Clinical trial NCT02535091
Conditions: Partial Epilepsy
Sponsor: SK Life Science, Inc.
Start date: 2016-08-03; Completion date: 2022-02-07
Enrollment: 1345 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open label study to assess the safety and pharmacokinetics of YKP3089 as adjunctive therapy in subjects with partial onset seizures. Initially, subjects taking phenytoin or phenobarbital will be enrolled followed by additional subjects taking anti-epileptic drugs (AED) other than phenytoin and phenobarbital to further investigate long-term safety.

Detailed description:
see above

Arms: arm 1: Multiple dose
Interventions: intervention 1: YKP3089
Intervention descriptions: intervention 1: see above

Protocol documents:
Prot_000.pdf: 
SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 1 of 135
SK Life Science Inc.
461 From Road 
Paramus, NJ 07652
An Open Label, Multicenter, Safety and Pharmacokinetic Study of YKP3089 
as Adjunctive Therapy in Subjects with Partial Onset Seizures
Clinical Study Protocol
May 21, 2015
Amendment 1, October 23, 2015
Amendment 2, April 14, 2016
Amendment 3, June 03, 2016
Amendment 4, July 28, 2017
Amendment 5, June 20, 2019




INVESTIGATOR SIGNATURE PAGE
Type of document:
Protocol
Protocol Amendment
Protocol title:
An 
Open 
Label, 
Multicenter, 
Safety 
and 
Pharmacokinetic Study of YKP3089 as Adjunctive 
Therapy in Subjects with Partial Onset Seizures
Original protocol date:
May 21, 2015
Amendment 1 Date
October 23, 2015
Amendment 2 Date
Amendment 3 Date 
Amendment 4 Date
Amendment 5 Date 
Protocol number:
April 14, 2016
June 03, 2016
July 28, 2017
June 20, 2019 
YKP3089C021
EudraCT number: 
2015-001859-67
By my signature, I confirm that my staff and I 
have carefully read and understand this protocol 
or protocol amendment, and agree to comply with 
the conduct and terms of the study specified 
herein and with any other study conduct 
procedures provided by SK Life Science Inc.
Investigator’s Signature
Date
______________________________
______________
Print Name
______________________________


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 5 of 135
PROTOCOL AMENDMENTS
Amendment 1
Reasons for amendment
1. To increase number of subjects to be enrolled in the study
2. To slow the rate of titration of YKP3089 in subjects taking AEDs other than phenytoin or 
phenobarbital
3. To allow enrollment of all three groups of subjects (phenytoin, phenobarbital and other 
concomitant AEDs) concurrently
4. To provide updated YKP3089 exposure, safety and efficacy data
5. To clarify felbamate exclusion requirements
6. To make administrative changes


