10.1.2. 
Cenobamate Oral Suspension 
The cenobamate oral suspension formulation is manufactured from commonly used inactive 
ingredients, suitable favor, preservative and sweetener. 
10.2. 
Study Drug Packaging and Labeling 
Packaging and labelling will be done in accordance with the Rules Governing Medicinal 
Products in the European Union, Volume 4: Good Manufacturing Practice (GMP). The Study 
drug (investigational medicinal product) labels will include all the information required by 
Annex 13 to GMP. 
The 200 mg tablets are packaged in High Density Polyethylene (HDPE) bottles with 
Polypropylene (PP) CRC cap. 
For oral suspension, contents are packed in amber glass bottle with CRC cap. A Push in Bottle 
Adapter (PIBA) suitable for the packaged bottle will be provided. The study site will obtain oral 
syringes of suitable capacity for dosing the oral suspension formulation of cenobamate. 
SKLSI will ship a sufficient supply of cenobamate (either oral tablet formulation or oral 
suspension formulation) to the study site. 
10.3. 
Study Drug Storage 
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 upright at room 
temperature in a dry area, protected from light, monitored for temperature. 
10.4. 
Study Drug Preparation 
The appropriate dose and formulation of cenobamate will be prepared and dispensed by a 
pharmacist at the clinical site. 
Before beginning the dispensing process, the pharmacy staff will read and understand the study 
protocol and accompanying study treatment preparation, dispensing, and administration 
instructions (if applicable). Only eligible subjects participating in the study will receive the study 
drugs. Only authorized research site staff may supply or administer the study drugs. Any 
questions related to dispensing of the study drugs will be resolved prior to the start of the study 
by communication with an SKLSI representative. Additional study drug preparation will be 
followed as per the pharmacy manual. 


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10.5. 
Administration 
Study drug will be administered orally in either tablet or suspension formulation.  
10.5.1. 
Timing of Doses in the Study 
10.5.1.1. Timing of Doses for Treatment A and Treatment B 
• The study drug will be orally administered to subjects in the morning after a 10-hour 
overnight fast (no food or beverages allowed except for tap water).  
• The study drug will be swallowed together with 240 mL tap water (room 
temperature). The study drug should be swallowed whole and should not be chewed. 
• Administration of the study drug will be supervised by the Investigator or designee. 
After drug administration, a mouth and hand inspection will take place. 
• Fasting will continue until approximately 4 hours post-dose when lunch will be 
served.  
• 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 water used for study 
drug administration. 
• A dinner will be provided approximately 10 hours after dosing. 
10.5.1.2. Timing of Doses for Treatment C 
• The study drug will be orally administered to subjects in the morning approximately 
30 minutes after the start of a high-calorie, high-fat meal.  
• The study drug will be swallowed together with 240 mL tap water (room 
temperature). The study drug should be swallowed whole. 
• Administration of the study drug will be supervised by the Investigator or designee. 
After drug administration, a mouth and hand inspection will take place. 
• A lunch and dinner will be served approximately 4 hours and 10 hours post-dose, 
respectively. 
10.5.2. 
High-Calorie, High-Fat Meal for Treatment C 
Subjects that are taking the oral suspension formulation under fed conditions (Treatment C) will 
be given a high-calorie (approximately 800 – 1000 calories) and high-fat (approximately 50% of 
total caloric content of the meal) meal as recommended by the FDA.4 This meal should derive 
approximately 150, 250, and 500 – 600 calories from protein, carbohydrate, and fat, respectively. 
For instance, the breakfast can contain 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast 
with butter, 4 ounces of hash brown potatoes and 8 ounces of whole milk. Substitutions in this 
test breakfast can be made provided that the meal provides a similar amount of calories from 
protein, carbohydrate, and fat and has comparable meal volume and viscosity. The final 
composition of the breakfast will be reported in the clinical study report. 


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Subjects receiving the high calorie, high-fat breakfast will need to adhere to the following 
schedule: 
• 
The meal will be taken about 30 minutes prior to the administration of cenobamate, 
• 
The meal should be eaten within 30 minutes or less, 
• 
Cenobamate will be administered approximately 30 minutes after the start of the meal. 
Water will be allowed ad libitum except for one hour before and after cenobamate 
administration, with the exception of the 240 mL of water taken with each dose. 
 
10.6. 
Study Drug Accountability 
The Investigator is responsible for confirming that all study drug supplies received by the study 
site are inventoried and accounted for throughout the study. A drug receipt log will be completed 
and signed by the person accepting the shipment. It is important that the designated study site 
personnel count and verify that the shipment contains all the items noted in the shipment 
inventory. Any damaged study drug found in a given shipment will be documented in the study 
files. The Investigator must notify the SKLSI of any damaged or unusable study drug supplies. 
10.7. 
Study Drug Handling and Disposal 
Upon destruction of study drug, a Certificate of Destruction (COD) will be provided to SKLSI. 
See the Pharmacy Manual for drug handling and disposal. The clinical site will be responsible 
for cenobamate drug disposal. 


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11. 
PHARMACOKINETIC ASSESSMENTS 
11.1. 
Blood Sample Collection 
Blood samples for determination of cenobamate plasma concentrations will be collected by 
direct venipuncture into a labeled tube containing the appropriate anticoagulant as specified by 
the bioanalytical facilities. If judged necessary by the clinical staff, blood samples may be 
collected from an indwelling cannula (catheter). 
The complete schedule for pharmacokinetic blood sampling is presented in Table 4. The time of 
blood sample collection will be calculated according to the treatment administration schedule. 
The clock time of the dose administration will be recorded (record time after all drug products 
have been swallowed). The exact actual time of blood draws will be recorded and reported for all 
subjects in the CRF. Actual blood collection times will be used for the PK analysis. Blood will 
be collected into tubes labeled with the nominal blood sampling times. 
It is important to avoid hemolysis during blood collection. In case of hemolysis, this will be 
reported in the CRF. The impact of any observed hemolysis on the plasma concentrations may be 
discussed with SKLSI.  
When a sampling time is close to a mealtime, the sample will be collected before the meal. 
Blood samples for PK analysis should be collected at the requested times, but the allowed 
windows for sample collection are presented in Table 6. 
Table 6: 
Acceptable Time Windows for PK Blood Sampling 
Nominal Sampling Time 
Acceptable Time Windows 
Pre-dose 
-30 mins before dose or immediately before dosing 
0.25 to 1.5 hour post-dose 
± 2 minutes 
2 to 12 hours post-dose 
± 5 minutes 
14 to 96 hours post-dose 
± 15 minutes 
120 to 456 hours post-dose 
± 2 hours 
Follow-up 
± 1 day 
The approximate blood volume to be collected per subject following a single oral dose of 
cenobamate (tablet or suspension) is presented in Table 7. 
Table 7: 
Blood Volume to be Collected per Subject for Drug Plasma Concentration 
Analysis After a Single Dose of Cenobamate (456 Hours) 
Formulation (Fed Status) 
Number of 
Timepoints 
Volume per 
Timepoint (mL) 
Total Volume 
(mL) 
Cenobamate Oral Tablet (Fasted) 
24 
2 
48 
Cenobamate Oral Suspension 
(Fasted) 
24 
2 
48 
Cenobamate Oral Suspension (Fed) 
24 
2 
48 
Total 
72 
6 
144 


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11.2. 
Urine Sample Collection 
Urine will not be collected for PK assessment in this Study. 
11.3. 
Sample Analysis 
11.3.1. 
Sample 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., Laboratory Manual). The shipment address and assay 
lab contact information will be provided to the investigational site prior to initiation of the trial. 
11.3.2. 
Bioanalysis 
Blood samples will be processed, split, stored, and shipped according to the sample processing 
manuals supplied by the bioanalytical facilities. 
Plasma samples will be analyzed for cenobamate concentrations using a validated liquid 
chromatography/tandem mass spectrometry method (LC-MS/MS) with a lower limit of 
quantification of 0.05 μg/mL. 
The method, data acceptance criteria, and criteria for sample re-assay will follow the 
bioanalytical facility’s SOPs and the guidelines set by the Regulatory Agencies. 
Pharmacokinetic sample analysis methods are further explained in Section 13.1.3.  
PK blood samples may be used for metabolite or methodology exploratory analyses. Possible 
results from these exploratory analyses may be reported in standalone report(s) if deemed 
necessary. 
11.3.3. 
Exploratory Pharmacogenomic Assessments 
At the time point defined in the Schedule of Assessments (Table 4), an optional blood sample 
will be collected to explore the possible effect of genetic variation in the PK of cenobamate. A 
separate informed consent for genotyping will be obtained from each subject prior to sampling. 
DNA will be extracted from the blood sample in order to sequence genes coding for enzymatic 
or transporter systems 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). It is not intended to 
include the pharmacogenomic data in the final CSR. However, this may be considered if deemed 
necessary. Possible results from these exploratory analyses may be reported in standalone 
report(s) if deemed necessary. 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety assessments will include physical examination, vital signs, safety laboratory tests, 
continuous AE monitoring, C-SSRS review and concomitant medication recording. Additional 
safety measurements may be performed at the discretion of the Investigator for reasons related to 
subject safety. 
Clinically significant physical examination findings prior to the first dose of the study treatment 
will be recorded as part of the medical history. Clinically significant findings after the first dose 
will be recorded as AEs. 
The procedures and associated collection windows for vital signs will be as follows: 
• On days that drug product is administered, within 2 hours for pre-dose assessments 
(Days 1, 22, and 43). 
• ± 10 minutes for post-dose assessments (Days 4, 6, 9, 12, 16, 20, 25, 27, 30, 33, 37, 
41, 46, 48, 51, 54, 58, 62 and 69). 
Unless otherwise stated in this protocol, the clinical site’s standard operating procedures (SOPs), 
which are available for all activities relevant to the quality of the study, will be followed during 
this study. 
The study procedures to be conducted for each subject in the study are detailed in Table 4. 
The order of the assessments when scheduled at the same theoretical time will be as follows: 
1. Vital signs; 
2. PK blood sampling; 
3. Blood and urine sampling for safety laboratory assays; 
4. Symptom oriented physical examination. 
Any deviation from the protocol procedures will be captured in the protocol deviation tracker 
and filed in the Transfer Master File (TMF). 
12.1.1. 
Adverse Events 
All AEs which occur during the clinical study will be reported in detail in the source documents 
and documented in the eCRF from Screening, throughout the clinical conduct until the final 
follow-up visit. SAEs will be continuously monitored starting after the time of informed consent 
through the follow-up visit. The Investigator should follow all unresolved AEs until the events 
have resolved or have stabilized, the subject is lost to follow-up, or it has been determined that 
the AE is not related to study drug or study participation. Outcome of AEs (and resolution date, 
if applicable) should be documented on the appropriate eCRF page(s) and in the subject’s 
medical record. 
Detailed information about intensity, relationship to study drug, expectedness, seriousness 
criteria, follow-up and reporting of AEs and SAEs are provided in the further sections 
(Section 12.2 to Section 12.5 ). 


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Special attention must be given to findings and symptoms related to rash and/or hypersensitivity 
that might be linked to DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) 
syndrome. For details, see Section 12.5.3). 
Pregnancy of female subjects and female partners of male subjects will be monitored along with 
follow-up, if warranted (see Section 12.1.7.7). 
 
12.1.2. 
Demographic/Medical History 
The medical history will include evaluation at Screening of ears, nose, and throat, and will 
comprise any ophthalmological, cardiovascular, respiratory, musculoskeletal, gastrointestinal, 
genitourinary, neurological, endocrine, psychiatric, immunological or allergic, dermatological, 
and hematological disease, and family history disorder. All findings on medical history will be 
evaluated by the Investigator for clinical significance. 
12.1.3. 
Vital Signs 
Vital sign measurements (oral body temperature, pulse rate, respiratory rate and blood pressure) 
are specified in Table 4. 
Blood pressure, pulse rate, and respiratory rate will be measured after being in supine position 
for at least 5 minutes. The allowable time frame for collecting pre-dose vital signs is within 2 
hours prior to dosing. 
Vital signs can also be monitored at any time during the study when judged necessary by the 
Investigator. 
12.1.4. 
Suicidality Assessment  
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 “Baseline/Screening Version” of the C-SSRS will be 
assessed at Screening. The C-SSRS “Since Last Visit” version will be assessed on Day -1,20, 41 
and 69, as specified in Table 4 of the Schedule Of Assessments. 
12.1.5. 
Weight and Height 
Height will only be recorded at the Screening visit. Weight will be measured, and BMI will be 
calculated at time points indicated in the Schedule of Assessments (Table 4). 
12.1.6. 
Physical Examination 
A complete physical examination consisting of a review of all body systems and a symptom-
directed physical examination will be performed at time points indicated in the Schedule of 
Assessments (Table 4). A symptom-directed physical examination may be conducted at any time 
per Investigator’s discretion.  
Demographic data (date of birth, gender, race, and ethnicity), and alcohol and smoking habits 
will be recorded in the site’s source document at the Screening Visit. 


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12.1.7. 
Electrocardiogram (ECG) 
ECG will be collected at screening and baseline only. A subject must be in the supine position 
for at least 10 mins prior to any ECG reading. An ECG may be repeated if necessary 
12.1.8. 
Laboratory Assessments 
The tests listed in Table 8 will be performed by the local laboratories at time points indicated in 
the Schedule of Assessments (Table 4). 
Table 8: 
Clinical Laboratory Tests 
Hematology and 
Coagulation 
Serum Chemistry 
Urinalysis 
Additional Tests 
Hemoglobin 
Sodium 
pH 
Serology: anti-HIV-1/2, HBsAg, 
anti-HCV 
Hematocrit 
Potassium 
Specific gravity 
Erythrocytes 
Chloride 
Color 
Platelets 
Calcium 
Protein 
FSH test  
for postmenopausal women, 
including women whose last 
menstruation was < 1 year before 
screening 
Leukocytes 
Inorganic phosphate 
Glucose 
Neutrophils 
Urea 
Ketones 
Eosinophils 
Creatinine 
Hemoglobin 
(erythrocytes)  
Lymphocytes 
Uric acid 
Monocytes 
Total bilirubin 
Leukocytes 
Serum pregnancy test for women 
of childbearing potential, 
including women whose last 
menstruation was < 1 year before 
screening 
Basophils 
Direct bilirubin 
Microscopic 
analysis, if urine is 
positive for protein, 
leukocytes or 
hemoglobin 
INR 
ALT 
aPTT 
AST 
PT 
GGT 
AP 
LDH 
Urine drugs of abuse test 
including but not limited to 
cannabinoids, amphetamines, 
methamphetamines, opiates, 
methadone, cocaine, 
benzodiazepines, and barbiturates 
CPK 
Amylase 
Lipase 
Triglycerides 
Total cholesterol 
HDL cholesterol 
LDL cholesterol 
Total protein 
Albumin 
Alcohol breath test 
Glucose 
INR: International Normalized Ratio; aPPT: Activated Partial Thromboplastin Time; PT: Prothrombin Time; ALT: 
Alanine Aminotransferase; AST: Aspartate Aminotransferase; GGT: Gamma-glutamyl Transferase; AP: Alkaline 
Phosphatase; LDH: Lactate Dehydrogenase; CPK: Creatine Phosphokinase; HDL: High Density Lipoprotein; LDL: 


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Low Density Lipoprotein; HIV: Human Immunodeficiency Virus; HBsAg: Hepatitis B Surface Antigen; HCV: 
Hepatitis C virus. 
 
The clinical laboratory will clearly mark all laboratory test values that are outside the normal 
range and the Investigator will indicate the clinical significance according to the applicable 
clinical site’s Standard Operating Procedure (SOP). Detailed information about follow-up of 
abnormal laboratory results is given in Section 12.5.1. The procedures for the collection, handling, 
and shipping of laboratory samples are specified in the laboratory manual(s) provided to the 
clinical site. 
 
Table 9 lists the blood volume to be collected throughout the course of the study per subject. The 
projected total blood volume to be collected during this study is 397.7 mL. For comparison, a 
blood donation is generally about 450 mL. 
Table 9: 
Blood Volume to be Withdrawn During the Conduct of the Study 
Blood Draw Reason 
N 
Volume 
(mL) 
Total 
(mL) 
Pharmacogenomic Sampling 
1 
6 
6 
Hematology 
12 
2 
24 
Clinical Chemistry at Screening (includes FSH, pregnancy, lipid 
panel, serology) 
1 
17 
17 
Clinical Laboratory Tests (During Study) 
12 
5 
60 
Coagulation Lab Tests (Screening) 
1 
2.7 
2.7 
PK Blood Sampling 
72 
4 
288 
TOTAL 
397.7 
12.1.8.1. Hematology 
Please refer to Table 8 for hematological assessments to be collected throughout the study at 
times specified in Table 4. 
12.1.8.2. Blood Chemistry 
Please refer to Table 8 for serum chemistry assessments to be collected throughout the study at 
times specified in Table 4. 
12.1.8.3. Urinalysis 
Please refer to Table 8 for  urinalysis assessments to be collected throughout the study at times 
specified in Table 4.. 
12.1.8.4. Virus Serology 
Please refer to Table 8 for viral serology tests to be collected throughout the study at times 
specified in Table 4. 


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12.1.8.5. Drug Screen 
Please refer to Table 8 for drugs that will be screened for at times specified in Table 4. 
12.1.8.6. Additional Tests 
Please refer to Table 8 for any assessments to be collected throughout the study at times 
specified in Table 4. 
12.1.8.7. Pregnancy 
Please refer to Table 8 for pregnancy tests to be collected throughout the study at times specified 
in Table 4. 
Pregnancy in a female subject in the study shall be reported to the Medical Monitor, SK Life 
Science, Inc. (SKLSI), and IQVIA on the Pregnancy Reporting Form, faxing and emailing the 
form as per the Table of Contact (Table 12 to Table 14), within 24 hours of the knowledge of its 
occurrence by the Investigator or designee (for pregnancies occurring during the course of the 
study or immediately following the end of the study). Pregnancy in itself is not regarded as an 
AE, unless there is a suspicion that an investigational product may have interfered with the 
effectiveness of a contraceptive medication. The Investigator must discuss with the medical 
monitor/Sponsor, in conjunction with the Institutional Board (IRB), whether or not it would be 
appropriate for the subject to continue in the study. Because of the possibility that the 
fetus/embryo could have been exposed to the investigational product through the parent and for 
the subject’s safety, the pregnancy will be followed up to determine its outcome, including 
spontaneous or voluntary termination, details of birth, presence or absence of any birth defects, 
congenital anomalies, or maternal and/or newborn complications. Pregnancy complications and 
elective terminations for medical reasons should not be reported as an AE or SAE. All reports of 
congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be 
reported and handled as SAEs. 
The pregnancy will be recorded on a Pregnancy Form and reported by the Investigator or 
designee to the Sponsor. Pregnancy follow-up will also be properly recorded to ensure quality 
and completeness of the data belonging to the investigational product and will include an 
assessment of the possible causal relation between the investigational product and any pregnancy 
outcome. 
12.1.8.8. Contraception for Female Subjects 
Sexually active female subjects of reproductive potential must use an approved method of 
contraception during the entire study and for 30 days after the last dose of study medication. 
Hormonal contraceptives alone will not be considered an adequate method of contraception. 
Women of childbearing/reproductive potential are defined as: Any female who has experienced 
menarche and does not meet the criteria for “Women Not of Childbearing Potential” (see below).  
Acceptable contraception methods include:  
• Hormonal contraception (for at least 3 months prior to the Screening visit) in 
combination with a barrier method; 
• Intrauterine device (placement at least 3 months prior to the Screening visit); 