Amendment 1 Summary of Changes
Section
Old Text
Amended Text
Rationale
1. PROTOCOL 
SYNOPSIS
Study Centers
Approximately 50 sites (multiple 
countries)
Approximately 75 sites (multiple countries)
To increase number 
of sites to account 
for increased 
number of subjects
1. PROTOCOL 
SYNOPSIS
Number of 
subjects
Initially at least 20 subjects taking 
phenytoin and at least 20 subjects taking 
phenobarbital; followed by an additional 
approximately 450 subjects taking AEDs 
other than phenytoin or phenobarbital, at a 
time to be determined by the Sponsor, to 
further evaluate long term safety.
At least 20 subjects taking phenytoin and at least 20 subjects 
taking phenobarbital and approximately an additional 700 subjects 
taking AEDs other than phenytoin or phenobarbital, to further 
evaluate long term safety.
To increase number 
of  subjects to be 
enrolled in the study
1. PROTOCOL 
SYNOPSIS
Design and 
methodology
Subjects on concomitant AEDs other than 
phenytoin or phenobarbital:
The titration phase for subjects on stable 
doses of other concomitant AEDs will be 4
weeks. Increasing doses of YKP3089 will 
be administered (50, 100, 150 and 
200mg/day) at 1-week intervals. The 
investigator may add, remove, or adjust 
the dosage of concomitant AEDs, as 
clinically indicated in this group of 
subjects. Monotherapy with YKP3089 will 
not be allowed.
Subjects on concomitant AEDs other than phenytoin or 
phenobarbital:
The titration phase for subjects on stable doses of other concomitant 
AEDs will be 8 weeks. Increasing doses of YKP3089 will be 
administered (50, 100, 150 and 200mg/day) at 2-week intervals. The 
investigator may add, remove, or adjust the dosage of concomitant 
AEDs, as clinically indicated in this group of subjects. Monotherapy 
with YKP3089 will not be allowed.
A recent  aggregate 
analysis revealed 
that the rate of 
rash/hypersensitivity 
reactions was lowest 
when the rate of 
titration was at 
50mg every two 
weeks
1. PROTOCOL 
SYNOPSIS
Statistics and 
analyses
The results of the open-label extension will 
be reported using summary tables, figures, 
and data listings. Summaries will be 
presented for demographic information and 
safety information only.
The results of the open-label extension will be reported using 
summary tables, figures, and data listings. Summaries will be 
presented for demographic information and safety information only.
To correct 
typographical error
3. STUDY 
ASSESSMENTS
Table 1
Colum 
headers 
were 
separate 
for 
phenytoin/phenobarbital 
vs 
other 
concomitant AEDs
All subjects have same titration rate with a single set of headers
All subjects will 
have the same 
titration rate
4.4.3
Clinical 
Safety and 
Efficacy
Cumulatively, approximately 800 subjects 
have been exposed to YKP3089 in a total of 
12 Phase 1 and 3 Phase 2 clinical studies. 
Cumulatively, 953 subjects have been exposed to YKP3089 in a 
total of 14 Phase 1 and 3 Phase 2 clinical studies. 
To provide updated 
exposure, safety and 
efficacy data


Amendment 2
Reasons for Amendment
1. To increase number of subjects to be enrolled in the study
2. To reduce the initial dose of YKP3089
3. To slow the rate of titration of YKP3089 
4. To update the exclusion criteria
5. To provide updated YKP3089 exposure, safety and efficacy data in the introduction
6. To increase the frequency of visits and evaluations during the first 16 weeks of therapy with YKP3089
7. To update the skin/hypersensitivity safety assessments
8. To provide information for two new dosage strengths
9. To update the risk benefit profile in the introduction
10. To make administrative changes


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 17 of 135
Amendment 2 Summary of Changes
Section
Old Text
Amended Text
Rationale
1. 
PROTOCOL 
SYNOPSIS
Study 
Center(s)
Approximately 75 sites (multiple countries)
Approximately 50-100  sites (multiple countries)
To increase 
number of 
sites to 
account for 
increased 
number of 
subjects
1. 
PROTOCOL 
SYNOPSIS
Number of 
subjects
At least 20 subjects taking phenytoin and at least 20 
subjects taking phenobarbital and approximately an 
additional 700 subjects taking AEDs other than 
phenytoin or phenobarbital, to further evaluate long 
term safety.
At least 20 subjects taking phenytoin and at least 20 subjects taking 
phenobarbital. Additional subjects taking AEDs other than phenytoin 
or phenobarbital, will be enrolled in order to expose a total of at least 
1,000 subjects for at least 6 months.
To increase 
number of 
subjects to be 
enrolled in 
the study
1. 
PROTOCOL 
SYNOPSIS
Design and 
methodology
The study will consist of a screening period, open-
label titration phase, open label maintenance phase 
and a taper and follow up.
Screening period
The screening period for subjects on stable doses of 
phenytoin or stable doses of phenobarbital or stable 
doses of other concomitant AEDs will be up to 21 
days. 
Titration phase 
Subjects on phenytoin or phenobarbital:
The titration phase for subjects on stable doses of 
phenytoin or stable doses of phenobarbital will be 8 
weeks. Increasing doses of YKP3089 will be 
administered (50, 100, 150 and 200mg/day) at 2-week 
intervals. 
Sparse 
sampling 
of 
phenytoin, 
phenobarbital and YKP3089 plasma levels will be 
The study will consist of a screening period, a 12 week open-label 
titration phase, an open label maintenance phase and a taper and follow 
up.  Clinic visits during the first 16 weeks of therapy will be every two 
weeks with a telephone contact between each visit.  At each visit during 
the first 16 weeks physical exams to evaluate signs of hypersensitivity 
will be performed and laboratory evaluations will be obtained. 
Screening period
The screening period for subjects on stable doses of phenytoin or stable 
doses of phenobarbital or stable doses of other concomitant AEDs will 
be up to 21 days. 
Titration phase 
Subjects on phenytoin or phenobarbital:
The titration phase for subjects on stable doses of phenytoin or stable 
doses of phenobarbital will be 12 weeks. Increasing doses of YKP3089 
will be administered (12.5, 25, 50, 100, 150 and 200mg/day) at 2-week 
intervals. Sparse sampling of phenytoin, phenobarbital and YKP3089 
To reduce the 
rate of 
DRESS 
incidence by 
lowering 
initial dose of 
YKP3089
and slowing 
the rate of 
titration