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• Diaphragm with spermicide; 
• Cervical cap; 
• Surgical sterilization (tubal ligation at least 6 months prior to the Screening visit or 
partner who has had vasectomy at least 6 months prior to the Screening visit) with 
appropriate medical documentation; 
• Abstinence (however, if the subject becomes sexually active, one of the above 
methods must be utilized). 
Women not of childbearing potential are defined as women who are postmenopausal or 
permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy). 
Postmenopausal status is defined as absent menses for at least 12 months and confirmed serum 
follicle-stimulating hormone (FSH) levels equal to or greater than 25.8 mIU/mL at the Screening 
visit. 
12.1.8.9. Contraception for Male Subjects 
Male subjects with female partners of childbearing potential may be enrolled if they are: 
• Surgically sterile (vasectomy) with appropriate medical documentation; 
• Practicing true abstinence; 
• Using two adequate forms of highly effective contraception including condom with 
spermicide gel/foam/cream and one additional barrier method for subject’s female 
partner like hormonal contraception, occlusive cap (cervical cap or diaphragm) with 
spermicide or intrauterine device.  
Contraception methods (including abstinence) must be used by male subjects from the first day 
of dosing through 90 days after the last dose of study drug. Subjects whose female partners 
become of child-bearing potential during the study must agree to the contraceptive requirements. 
For male subjects with female partner(s) of non-childbearing potential (i.e., post-menopausal or 
post-surgical sterilization) for at least 6 months before the first dose of study drug, no additional 
contraception method is required. 
12.2. 
Adverse and Serious Adverse Events 
The site staff will record all AEs observed, queried, or spontaneously reported by the subjects. 
Review of concomitant medications will occur throughout the study. 
Should subjects choose to withdraw early from the study, they will be advised of the safety 
precautions that should be taken. The subjects that withdraw early from the study will be 
contacted by site personnel via phone as a follow-up one-week (± 2 days) post discharge or 
withdrawal date. 
Pregnancies identified during the study will be reported to SKLSI with 24 hours. 


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12.2.1. 
Definitions of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An 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. 
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 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. 
12.2.1.2. Serious Adverse Event (SAE) 
An 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, 
• 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 


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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. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome 
of an AE if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization for therapy of the target disease, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
• An Emergency Room visit is not considered hospitalization.  
• 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. 
Detailed information about intensity, relationship to study drug, expectedness, serious criteria, 
follow-up and reporting of AEs and SAEs are provided in Section 12.2. 
Special attention must be given to findings and symptoms related to rash and/or hypersensitivity 
that might be linked to DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) 
syndrome. For details, see Section 12.5.3. 
12.2.1.3. 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 10 
Table 10: 
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. 


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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. 
12.2.1.4. 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 11. 
Table 11: 
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) 
12.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.”  If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 


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If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient/subject and/or in response to an open 
question from the study personnel or revealed by observation will be recorded during the study at 
the investigational site. Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as AEs.  However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study drug must be reported and recorded as an AE.  
Information about AEs and SAEs will be collected from the from first administration of study 
drug through the follow up visit. The AE term should be reported in standard medical 
terminology when possible.  For each AE, the investigator will evaluate and report the onset 
(date and time), resolution (date and time), intensity, causality, action taken, serious outcome (if 
applicable), and whether or not it caused the patient to discontinue the study. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.  An AE of severe intensity may 
not be considered serious. 
Should a pregnancy occur in a subject or a male subject’s partner, it must be reported and 
recorded on SKLSI’s pregnancy form.  Pregnancy in itself is not regarded as an AE unless there 
is a suspicion that an investigational product may have interfered with the effectiveness of a 
contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as AEs. 
12.5. 
Reporting Adverse Events 
12.5.1. 
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 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. 


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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, 
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 Medical Dictionary for Regulatory Activities (MedDRA) with the version specified by 
sponsor in DMP. 
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. 
12.5.2. 
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 12 and Table 13).  


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Table 12: 
Contact Information for IQVIA 
Name 
IQVIA 
Email 
QPV_SKLSI_SafetyMailbox@quintiles.com 
Telephone 
+1 (855) 564-2229 
Fax 
+1 (855) 638-1674 
Table 13: 
Contact Information for Sponsor Medical Monitor 
Name 
Marc Kamin  
Email 
mkamin@sklsi.com 
Telephone 
+1 (201) 421-3830 
Table 14: 
Contact Information for PRA Principal Investigator 
Name 
Ahad Sabet, MD, CPI 
Email 
SabetAhad@prahs.com 
Telephone 
+1 (801) 904-4638 
Fax 
+1 (801) 261-3341 
In addition, reporting of serious adverse events should follow the procedures outlined in 
Table 15 based on the type of SAE. 
Table 15: 
Serious Adverse Event Reporting Requirement 
Type of SAE 
Reporting  
Time Frame 
Reporting  
Method 
Contact Details 
Rash with involvement 
of 1 other organ system 
or a suspected case of 
DRESS 
Immediate 
Emaila 
 
Fatal or 
Life-threatening 
Immediate 
Emaila 
 
All other SAEs 
Within 24 hours of 
awareness 
Emaila 
 
Urgent safety concerns 
requiring a Medical 
Monitor 
As needed 
Telephone 
 
aThe SAE report must be used for reporting 
DRESS=Drug Reaction with Eosinophilia and Systemic Symptoms; SAE=serious adverse event; SKLSI=SK Life Science, Inc.; 
At the time of the initial SAE report, the investigator should provide as much of the following 
information as possible: 
• Study identifier; 


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• 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. 
Any adverse event that is considered serious will be reported to the IRB by the clinical site by 
telephone and/or by email within 3 working days. Any unexpected fatal or life-threatening SAE 
will be reported to the IRB by telephone and in writing within 24 hours. 
SKLSI 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 SKLSI during the clinical portion 
of this study (related or not to the present study), SKLSI must advise the clinical site, through its 
Principal Investigator, of those events. 
12.5.3. 
Rash/Hypersensitivity/DRESS Syndrome 
Drug-induced hypersensitivity reactions with or without multi organ involvement (allergic 
reactions which may be fatal) including DRESS syndrome have been seen in patients taking 
cenobamate. DRESS which has occurred in <1% of clinical trial participants taking cenobamate 
stands for Drug Reaction (or Rash) with Eosinophilia and Systemic Symptoms. This condition 
occurs usually in the first 8 weeks after initiation of treatment and rarely happens afterwards. 
Symptoms of DRESS may include: 
• Rash; 
• Fever; 
• Inflammation of internal organs; 
• Lymphadenopathy; 
• Eosinophilia; 
• Thrombocytopenia. 
In order to ensure patient safety, and allow early identification and rapid intervention in 
suspected DRESS cases, the following measures must be followed: 
• Any patient who reports a rash or is observed to have a rash should be carefully 
evaluated for a drug hypersensitivity syndrome; the evaluation should include 
hematology and chemistry blood tests. If a subject reports a rash by telephone, an 
unscheduled visit should be performed promptly. 


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• At the end of their study participation, all subjects must be informed to report any 
rash, hypersensitivity reaction or DRESS related symptoms to the investigative site as 
soon as they experience it. 
During Study Day 4 (prior to discharge from CRU), subjects will be provided a safety card with 
the following hypersensitivity information and will be instructed to carry with them at all times: 
• Rash may occur and may progress to Drug Reaction with Eosinophilia and Systemic 
Symptoms (DRESS). 
• Rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy, 
and swelling) may herald a serious medical event and that the patient should report 
any such occurrence to the investigative site immediately. 
• Instructions on whom and where to call in the event a symptom arises and 
information that can be provided to an emergency room in the event the subject 
cannot reach the investigator site. 
• Reminder to check skin daily for evidence of rash for the first four months of therapy 
At the end of their study participation, all subjects must be informed to report any rash, 
hypersensitivity reaction or DRESS related symptoms to the investigative site as soon as they 
experience it. 
In addition, please remind all patients to call your office immediately if they experience any of 
the following symptoms: 
• Rash; 
• Fever; 
• Swollen lymph nodes in your neck; 
• Abdominal or chest pain; 
• Puffy face or ankles; 
• Yellowing of skin or eyes. 
Investigators will be instructed to identify local specialists in dermatology, cardiology, 
nephrology and hepatology who can be call upon onto immediately to see the patient and 
manage their condition if DRESS syndrome is suspected. 
The SK Life Science, Inc. (SKLSI) and their designee (see SAE Contact Information in 
Section 12.5.2) must be notified immediately of any suspected cases of DRESS syndrome as an 
SAE. 


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13. 
STATISTICS 
13.1. 
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. Clinical pharmacology analysis details (including the definition of the PK population) will 
be provided in the Clinical Pharmacology Data Analysis Plan (CPAP). 
The Biostatistics Department of the CRO or SKLSI will generate the SAP. The SKLSI Clinical 
Pharmacology Department will generate the CPAP. Both the SAP and CPAP 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. 
Any deviation from the SAP and/or CPAP will be reported in the section “Changes in Planned 
Analysis” in the Clinical Study Report (CSR). 
Statistical analyses will be performed using appropriate statistical software, such as SAS 
(Version 9.4 or above). PK parameters will be calculated using Phoenix WinNonlin (Version 8.1 
or above). 
13.1.1. 
Sample Size and Power 
The number of subjects to be enrolled was chosen based on practical considerations and is 
considered sufficient for the study objectives. No formal sample size calculation was performed. 
13.1.2. 
Analysis Populations 
• Safety Population: All subjects who have received one dose of cenobamate   
• PK Population: All subjects who have received one dose of cenobamate and have 
sufficient quantifiable PK samples to calculate primary PK parameters appropriately. 
The final decision to include subjects in the PK population set took into consideration 
possible AEs affecting the disposition of cenobamate (e.g., vomiting or diarrhea). 
Reasons supporting each decision will be clearly stated in the clinical study report. A 
sensitivity analysis may be performed if deemed necessary to support a subject’s 
exclusion or inclusion. 
13.1.3. 
Pharmacokinetic Analysis 
This section will be further detailed in the CPAP. 
13.1.3.1. Pharmacokinetic Parameters 
The PK parameters that will be derived from the cenobamate concentration versus time profiles, 
where data permit, are listed in Table 16. 
The plasma PK parameters will be estimated using a non-compartmental approach. A linear-up, 
log-down approach will be used to estimate the area under the plasma concentration versus time 
curve, and the terminal half-life will be estimated where appropriate. 


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Further information on the determination of PK parameters is outlined in the Clinical 
Pharmacology Analysis Plan (CPAP). 
Table 16: 
Primary Pharmacokinetic Parameters 
PK Parameter 
Definition 
Cmax  
Maximum plasma concentration 
AUClast  
Area under the plasma concentration vs. time curve calculated from time zero to the 
last sampling point that is above the lower limit of quantification 
AUC∞  
Area under the plasma concentration vs. time curve from time zero to the last 
sampling point that is above the lower limit of quantification and extrapolated to 
infinite time 
AUC%extrap 
Ratio of AUCt to AUC∞ expressed as percentage 
λz  
Terminal rate constant 
t½  
Terminal half-life 
tmax  
Time of maximum plasma concentration 
Clast 
Concentration measured at the last time point 
CL/F 
Oral clearance 
Vz/F 
Apparent volume of distribution 
Other PK parameters will be determined if deemed appropriate. Details of the PK analysis will 
be provided in the CPAP. 
13.1.3.2. Formulation and Food Effect Analysis 
An analysis of variance (ANOVA) will be used to compare suspension vs. tablet formulations 
and suspension under fed vs. suspension under fasted conditions. PK parameter (Cmax, AUClast, 
and AUC∞) values will be log-transformed for all subjects included in the PK population set and 
the ratio and corresponding 90% CIs for the ratio of the test (suspension or fed) vs. reference 
(tablet or fasted) will be compared. An absence of effect will be concluded if the 90% CIs lie 
within the 80% - 125% predefined boundaries. 
13.1.3.3. Analysis on Tmax 
For each subject, the Wilcoxon signed-rank test will be used to test for differences in tmax. 
13.1.3.4. Summary and Presentation of PK Data and Parameters in the CSR 
Individual and mean plasma concentrations at each sampling time point for cenobamate will be 
presented in listings and tables with descriptive summary statistics including mean, geometric 
mean, range, standard deviation (SD) and coefficient of variation (CV). Individual, mean and/or 
median concentrations per treatment group will be plotted versus time on semi-logarithmic 
scales.  
Summary statistics of PK parameters including mean, geometric mean, median, range, SD and 
CV will be presented by treatment group. 


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13.2. 
Other Statistical Analyses 
13.2.1. 
Efficacy Analysis 
No formal efficacy analysis will be performed. 
13.2.2. 
Safety Analysis 
Safety and tolerability will be assessed through AEs, clinical laboratory, vital signs, and physical 
examination findings, and any other parameter that are relevant for safety assessment. Full 
details of the safety analysis to be performed will be included in the SAP. 
13.2.3. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). MedDRA terms will be used to summarize AEs by system organ class (SOC) and 
preferred term (PT). 
Treatment-emergent adverse events (TEAEs) are defined as adverse events that were started or 
worsened on or after the date of the first dose of study medication (Day 1) to the follow-up visit 
(Day 69). 
A listing of all individual AEs will be provided. Summary tables of TEAEs will be presented by 
SOC and PT, including a table containing the number of subjects experiencing AEs by treatment 
group, and a table containing the number of subjects experiencing SAEs by treatment group (if 
applicable). Details of the AE summary analyses will be described in Statistical Analysis Plan 
(SAP). 
13.2.4. 
Clinical Laboratory Assessments 
All lab data will be displayed as International System of units (SI) and may be converted into 
other systems (e.g., United States customary system [USCS or USC]) for reporting and 
processing purposes, as appropriate. 
Clinical laboratory data will be listed and accompanied by an indication flag if the parameter is 
outside the reference range and a summary listing of all data assessed by the Investigator as 
clinically significant will be prepared. Clinical laboratory data will also be summarized 
descriptively.  
13.2.5. 
Vital Signs 
Vital signs will be listed, and presented descriptively, where applicable. 
13.2.6. 
Physical Examinations 
Physical examination data will be listed by subject. 
13.2.7. 
Demographic Data 
Demographic data will be listed by subject and summarized across all subjects and by treatment 
group. 


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13.2.8. 
Baseline Characteristics and Other Data 
Baseline characteristics, medical history, prior and concomitant medications, protocol deviations, 
study treatment exposure, disposition, etc., will be listed and summarized across all subjects, 
where applicable.  


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Monitoring and auditing procedures developed or approved by SKLSI will be followed, in order 
to comply with Good Clinical Practice (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 SKLSI 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. 
14.2. 
Audits and Inspections 
Authorized representatives of SKLSI, a regulatory authority, an Independent Ethics Committee 
or an Institutional Review Board may visit the site to perform audits or inspections, including 
source data verification.  The purpose of an SKLSI audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements.  The investigator should contact 
SKLSI immediately if contacted by a regulatory agency about an inspection. 
14.2.1. 
Electronic Data Capture (EDC) 
SKLSI 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.  
SKLSI 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. 


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14.2.2. 
Case Report Forms 
Source documents will be used to record all study-related data. Designated staff will enter the 
data required by the protocol into the Electronic Case Report Forms (eCRF) using Medrio, a 
fully validated software that conforms to 21 CFR Part 11 requirements. 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse events (SAEs) will be captured in EDC. 
14.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
SKLSI may conduct a quality assurance audit.  Please see Section 14.2 for more details 
regarding the audit process. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  The 
investigator must submit written approval to SKLSI before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  SKLSI will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the current International Conference on 
Harmonisation-Good Clinical Practice (ICH-GCP) Guidelines, which are consistent with the 
ethical principles founded in the Declaration of Helsinki, and according to local regulations. The 
Institutional Review Board (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, IB, 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.  
16.2.1. 
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 SKLSI. 
16.2.2. 
Investigator Compliance 
No modifications to the protocol will be made without the approval of SKLSI. 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. (SKLSI) will submit all protocol modifications to the required regulatory 
authorities. 


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When circumstances require an immediate departure from procedures set forth in the protocol, 
the Investigator will contact SKLSI 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. 
16.2.3. 
Access to Records 
The Investigator must make the source documents of subjects enrolled in this study available for 
inspection by SKLSI 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.  
16.2.4. 
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 SKLSI 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. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Patients must also be notified that they are free to discontinue from the study at any time.  The 
patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the patient. 
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
SKLSI will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study.  The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
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 SKLSI must be notified.  
17.2.1. 
Screening 
After signing of the ICF/assent form, each subject will be assigned an 8-digit subject 
identification number (i.e. 01001001). The first two digits is for country, the next 3 digits is for 
site, and the last 3 digits is for subject.  
The subjects who screen-fail will be allowed to re-screen only once. The re-screened subject will 
be assigned a new subject ID, and the 2 subject IDs will be linked in the clinical database. 
17.2.2. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the sponsor or designee electronically (e.g., laboratory data). 
• The investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring 
thresholds, quality tolerance thresholds, controls, and mitigation plans will be 
documented in a risk management register. Additional details of quality checking to 
be performed on the data may be included in a Data Management Plan. 
• A study monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 


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approved protocol and any other study agreements, ICH-GCP, and all applicable 
regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator in accordance with local regulations or institutional policies. No 
records may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to the 
sponsor. 
17.2.3. 
Investigator Documentation Responsibilities 
• All individual, subject-specific study data will also be entered into a 21 Code of 
Federal Regulations Part 11-compliant electronic data capture (EDC) system on an 
eCRF in a timely fashion. 
• All data generated from external sources (e.g., laboratory and bioanalytical data), and 
transmitted to the sponsor or designee electronically, will be integrated with the 
subject’s eCRF data in accordance with the Data Management Plan. 
• An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The sponsor, or CRO, 
will review the supporting source documentation against the data entered into the 
eCRFs to verify the accuracy of the electronic data. The investigator will ensure that 
corrections are made to the eCRFs and that data queries are resolved in a timely 
fashion by the study staff. 
• Terms will be coded in accordance with MedDRA and WHO Drug dictionary 
versions specified in Data Management Plan. 
• The investigator will sign and date the eCRF via the EDC system’s electronic 
signature procedure. These signatures will indicate that the investigator reviewed and 
approved the data on the eCRF, data queries, and site notifications. 