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 39 of 135
Amendment 3
Reasons for Amendment 
1. To allow subjects to increase the target dose up to 400 mg/day
2. Minor administrative changes 


Amendment 3 Summary of Changes
Section
Old Text
Amended Text
Rationale
1. PROTOCOL 
SYNOPSIS
Open Label 
Maintenance Phase
Subjects on phenytoin 
or phenobarbital
If the investigator feels that a subject 
requires a dose that is lower than 200 
mg/day, the dose can be reduced to a 
minimum of 50 mg/day once the target 
dose of 200 mg/day was reached. The 
dose adjustments may occur in weekly 
increments of 100-mg/day or 50-mg/day. 
However, the rate of change may be more 
rapid or slow as clinically indicated. The 
investigator may add, remove, or adjust 
the dosage of concomitant AEDs, as 
clinically indicated. Monotherapy with 
YKP3089 will not be allowed.
If the investigator feels that a subject requires a dose that is higher 
than 200 mg/day, the dose can be increased to a maximum of 400 
mg/day once the target dose of 200 mg/day was reached The 
upward dose adjustments should occur every other week in
increments of 50-mg/day. If the investigator feels that a subject 
requires a dose that is lower than 200 mg/day, the dose can be 
reduced to a minimum of 50 mg/day once the target dose of 200 
mg/day was reached. The downward dose adjustments may occur 
weekly by 100-mg/day or 50-mg/day. However, the downward 
rate of change may be more rapid or slow as clinically indicated. 
The investigator may add, remove, or adjust the dosage of 
concomitant AEDs, as clinically indicated. Monotherapy with 
YKP3089 will not be allowed.
To increase to a 
maximum of 
400mg/day
PROTOCOL 
SYNOPSIS
Open Label 
Maintenance Phase
Subjects on 
concomitant AEDs 
other than phenytoin  
or phenobarbital
If the investigator feels that a subject 
requires a dose that is lower than 200 
mg/day, the dose can be reduced to a 
minimum of 50 mg/day once the target 
dose of 200 mg/day was reached. The 
dose adjustments may occur in weekly 
increments of 100-mg/day or 50-mg/day. 
However, the rate of change may be more 
rapid or slow as clinically indicated.
For subjects taking other concomitant AEDs, the initial target 
dose will be 200 mg/day.  If the investigator feels that a subject 
requires a dose that is higher than 200 mg/day, the dose can be 
increased to a maximum of 400 mg/day once the target dose of 
200 mg/day was reached. The upward dose adjustments should 
occur every other week in increments of 50-mg/day. If the 
investigator feels that a subject requires a dose that is lower than 
200 mg/day, the dose can be reduced to a minimum of 50 mg/day 
once the target dose of 200 mg/day was reached. The downward 
dose adjustments may occur weekly by 100-mg/day or 50-
mg/day. However, the downward rate of change may be more 
rapid or slow as clinically indicated.
To increase to a 
maximum of 
400mg/day
Section 4.5 Rationale
Section 4.5.2.Dose 
Justification 
After reaching a target dose of 200mg, all subjects will be allowed 
to titrate up to a maximum dose of 400mg/day of YKP3089. A 
maximum dose of 400mg/day is justified by the additional efficacy  
To increase to a 
maximum of 
400mg/day