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18. 
PUBLICATION POLICY 
18.1. 
Publication of Study Results 
Any and all scientific, commercial, and technical information disclosed by SKLSI in this 
protocol or elsewhere should be considered confidential and proprietary property of SKLSI 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 SKLSI 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 SKLSI 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 SKLSI and the Investigator and/or the 
Investigator’s institution. 
18.2. 
Clinical Study Report 
A clinical study report that is written in accordance with ICH Guideline E35 will be submitted in 
accordance with local regulations.  
 


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19. 
LIST OF REFERENCES 
1. Cenobamate (YKP3089) Investigator’s Brochure, October 05, 2020 (Version 14). 
2. Vernillet L, Greene SA, Kamin M, Pharmacokinetics of Cenobamate: Results from 
Single and Multiple Ascending Dose Studies in Healthy Subjects. Clinical Pharmacology 
in Drug Development. 2020 Feb 22. Doi:10.1002/cpdd.769 
3. Vernillet L, Greene SA, et al., Mass Balance, Metabolism, and Excretion of Cenobamate, 
a New Antiepileptic Drug, After a Single Oral Administration in Healthy Male Subjects. 
Eur J Drug Metab Pharmacokinet. 2020 Apr 16. doi:10.1007/s13318-020-00615-7 PMID: 
32301064 
4. Assess the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology 
Considerations, Guidance for Industry, U.S. Department of Health and Human Services, 
Food and Drug Administration, Center for Drug Evaluation and Research, February 
2019. 
5. International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline, E3: Structure 
and Content of Clinical Study Reports (CPMP/ICH/137/95), Nov 1995. 


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20. 
APPENDICES 
 
 

SAP_001.pdf: 
Confidential and Proprietary, SK Life Science, Inc. 
 
 
 
 
 
CLINICAL STUDY PROTOCOL: SKLYKP3089C037 
 
 RELATIVE BIOAVAILABILITY OF A SINGLE 200 MG DOSE OF CENOBAMATE 
(YKP3089) GIVEN AS AN ORAL TABLET OR AS AN ORAL SUSPENSION AND THE 
EFFECT OF FOOD ON A SINGLE 200 MG DOSE OF CENOBAMATE GIVEN AS AN 
ORAL SUSPENSION 
 
 
Statistical Analysis Plan 
 
 
 
Version 1.0: 26 Jul 2021 
 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 




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REVISION HISTORY 
Draft Version 
Date 
Author 
Description 
0.1 
14 January 2021 
Jacqueline Cater 
Based on Protocol v1.0 
0.2 
29 March 2021 
Jacqueline Cater 
Based on Protocol Amendment 1, v2.0 
0.3 
21 June 2021 
Jacqueline Cater 
Revisions based on SK comments 
0.4 
26 July 2021 
Jacqueline Cater 
Revisions based on SK comments 
 
 
 


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TABLE OF CONTENTS 
Table of Contents .................................................................................................................3 
LIST OF ABBREVIATIONS ..............................................................................................5 
1 
Introduction ...................................................................................................................6 
1.1  Study Design .......................................................................................................6 
1.2  Number of Subjects ...........................................................................................12 
2 
Study Objectives and Endpoints .................................................................................13 
2.1  Objectives ..........................................................................................................13 
2.1.1 Primary Objectives ................................................................................13 
2.1.2 Secondary Objectives ............................................................................13 
2.2 Endpoints ...........................................................................................................13 
2.2.1  Primary Endpoints .................................................................................13 
2.2.2  Secondary Endpoints .............................................................................13 
3 
Analysis Populations ...................................................................................................14 
3.1 Safety Population ..............................................................................................14 
3.2 Pharmacokinetic Population ..............................................................................14 
4  Statistical Methodology...............................................................................................15 
4.1 Subject Disposition ............................................................................................15 
4.2 Protocol Deviation .............................................................................................15 
4.3 Demographics and Other Baseline Characteristics ...........................................15 
4.4 Medical History .................................................................................................15 
4.5 Prior and Concomitant Medications ..................................................................15 
4.6  Pharmacokinetic Analysis .................................................................................16 
4.6.1 Plasma Drug Concentrations and Pharmacokinetic Parameters...............16 
4.6.2 Statistical Analysis of Pharmacokinetic Data to Assess Formulation Effect
 
16 
4.6.3 Statistical Analysis of Pharmacokinetic Data to Assess Food Effect ......17 
5 
Extent of Exposure and Treatment Compliance .........................................................19 
5.1 Extent of Exposure ............................................................................................19 
5.2 Treatment compliance .......................................................................................19 
5.3 Meal Record ......................................................................................................19 
6 
Safety Analysis ............................................................................................................20 
6.1 Adverse Events ..................................................................................................20 
6.2 Clinical Laboratory Parameters .........................................................................20 
6.3 Vital Signs .........................................................................................................22 
6.4 Safety 12-Lead Electrocardiogram ....................................................................22 
6.7 Columbia Suicide Severity Rating Scale ...........................................................22 


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6.8 Other Safety Assessments .................................................................................23 
7 
Interim Analysis ..........................................................................................................24 
8 
General Statistical Consideration for Data Analysis and Handling ............................25 
8.1 General Statistical Procedures ............................................................................25 
8.2 Study Day and Baseline ....................................................................................25 
8.3 Data Handling Conventions ..............................................................................26 
8.3.1  Repeated or Unscheduled Assessments of Safety Parameters ..............26 
8.3.2  Missing/Incomplete Date Conventions ................................................26 
8.3.3 Missing Severity Assessment for Adverse Events ................................28 
8.3.4 Missing Causal Relationship to study drug for Adverse Events ...........28 
8.3.5 Character Values of Clinical Laboratory Parameters ............................28 
9 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ......................................30 
10 References ...................................................................................................................31 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CPAP 
clinical pharmacology analysis plan 
CRU 
clinical research unit 
DB 
Double-blind 
ECG 
electrocardiogram 
ET 
Early termination 
HBsAG 
Hepatitis B Surface Antigen 
HCV (C) 
Hepatitis C Virus 
ICF 
Informed consent form 
IP 
investigational product 
LLN 
Lower limit of normal 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
N, n 
number of subjects, observations 
PE 
physical examination 
PI 
principal investigator 
PK 
pharmacokinetic 
PT 
preferred term 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using the Fridericia correction 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
systéme international  
SOC 
system organ class 
SOP 
standard operating procedures 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
LLN 
lower limit of normal 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data presentation 
to be used for the analysis and summarization of the safety data from Protocol 
SKL-YKP3089C037. The clinical pharmacology analysis plan (CPAP) which details the planned 
analyses for the pharmacokinetic (PK) data for this study will be a separate document. 
The SAP will be finalized before database lock. Any changes made after finalization of the SAP 
will be documented in the clinical study report (CSR). Related documents are the study protocol 
and electronic case report forms.  
1.1  
Study Design 
This study is an open-label, randomized, single-dose, single-center, three-period, six-sequence, 
balanced crossover study in which healthy subjects, balanced amongst gender and ethnic groups to 
the extent possible, will receive either a single oral 200 mg dose of cenobamate given as a tablet 
under fasted conditions (Treatment A), a single oral 200 mg dose of cenobamate given as an oral 
suspension under fasted conditions (Treatment B), or a single oral 200 mg dose of cenobamate 
given as an oral suspension under fed conditions (Treatment C). A schematic of the study design is 
presented below in Figure 1. 
 
Figure 1 
Schematic of Study Design 
 
 


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Following Screening, eligible subjects will be randomized to one of the 6 treatment sequences. 
Each sequence will include a single dose of the following treatments: 
• Treatment A:  single oral 200 mg dose of cenobamate tablet under fasting conditions  
• Treatment B:  single oral 200 mg dose of cenobamate suspension under fasting conditions 
• Treatment C:  single oral 200 mg dose of cenobamate suspension under fed conditions 
The three-period, six-sequence Williams Design to be used in this study is displayed in Table 1 
below.  
 
Table 1: 
Three-period Six-sequence Williams Design 
Treatment Sequence 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
C 
B 
A 
5 
A 
C 
B 
6 
B 
A 
C 
The letters in the table correspond to:  
A: single oral 200 mg dose of cenobamate tablet under fasting conditions 
B: single oral 200 mg dose of cenobamate suspension under fasting conditions 
C: single oral 200 mg dose of cenobamate suspension under fed conditions 
 
The study will be conducted in three periods each with a single dose followed by a 21-day washout 
during which PK samples will be taken. The study periods will be conducted as follows: 
Period 1 
• Day -1 to Day 4 (morning) – Subject Confinement 
• Day 1 – Dosing 
• Day 6 (morning) – Subject to return to clinic for 120-hour PK sample and 
medical check 
• Day 9 (morning) – Subject to return to clinic for 192-hour PK sample and medical 
check 
• Day 12 (morning) – Subject to return to clinic for 264-hour PK sample and medical 
check 
• Day 16 (morning) – Subject to return to clinic for 360-hour PK sample and medical 
check 
• Day 20 (morning) – Subject to return to clinic for 456-hour PK sample and medical 
check and begin confinement for Period 2 


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Period 2 
• Day 20 to Day 25 (morning) – Subject Confinement 
• Day 22 – Pre-dose PK Sample and Dosing 
• Day 27 (morning) – Subject to return to clinic for 120-hour PK sample and 
medical check 
• Day 30 (morning) – Subject to return to clinic for 192-hour PK sample and 
medical check 
• Day 33 (morning) – Subject to return to clinic for 264-hour PK sample and 
medical check 
• Day 37 (morning) – Subject to return to clinic for 360-hour PK sample and 
medical check 
• Day 41 (morning) – Subject to return to clinic for 456-hour PK sample and 
medical check and begin confinement for Period 3 
Period 3 
• Day 41 to Day 46 (morning) – Subject Confinement 
• Day 43 – Pre-dose PK Sample and Dosing 
• Day 48 (morning) – Subject to return to clinic for 120-hour PK sample and 
medical check 
• Day 51 (morning) – Subject to return to clinic for 192-hour PK sample and 
medical check 
• Day 54 (morning) – Subject to return to clinic for 264-hour PK sample and 
medical check 
• Day 58 (morning) – Subject to return to clinic for 360-hour PK sample and 
medical check 
• Day 62 (morning) – Subject to return to clinic for 456-hour PK sample and 
medical check 
Follow-Up 
Day 69 ± 1 day (morning) – Subject to return to clinic for follow-up visit.  
 
Study procedures will be completed as per the Schedule of Assessments outlined in Table 2. 


9 
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    Table 2: 
 Schedule of Assessments 
Assessment 
Screening 
Base 
Treatment Period 
FU 
Visit(s) 
1 
2,7,12j 
3,8, 
13 
4,9, 
14 
5,10, 
15 
6,11, 
16 
7,12, 
17i 
18 
Study 
Day(s) 
-28 to 
-2 
-1 
1,22,43 
2,23, 
44 
3,24, 
45 
4,25, 
46 
6,27, 
48 
9,30, 
51 
12,33, 
54 
16,37, 
58 
20,41, 
62 
69 
(±1) 
Post-Dose 
Time (hr) 
-- 
-- 
0 
0.5 
1 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
14 
18 
24 
36 
48 
72 
120 
192 
264 
360 
456 
504 
Informed Consent 
X 
Inclusion/ Exclusion 
X 
X 
Eligibility 
Confirmation 
Xa 
C-SSRS 
Xb 
Xc 
Xc 
Xc 
Dispense Safety 
Card 
X 
Randomizationd 
X 
Medical History 
X 
Demographics 
X 
Weight/ BMI 
X 
X 
Height 
X 
Serum Pregnancye 
X 
Urine Pregnancye 
X 
X 
Serum FSHe,f 
X 


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Assessment 
Screening 
Base 
Treatment Period 
FU 
Visit(s) 
1 
2,7,12j 
3,8, 
13 
4,9, 
14 
5,10, 
15 
6,11, 
16 
7,12, 
17i 
18 
Study 
Day(s) 
-28 to 
-2 
-1 
1,22,43 
2,23, 
44 
3,24, 
45 
4,25, 
46 
6,27, 
48 
9,30, 
51 
12,33, 
54 
16,37, 
58 
20,41, 
62 
69 
(±1) 
Post-Dose 
Time (hr) 
-- 
-- 
0 
0.5 
1 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
14 
18 
24 
36 
48 
72 
120 
192 
264 
360 
456 
504 
Clinical Laboratory 
X 
X 
X 
X 
X 
HIV, Hep B/C 
X 
Urine Drug Screen 
X 
X 
X 
X 
X 
X 
X 
Breath Alcohol 
X 
X 
X 
X 
X 
X 
X 
Physical Examg 
X 
X 
X 
Vital Signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
AE Monitoring 
Continuous Throughout 
Treatment 
Administration 
X 
PK Blood Sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacogenomic 
Blood Sampling 
X 
Discharge 
X 
Outpatient Visit 
X 
X 
X 
X 
Xi 
X 
Note: C-SSRS= Columbia Suicide Severity Rating Scale; AE = adverse event; BMI = body mass index; ECG = electrocardiogram; FSH = follicle stimulating 
hormone; h = hour; PK = pharmacokinetic 
a Review Inclusion/Exclusion on Day -1 
b Baseline “Baseline/Screening” version of C-SSRS will be used 


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c “Since Last Visit” version of the C-SSRS will be used 
d Randomization to occur prior to dosing on Day 1. 
e Pregnancy testing for female subjects of childbearing potential only; postmenopausal women with last menses less than one year will have a serum pregnancy 
and FSH test during screening only 
f Postmenopausal women only, including women with last menses less than one year 
g Complete physical examination at Screening; Symptom-oriented physical examination on Day 1, Day 22, Day 43 and at follow-up 
h Vital signs (supine systolic and diastolic blood pressure, pulse rate, respiratory rate, and body temperature) measurement in supine position (at least 5 minutes). 
i Note that Visit 17 only is an outpatient visit while Visit 7 and 12 are CRU admission days to bridge between periods 
j Visit 2 is baseline visit Visits 7 and 12 are the start of periods 2 and 3 respectively 
 
 


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1.2  
Number of Subjects 
A total of 24 (4 subjects per sequence) healthy female and male subjects, balanced by gender and 
race/ethnicity to the extent possible, who satisfy all of the inclusion criteria (and none of the 
exclusion criteria), as well as all screening evaluations, before enrollment in the study, will be 
included in the study. If needed and agreed upon by SKLSI and investigator, replacement 
subjects will be assigned to the same treatment sequence as the subject they are replacing in 
order to have at least 15 subjects completing all three treatments, 
The number of subjects to be enrolled was chosen based on practical considerations and is 
considered sufficient for the study objectives. No formal sample size calculation was 
performed. Subjects who do not complete all the treatments and assessments specified in this 
protocol may be replaced.  


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1  
Objectives 
2.1.1 
Primary Objectives 
• To assess relative bioavailability of 200 mg of cenobamate given as an oral tablet vs 
200 mg of cenobamate given as an oral suspension in fasting condition 
• To assess the effect of food on the bioavailability of a 200 mg oral dose of 
cenobamate given as a suspension 
The primary PK objectives are discussed in further detail in the CPAP. 
2.1.2 
Secondary Objectives 
To assess the safety and tolerability of a single 200 mg dose of cenobamate given as either an 
oral tablet in fasting condition or an oral suspension in fasting and fed condition.  
2.2 
Endpoints 
2.2.1  
Primary Endpoints 
PK parameters will be calculated for cenobamate from plasma data. PK endpoints will be 
defined in the CPAP.  
 
2.2.2  
Secondary Endpoints 
1. Adverse events (AEs) 
2. Safety laboratory tests (including clinical chemistry, hematology, coagulation and 
urinalysis) 
3. Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature) 
4. Physical examination 
5. Columbia-Suicide Severity Rating Scale (C-SSRS) score. 
 


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3 
ANALYSIS POPULATIONS 
3.1 
Safety Population 
The safety population includes all subjects who are randomized and receive at least 1 dose of 
cenobamate.  
3.2 
Pharmacokinetic Population 
All subjects who have received one dose of cenobamate and have sufficient quantifiable PK 
samples to calculate primary PK parameters appropriately. The final decision to include subjects 
in the PK population set takes into consideration possible AEs affecting the disposition of 
cenobamate (e.g., vomiting or diarrhea). Reasons supporting each decision will be clearly stated 
in the clinical study report. A sensitivity analysis may be performed if deemed necessary to 
support a subject’s exclusion or inclusion. 


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4  
STATISTICAL METHODOLOGY 
4.1 
Subject Disposition 
The number and percentage of subjects in the study populations (Safety and PK) will be 
summarized by sequence and overall. 
The number and percentage of subjects who enter, complete and prematurely discontinue from 
the study as recorded on the termination pages of the eCRF will be summarized (number and 
percentage) by sequence and overall.  
Screen failure subjects (i.e.; subjects screened but not randomized) and the associated reasons for 
failure, inclusion (not met) and exclusion (met) criteria will be listed. A listing of subjects who 
prematurely discontinued will be provided. A data listing of subject disposition, study 
completion status, and reason for study discontinuation will also be provided. Table and listings 
for disposition will be provided for all randomized subjects. 
4.2 
Protocol Deviation 
Protocol deviations for all randomized subjects will be captured in a log by the project manager, 
exported into a clinical dataset, and presented in a data listing. 
The number and percentage of subjects with any protocol deviation will be tabulated for each 
type of deviation (Major/Minor and overall) by sequence and overall. A listing of all protocol 
deviations will also be provided for all randomized subjects. 
4.3 
Demographics and Other Baseline Characteristics 
Demographic parameters (age; race; ethnicity; sex), baseline characteristics (weight; height; and 
body mass index[BMI]) will be summarized descriptively by treatment sequence and overall for 
the Safety population. Continuous variables will be summarized by number of subjects and 
mean, standard deviation (SD), median, minimum, and maximum values. Categorical variables 
will be summarized by number and percentage of subjects. 
A data listing will be presented for all demographic and other baseline characteristics data. 
4.4 
Medical History 
Abnormalities collected in subjects’ CRF pages of medical and surgical histories will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0. The number 
and percentage of subjects with abnormalities in each system organ class (SOC) and preferred 
term (PT) will be summarized overall for the Safety Population. 
 
4.5 
Prior and Concomitant Medications 
Prior medication is defined as any medication taken before the date of the first dose of IP. 
Concomitant medication is defined as any medication taken on or after the date of the first dose 
of IP.  