Amendment 4
Reasons for Amendment 
1. To update inclusion and exclusion criteria to more effectively screen patients for a safety study
2. To update Birth Control Methods Allowable for Enrollment of Subjects
3. To addvital signs details to the Study Assessment table
4. To update screening number assignment
5. To clarify prohibited medications or devices
6. To clarify pharmacokinetics sampling
7. To update Medical Monitor contact information
8. Minor administrative and editorial changes


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 43 of 135
Amendment 4 Summary of Changes
Section
Old Text
Amended Text
Rationale
3. STUDY 
ASSESSME
NTS
Table 1. 
Study 
Assessment 
Flow Chart
b. Vital signs include blood pressure, and heart rate (supine 
for 5 minutes).
b. Vital signs include blood pressure, heart rate (supine for 5 
minutes), temperature, and respiratory rate.
To update 
vital sign
details in the 
study 
assessment 
table 
3. STUDY 
ASSESSME
NTS
Table 1. 
Study 
Assessment 
Flow Chart
i. Two blood samples will be collected for the determination 
of YKP3089 plasma levels: the first one will be collected 
upon subjects’ arrival to the study unit; the second one 
should be collected within 2 to 4 hours after the first blood 
draw. Collect at visit 8 and/ or 9 depending on stability of 
dosing (doses must be stable for 2 weeks prior to these 
visits) of all concomitant AEDs including oxcarbazepine, 
topiramate, lamotrigine, lacosamide, clobazam, perampanel, 
levetiracetam, phenytoin and phenobarbital and YKP3089.
i. Two blood samples will be collected for the determination 
of YKP3089 plasma levels: For patients that are taking 
YKP3089 in the morning and coming into the visits in the 
morning, the first blood draw will be collected upon 
subjects’ arrival to the study unit; the second blood draw
should be collected within 30 minutes to 2 hours after the 
medication is taken. Collect at visit 8 and/ or 9 depending on 
stability of dosing (doses must be stable for 2 weeks prior to 
these visits) of all concomitant AEDs including 
oxcarbazepine, topiramate, lamotrigine, lacosamide, 
clobazam, perampanel, levetiracetam, phenytoin and 
phenobarbital and YKP3089.  YKP3089 PK draw is 
applicable for subjects on phenytoin and phenobarbital 
globally and all subjects at US sites.
To clarify 
pharmacokine
tics sampling
3. STUDY 
ASSESSME
NTS
Table 1. 
Study 
Assessment 
Flow Chart
j. At Visit 2, a single trough level of phenytoin or 
phenobarbital will be obtained. At visits 4, 5, 6, 7 and 8 two 
blood samples will be collected for the determination of 
phenobarbital and phenytoin plasma levels: the first one will 
be collected upon subjects’ arrival to the study unit; the 
second one should be collected within 2 to 4 hours after the 
first blood draw.
j. At Visit 2, a single trough level of phenytoin or 
phenobarbital will be obtained. At visits 4, 5, 6, 7 and 8 two 
blood samples will be collected for the determination of 
phenobarbital and phenytoin plasma levels: For subjects that
are taking phenytoin or phenobarbital in the morning and 
coming into the visits in the morning, the first blood draw
will be collected upon subjects’ arrival to the study unit; the 
second blood draw should be collected within 2 to 4 hours 
after the medication is taken.  
To clarify 
pharmacokine
tics sampling
3. STUDY 
ASSESSME
NTS
k. At Visit 2, a single trough level of concomitant AEDs will 
be obtained. At Visits 8 and 9, two blood samples will be 
collected for the determination of concomitant AED plasma 
k. Concomitant AED PK draw will be done at US sites only. 
At Visit 2, a single trough level of concomitant AEDs will 
be obtained. At Visits 8 and 9, two blood samples will be 
To clarify 
pharmacokine
tics sampling