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The use of prior and concomitant medications will be summarized for the Safety Population by 
the number and percentage of subjects overall for prior medications, and by sequence and overall 
for concomitant mediations. If a subject took a specific medication multiple times or took 
multiple medications within a specific therapeutic class, the subject would be counted only once 
for the coded drug name or therapeutic class.  
World Health Organization (WHO) Drug Dictionary (WHODrug Global B3 Mar2020 version), 
will be used to classify prior and concomitant medications by therapeutic class and drug name. 
4.6  
Pharmacokinetic Analysis 
4.6.1 Plasma Drug Concentrations and Pharmacokinetic Parameters 
The individual plasma drug concentration versus time profiles will be presented using the actual 
sampling times whereas the mean plasma drug concentration versus time profiles will be 
presented using the nominal sampling times. Descriptive statistics, N (number of datapoints 
available), arithmetic mean, median, arithmetic coefficient of variation (%CV), SD of the mean, 
geometric mean, geometric %CV, minimum value observed, and maximum value observed, will 
be calculated for plasma drug analyte concentrations at each individual time point for 
cenobamate.  
PK parameters will be calculated using a non-compartmental approach. The primary PK 
endpoints will include AUC from 0 to infinity (AUC∞), area under the concentration versus time 
curve (AUC) from 0 to the last time point with a concentration above the lower limit of 
quantitation (AUClast), and maximum observed drug concentration (Cmax) for cenobamate. These 
parameters will be derived for all treatments received by each subject. 
Further PK endpoints for cenobamate as the data permits will include the following: terminal 
half-life (t1/2), time to maximum cenobamate plasma concentration (tmax), oral clearance (CL/F), 
terminal rate constant (λz), apparent volume of distribution during terminal phase (Vz/F), and last 
observed cenobamate plasma concentration (Clast).  
Refer to CPAP for description of summary statistics for the primary and further PK endpoints.  
4.6.2 Statistical Analysis of Pharmacokinetic Data to Assess Formulation 
Effect 
For the evaluation of the formulation effect on cenobamate PK, an analysis of variance 
(ANOVA) model will be used and the differences between test and reference treatments for 
AUC∞, AUClast, and Cmax of cenobamate will be estimated (test and reference treatments are 
outlined below in Table 3). The PK parameters will be logarithmically transformed prior to 
analysis and the ANOVA models will include treatment, sequence, and period as fixed effects, 
and subject nested within sequence as a random effect. From this model, the difference and 90% 
confidence limits between the test and reference treatments on the log scale will be 
exponentiated to present the estimates of the geometric mean ratio and associated 90% 
confidence limits.  The absence of a formulation effect will be concluded if the 90% CIs lie 
within the reference range of [0.80-1.25]. No adjustments will be made for multiplicity.  
 
 


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The following SAS pseudo code will be used: 
   proc mixed data=dataset; 
   by parameter; 
   class treatment sequence period subject; 
   model ln_aval = treatment sequence period /  ddfm=kr; 
   random subject (sequence); 
   estimate  “BioAv Trt B (Test: Suspension Fasted)  vs Trt A (Ref: Tablet Fasted)”   
             treatment  -1  1  0  / cl  alpha=0.1; 
   run; 
 
A forest plot of the geometric LS mean ratios of AUC0-∞, AUC0-last, and Cmax of cenobamate will 
be provided for a visual representation of the data. A single plot will be provided for the test 
versus reference formulation comparison, with all PK parameters on the plot. 
In addition, Wilcoxon signed-rank tests will be used to test for the differences in tmax.   
The following SAS pseudo code may be used for the Wilcoxon signed-rank test for each 
treatment comparison: 
data data2; 
set data1; 
diffBA= TRTB – TRTA; 
run; 
  
ods output TestsForLocation=Tests(where=(test='Signed Rank')); 
proc univariate data= data2; 
var diffBA; 
run; 
4.6.3 Statistical Analysis of Pharmacokinetic Data to Assess Food Effect 
The food effect will be assessed from the same ANOVA model as in section 4.6.2, with the 
specific contrasts as indicated in the SAS pseudo code below. 
 
proc mixed data=dataset; 
   by parameter; 
   class treatment sequence period subject; 
   model ln_aval = treatment sequence period /  ddfm=kr; 
   random subject (sequence); 
   estimate “BioAv Trt C (Test: Suspension Fed)  vs Trt B (Ref: Suspension Fasted)”   
              treatment  0  -1  1 / cl  alpha=0.1; 
   run; 
 
A forest plot of the geometric LS mean ratios of AUC∞, AUClast, and Cmax of cenobamate will be 
provided for a visual representation of the data. A single plot will be provided for the test versus 
reference food effect comparison, with all PK parameters on the plot. 
 


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In addition, Wilcoxon signed-rank tests will be used to test for the differences in tmax for the food 
effect.   
The following SAS pseudo code will be used for the food effect comparison: 
data data2; 
set data1; 
diffCB = TRTC – TRTB; 
run; 
  
ods output TestsForLocation=Tests(where=(test='Signed Rank')); 
proc univariate data= data2; 
var diffCB; 
run; 
 
 
Table 3: 
Test Treatment and Reference Formulation Treatment for ANOVA Analysis  
Assessment 
Test Treatment 
Reference Treatment 
Bioavailability a 
Oral Suspension administered 
under fasted conditions 
Oral Tablet administered under 
fasted conditions 
Food Effect  
Oral Suspension administered 
under fed conditions 
Oral Suspension administered 
under fasted conditions 
a Bioavailability is assessed for treatments administered under fasting conditions  
 
 


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5 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
5.1 
Extent of Exposure 
Study treatment exposure will be summarized by sequence, treatment period, and study day.  
IP administration dates and times will be provided in a data listing. 
 
5.2 
Treatment compliance  
There will be no planned table or listing for treatment compliance for this study. Treatment 
compliance will be seen from the table above and the listing of Investigational Product Dosing 
Records.  
 
5.3 
Meal Record 
Details of meal records, such as meal type, date/time of meal, and amount consumed will be 
listed.  


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6 
SAFETY ANALYSIS 
The safety analysis will be performed using the safety population. The safety parameters will 
include adverse events (AEs), clinical laboratory parameters, vital signs, and 
electrocardiographic (ECG) assessments. The last non-missing safety assessment before the date 
of first dose of study treatment will be used as the baseline for all analyses of that safety 
parameter. Continuous variables will be summarized by the number of subjects and mean, SD, 
median, minimum, and maximum values. Categorical variables will be summarized by the 
number and percentage of subjects. 
 
6.1 
Adverse Events 
Adverse events will be coded by system organ class and preferred term using the MedDRA, 
Version 23.0. 
 
Treatment-emergent AEs (TEAEs) are defined as AEs that start or worsen (increase in severity) 
on or after the first dose date of study medication (Day 1) to the follow-up visit (Day 69). 
 
If more than 1 AE is coded to the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the greatest severity and strictest causality for the 
summarization by severity and causal relationship. 
Related TEAEs include all those classified by the investigator as having a possible, probable, or 
definite relationship to the Investigational product. Unrelated TEAEs are those events classified 
as unrelated or having a remote likelihood of being related to the Investigational product. If the 
same event occurs more than once per subject and treatment, and there is more than 1 
relationship classification, the most related value will be summarized. For summaries by 
severity, the most severe grade will be selected. 
The number and percentage of subject with TEAEs by system organ class and preferred term, 
and by severity, and by causal relationship to the IP, will be summarized by treatment and 
overall. 
A listing of all AEs, along with SAEs, AEs leading to death, and AEs leading to discontinuation 
of IP will be provided.  
The MedDRA version will be specified in a footnote in both tables and data listings.  
 
6.2 
Clinical Laboratory Parameters  
Descriptive statistics for clinical laboratory values in Table 4 (in SI units) and changes from the 
baseline values at each assessment time point will be presented by treatment for the following 
laboratory parameters, measured at Screening visit (Days -28 to -2), Day -1, post-dose Days 4 
and 20 of each treatment period and Day 69 (end of study).  


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   Table 4: 
Clinical Laboratory Tests 
Hematology and 
Coagulation 
Serum Chemistry 
Urinalysis 
Additional Tests 
Hemoglobin 
Sodium 
pH 
Serology: anti-HIV-1/2, HBsAg, 
anti-HCV 
Hematocrit 
Potassium 
Specific gravity 
Erythrocytes 
Chloride 
Color 
Platelets 
Calcium 
Protein 
FSH test 
for postmenopausal women, 
including women whose last 
menstruation was < 1 year before 
screening 
Leukocytes 
Inorganic phosphate 
Glucose 
Neutrophils 
Urea 
Ketones 
Eosinophils 
Creatinine 
Hemoglobin 
(erythrocytes) 
Lymphocytes 
Uric acid 
Monocytes 
Total bilirubin 
Leukocytes 
Serum pregnancy test for women 
of childbearing potential, 
including women whose last 
menstruation was < 1 year before 
screening 
Basophils 
Direct bilirubin 
Microscopic 
analysis, if urine is 
positive for protein, 
leukocytes or 
hemoglobin 
INR 
ALT 
aPTT 
AST 
PT 
GGT 
AP 
LDH 
Urine drugs of abuse test 
including but not limited to 
cannabinoids, amphetamines, 
methamphetamines, opiates, 
methadone, cocaine, 
benzodiazepines, and barbiturates 
CPK 
Amylase 
Lipase 
Triglycerides 
Total cholesterol 
HDL cholesterol 
LDL cholesterol 
Total protein 
Albumin 
Alcohol breath test 
Glucose 
INR: International Normalized Ratio; aPPT: Activated Partial Thromboplastin Time; PT: Prothrombin Time; 
ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; GGT: Gamma-glutamyl Transferase; AP: 
Alkaline Phosphatase; LDH: Lactate Dehydrogenase; CPK: Creatine Phosphokinase; HDL: High Density 
Lipoprotein; LDL: Low Density Lipoprotein; HIV: Human Immunodeficiency Virus; HBsAg: Hepatitis B 
Surface Antigen; HCV: Hepatitis C virus. 