Amendment 5
Reason for Amendment Change 
1. Version number and date updated - Version number and date updated throughout 
document.
2. SK Life Science Address update - SK Life Science, Inc. address updated from: 
SK Life Science, Inc., 22-10 Route 208 South Fair Lawn, NJ 07410 USA. To: SK 
Life Science, Inc., 461 From Road, 5th FL, Paramus, NJ 07652 USA


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 53 of 135
TABLE OF CONTENTS
TABLE OF CONTENTS ......................................................................................................53 
1 
PROTOCOL SYNOPSIS ..........................................................................................57 
2 
LIST OF ABBREVIATIONS ...................................................................................60 
3 
STUDY ASSESSMENTS ..........................................................................................62 
4 
BACKGROUND AND DOSE SELECTION ..........................................................66 
4.1 
Introduction..................................................................................................................66 
4.2 
Considerations for Studies of Epilepsy........................................................................66 
4.3 
Background..................................................................................................................67 
4.3.1 
YKP3089 Structure ................................................................................................67 
4.4 
Pharmacology ..............................................................................................................67 
4.4.1 
Absorption, Distribution, Metabolism, and Excretion...........................................67 
4.4.2 
Safety Pharmacology and Toxicity Studies............................................................69 
4.4.3 
Clinical Safety and Efficacy...................................................................................69 
4.5 
Rationale ......................................................................................................................74 
4.5.1 
Study Rationale......................................................................................................74 
4.5.2 
Dose Justification...................................................................................................75 
4.6 
Potential Risks and Benefits ........................................................................................76 
5 
STUDY OBJECTIVES ..............................................................................................77 
6 
STUDY DESIGN ........................................................................................................77 
6.1 
Overview......................................................................................................................77 
6.1.1 
Screening Period....................................................................................................77 
6.1.2 
Open label Treatment Period.................................................................................78 
6.1.2.1 
Titration Phase............................................................................................................78 
6.1.2.2 
Open Label Maintenance Phase..................................................................................80 
6.1.2.3 
Taper and follow up....................................................................................................83 
6.2 
Study Endpoints...........................................................................................................83 
6.2.1 
Pharmacokinetic Endpoints...................................................................................83 
6.2.2 
Safety Endpoints.....................................................................................................84 
7 
SELECTION OF STUDY POPULATION .............................................................84 
7.1 
Study Population and Sites ..........................................................................................84 


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 57 of 135
1
PROTOCOL SYNOPSIS
Name of 
company
SK Life Science Inc
Title of study
An Open Label, Multicenter, Safety and Pharmacokinetic Study of 
YKP3089 as Adjunctive Therapy in Subjects with Partial Onset Seizures
Protocol number 
YKP3089C021
Phase of 
development
Phase 3
Study duration
After 12 months of participation in the study, subjects will be evaluated for 
treatment response. Those who are benefiting from treatment with 
YKP3089 may continue use of the drug at the discretion of the investigator, 
until development is stopped by SK Life Science Inc or the product is 
approved for marketing, or anytime at the discretion of SK Life Science 
Inc.
Indication
Partial-onset epilepsy
Study center(s)
Approximately 80-110 sites (multiple countries)
Number of 
subjects
At least 20 subjects taking phenytoin and at least 20 subjects taking 
phenobarbital. Additional subjects taking AEDs other than phenytoin or 
phenobarbital, will be enrolled in order to expose a total of at least 1,000 
subjects for at least 6 months.
Objectives
The objective is to evaluate the safety and pharmacokinetics of YKP3089 
and concomitant AEDs when administered as adjunctive therapy for the 
treatment of partial seizures. The evaluations will include:
1. Phenytoin-YKP3089 interaction
2. Phenobarbital-YKP3089 interaction
3. Long term safety of YKP3089 as adjunctive therapy in partial onset 
seizures 
4. Population pharmacokinetics of YKP3089 and concomitant AEDs.
Inclusion and 
exclusion criteria
Subjects to be enrolled in the study include:
1. Subjects on stable doses of phenytoin
2. Subjects on stable doses of phenobarbital
3. Subjects on stable doses of other concomitant AEDs
Subjects who meet all inclusion and no exclusion criteria listed in Section 
7.3 and Section 7.4 of the protocol are eligible to enroll.