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Smoking history and Drug of Abuse/Alcohol Screen will be measured at Screening visit and Day 
-1 visits.  
 
The following clinical laboratory levels will be measured at Screening only: 
• Serology:  HIV-1/HIV-2 antibody, HbsAg and Anti-HCV  
• FSH and Pregnancy Test for female subjects  
 
A shift table from baseline to worst postbaseline evaluations will be presented by treatment for 
the following categories: low, normal, and high. The denominators for calculating the 
percentages will be based on the number of subjects with non-missing assessments at Baseline 
and at least 1 post-baseline value for each parameter. 
Unscheduled assessments that are not used as Baseline will not be included in summary tables 
except in the shift summaries; however, all clinical laboratory values will be presented in a data 
listing, in chronological order, or by date for unscheduled values. 
The actual values of clinical laboratory evaluations, date of collection/time, and reference range 
and clinical significance will be listed for each visit. 
6.3 
Vital Signs 
Descriptive statistics for actual values and changes from Baseline for vital signs (systolic and 
diastolic blood pressures, heart rate, respiratory rate, and temperature in supine position) will be 
summarized at Screening visit (Days -28 to -2), pre-dose on Day 1, post-dose on Days 4, 6, 9, 12, 
16, 20 of each treatment period and Day 69 (end of study).  
The actual values of vital signs, date of collection/time, reference ranges, and clinical 
significance will be listed for each scheduled visit. 
6.4 
Safety 12-Lead Electrocardiogram 
ECG parameters (heart rate (HR), RR, PR, QT, QTc intervals, and QRS duration) collected at  
Screening visit (Days -28 to -2), and Day -1 (prior to study drug administration) will be provided 
in a listing. 
The actual values of ECG parameters, date of collection/time, reference ranges, and clinical 
significance will be listed for each scheduled time point and visit. 
6.7 
Columbia Suicide Severity Rating Scale 
For the Columbia-Suicide Severity Rating Scale (C-SSRS), the number and percentage of 
subjects with suicidal ideation and suicidal behavior before the study treatment (life time history 
and past 6 months) and after study treatment (treatment period) will be summarized by treatment 
for the Safety population.  


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The distribution of the most severe suicidal ideation and suicidal behavior will also be presented 
for life history, in the past 6 months and after study treatment. Any subjects with postbaseline 
suicidal ideation or suicidal behavior will be included in a data listing and a separate listing will 
include any reported AEs. A listing of C-SSRS data for all subjects will also be provided, which 
will include subject number, treatment, visit, intensity of suicidal ideation, suicidal behavior type 
and lethality of suicidal behavior, in chronological order.  
6.8 
Other Safety Assessments 
The physical examination findings and other safety assessments will be presented in data listings. 
Abnormal findings will be flagged for clinical significance based on the principal investigator’s 
(PI) judgment. 
 


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7 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
 


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8 
GENERAL STATISTICAL CONSIDERATION FOR DATA 
ANALYSIS AND HANDLING 
8.1 General Statistical Procedures 
The descriptive statistics for continuous variables will be the number of subjects, mean, median, 
standard deviations (SD), minimum, and maximum. Mean and median will be reported to 1 more 
decimal places than the raw data, while the SD will be reported to 2 more decimal places than 
the raw data. Minimum and maximum will be reported with the same decimal places as that of 
the original data. 
 
Frequency distributions for all categorical variables will be presented using counts and 
percentages. Percentages will be reported to 1 decimal place. 
 
Unless otherwise stated, denominators for calculating the percentages in shift analysis (to worst 
assessment) will be based on the number of subjects with non-missing values at both baseline 
and at least one post-baseline analysis visit in the Safety Population.  
 
Unless otherwise stated, statistical analysis will be summarized for each treatment (and overall 
where indicated) using the Safety Population. Listings will be sorted by subject ID, sequence, 
and visit.  
Missing data will not be imputed. 
Reporting and analyses are performed using the SAS System, Version 9.4.  The following 
CDISC version specified in Table 5 will be used. 
 
Table 5. CDISC version 
SDTM/SDTMIG 
Versions 
ADaM/ADaMIG 
Version 
SDTM/ADaM 
Controlled 
Terminology 
SDTM/ADaM 
define.xml 
Pinnacle 
21 
Validator  
1.4/3.2 
2.1/1.1 
2019-06-28/2018-12-
21 
2.0/2.0 
2.2.0 
 
8.2 
Study Day and Baseline 
Study Day is relative to treatment start date; 
If analysis date ≥ treatment start date,  
Day = analysis date – treatment start date +1 
Day 1= treatment start date 
If analysis date ≤ treatment start date,  


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Day = analysis date – treatment start date +1 
Day -1= day before treatment start date 
There is no Day 0.   
Baseline value is defined as the last available value collected before the first dose date of 
investigational product for all safety laboratory, safety ECG, and vital sign values, unless 
otherwise specified. 
8.3 
Data Handling Conventions 
8.3.1  
Repeated or Unscheduled Assessments of Safety Parameters 
If a subject has repeated assessments before the start of the first treatment, the results from the 
final nonmissing assessment made prior to the start of the IP will be used as baseline. If a subject 
has repeated postbaseline assessments for that time point, the last nonmissing postbaseline 
assessment within the assessment window will be used.  
 However, all assessments will be presented in the data listings.  
8.3.2 
 Missing/Incomplete Date Conventions 
8.3.2.1 
 Missing Date of the Last Dose of Study Treatment 
When the date of the last dose of study treatment is missing for a subject in the Safety 
Population, all efforts should be made to obtain the date from the Investigator. If after all efforts 
are made it is still missing, the last available dosing record date will be used as the last dose date. 
8.3.2.2 
Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(i.e., partly missing). 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
treatment, the month and day of the first dose of study treatment will be assigned to the 
missing fields 
• If the year of the incomplete start date is before the year of the first dose of study treatment, 
December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the first dose of study treatment, 
January 1 will be assigned to the missing fields 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure 
Missing day only 


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• If the month and year of the incomplete start date are the same as the month and year of the 
first dose of study treatment, the day of the first dose of study treatment will be assigned to 
the missing day 
• If either the year of the incomplete start date is before the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is 
before the month of the date of the first dose of study treatment, the last day of the month 
will be assigned to the missing day 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
study treatment or if both years are the same but the month of the incomplete start date is 
after the month of the date of the first dose of study treatment, the first day of the month will 
be assigned to the missing day 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date: 
• If the stop date is after the date of the first dose of study treatment, the date of the first dose 
of study treatment will be assigned to the missing start date 
• If the stop date is before the date of the first dose of study treatment, the stop date will be 
assigned to the missing start date 
8.3.2.3 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (i.e., partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a subject, the start date will be imputed first. 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date. Detail rules 
regarding the missing date information will refer to section 8.3.2.2 Missing Date Information for 
Adverse Events.  
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study treatment is missing, 
impute it as described in Section 8.3.2.1 Missing Date of the Last Dose of Study Treatment. If 
the imputed stop date is before the start date (imputed or non-imputed start date), the imputed 
stop date will be equal to the start date. Detailed rules regarding the missing date information are 
outlined in section 8.3.2.2  Missing Date Information for Adverse Events.  
 


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8.3.3 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the first dose of study treatment, an 
intensity of mild will be assigned. If severity is missing for an AE that started on or after the date 
of the first dose of study treatment, an intensity of severe will be assigned. The imputed values 
for severity assessment will be used for the incidence summary; the values will be shown as 
missing in the data listings. 
 
8.3.4 
Missing Causal Relationship to study drug for Adverse Events 
If the causal relationship to the study treatment is missing for an AE that started on or after the 
date of the first dose of study treatment, a causality of yes will be assigned. The imputed values 
for causal relationship to study treatment will be used for the incidence summary; the values will 
be shown as missing in the data listings. 
 
8.3.5 
Character Values of Clinical Laboratory Parameters 
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, a character string is reported for a parameter of the numeric type, a 
coded value must be appropriately determined for use in the statistical analyses. The actual 
values, however, as reported in the database will be presented in the data listings.  Table 6 shows 
examples of how some possible laboratory results should be coded for the analysis. 
 
 


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Table 6. Examples of Coding Special Character Values for Clinical Laboratory Parameters 
Laboratory Test, 
SI Unit 
Possible Laboratory Results 
Coded Value for Analysis 
1 CHEMISTRY 
ALT, U/L 
< 5 
5 
AST, U/L 
< 5 
5 
Bilirubin, total, 
μmol/L 
< 2 
2 
URINALYSIS 
Glucose, mmol/L 
= OR > 55, ≥ 55, > 0 
Positive 
≤ 0, negative 
Negative 
pH 
> 8.0, ≥ 8.0 
8.0 
≥ 8.5 
8.5 
Protein 
= OR > 3.0, ≥ 3.0, > 0 
Positive 
≤ 0 
Negative 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = Le Système International d’Unités (International 
System of Units). 
 
 
 


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9 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
None 


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10 
REFERENCES 
Not applicable.