2
LIST OF ABBREVIATIONS
AE
Adverse event
AED
Antiepileptic drug
ALT
Alanine aminotransferase 
AST
Aspartate aminotransferase 
AUC
Area under the plasma concentration versus time curve 
β-hCG
β-human chorionic gonadotropin
CBZ
Carbamazepine
CFR
Code of Federal Regulations
CNS
Central nervous system
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Computed tomography
CYP
Cytochrome P450
DRESS 
Drug reaction (or rash) with eosinophilia and systemic symptoms
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EEG
Electroencephalograph
FDA
Food and Drug Administration
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IND
Investigational new drug
IRB
Institutional review board
IWRS
Interactive Web response system
kg
Kilogram
mg
Milligram
MRI
Magnetic resonance imaging
PHI
Protected health information
PI 
Principal Investigator
SAE
Serious adverse event
SKLSI
SK Life Science, Inc.
SUDEP
Sudden unexpected death in epilepsy
SUSAR
Suspected unexpected serious adverse reaction
VNS
Vagal nerve stimulator
VPA
Valproic acid (divalproex sodium)


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 61 of 135
3
STUDY ASSESSMENTS
Table 1. Study Assessment Flow Chart


4
BACKGROUND AND DOSE SELECTION
4.1
Introduction
This is a protocol for a human research study. This study is being conducted according to US and 
international standards of Good Clinical Practice (GCP) (Food & Drug Administration [FDA] Title 
21 Part 312 and International Conference on Harmonisation [ICH] guidelines), applicable 
government regulations, and Institutional research policies and procedures.
4.2
Considerations for Studies of Epilepsy
According to the World Health Organization, epilepsy afflicts more than 50 million people 
worldwide.1 Epilepsy leads to an increased risk of injury from accidents and an increased rate of 
mortality and has a significant impact on quality of life. First-generation antiepileptic drugs 
(AEDs) are still commonly used, even though they can produce a diversity of serious adverse 
events (SAEs). New AEDs approved since the early 1990s have shown an improved tolerability 
profile. Nonetheless, approximately 30% of epilepsy cases, particularly those with partial seizures, 
are refractory to treatment. Many of these patients are taking multiple antiepileptic drugs. It is 
important to understand any interaction that occurs between them as well as the long term safety 
profile of YKP3089 when given as adjunctive therapy.
Choice of add-on (adjunctive) design. The initial evaluation of a new antiepileptic drug generally 
includes a determination of its efficacy in reducing the frequency of seizures in adults who are 
refractory to treatment with other AEDs.2,3,4 Because of the risk of exacerbation of seizure severity 
and frequency upon withdrawal of long-term AED therapy, even in the refractory population, the 
new AED under study is added to the existing therapy instead of being used as monotherapy.
Because partial seizures represent the most common type in both adults and children and claim a 
disproportionate share of medically refractory cases, they have been the most frequently selected 
seizure type in the investigation of new AEDs.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5
June 20, 2019
Page 67 of 135
4.3
Background 
4.3.1
YKP3089 Structure
YKP3089 is (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester, which has the chemical 
formula C10 H10 Cl N5. YKP3089 is being provided in tablets that contain 50 or 100 mg of the 
active ingredient. It is a novel small molecule of molecular weight 267.68. Its structure is shown 
in Figure 1.
Figure 1. Structure of YKP3089
YKP3089 is a novel small molecule with open INDs for epilepsy (76,809), neuropathic pain (IND 
108,178), and anxiety (IND 72,741). It is currently in Phase 2 of development as an antiepileptic 
agent for partial onset seizures. YKP3089 was shown to be active in standard animal models of 
epilepsy, neuropathic pain, and anxiety when administered orally. 
4.4
Pharmacology
Receptor test systems have shown that YKP3089 does not show significant activity at any of the 
classical receptor types (eg, adrenergic, GABAergic) or pharmacologic receptors. However, in 
vitro electrophysiology assays showed YKP3089 to be an inhibitor of the slow inactivated state of 
sodium channels. YKP3089 may also increase inhibitory synaptic transmission by facilitating the 
release of GABA.
4.4.1
Absorption, Distribution, Metabolism, and Excretion
In vitro studies with human microsomes revealed that YKP3089 directly inhibited CYP2B6 (IC50
= 280 μM), CYP2C19 (IC50 = 170 μM), and CYP3A4/5 (as measured by testosterone 6β-
hydroxylation, IC50 = 890 μM; and midazolam 1′-hydroxylation, IC50 = 720 μM). These IC50


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 69 of 135
the reciprocal effects of phenytoin and YKP3089, plasma phenytoin exposure increased with co-
administration of YKP3089 by 67% (Cmax) and 84% (AUC) and plasma YKP3089 exposure (Cmax,
AUC) decreased with co-administration of phenytoin by 27 - 28%. Preliminary results of a drug 
interaction study examining the reciprocal effects of phenobarbital and YKP3089, plasma 
phenobarbital exposure increased with co-administration of YKP3089 by 34% (Cmax) and 37%
(AUC) and plasma YKP3089 exposure (Cmax, AUC) decreased with co-administration of 
phenobarbital by 10-15% based on historical controls.
4.4.2
Safety Pharmacology and Toxicity Studies
YKP3089 has been assessed in a large number of safety pharmacology and toxicology studies 
including single-dose toxicity, repeat-dose toxicity, cardiotoxicity, genetic toxicity, and 
reproductive toxicity studies in animals. Safety pharmacology studies showed that the doses that 
produced beneficial central nervous system (CNS) effects of YKP3089 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. 
Details of the preclinical safety and toxicity studies of YKP3089 can be found in the Investigator’s
Brochure. The most common AEs in preclinical studies of YKP3089 involved the central nervous 
system (CNS).
Reproductive toxicity studies showed adverse effects on reproductive performance when the 
dosage of YKP3089 was high enough to induce maternal toxicity, as evidenced by decreased food 
consumption and decreased body weight. However, there was no evidence of teratogenicity.
The results of standard genotoxicity studies of YKP3089 were negative. There is no evidence of 
carcinogenicity in standard testing of two rodent species.
4.4.3
Clinical Safety and Efficacy
Cumulatively, 953 subjects have been exposed to YKP3089 in a total of 14 Phase 1 and 3 Phase 2 
clinical studies.
The results of the first completed double-blind, randomized, placebo-controlled trial in subjects 
with partial epilepsy demonstrated that treatment with 200 mg of YKP3089 produced a highly 


statistically significant reduction in the frequency of partial onset seizures (Table 2) and seizure 
free rates (Table 3). YKP3089 was generally well-tolerated.  The rate of adverse event withdrawals 
was similar between the YKP3089 and placebo groups.  No life threatening serious adverse events 
were identified among YKP3089-treated subjects. The most common central nervous system 
adverse events in the YKP3089 group were somnolence, dizziness, fatigue, and gait disorder.
The second randomized, double-blind, placebo-controlled, dose response trial with a 18 week 
treatment period enrolled a total of 437 subjects, 108 in a 100 mg YKP3089 group, 110 in a 200 
mg YKP3089 group, 111 in a 400 mg YKP3089 group and 109 in a placebo group. The trial 
confirmed that treatment with 200 mg/day and 400mg/day of YKP3089 produces a highly 
statistically significant reduction in the frequency of partial onset seizures in patients with partial 
epilepsy (Table 2) and high seizure free rates (Table 4).
Table 2:  Effect Size of Median Percent Reduction and 50% Responder Rate Relative to 
Placebo in YKP3089 Trials
 
YKP3089C013 
Study 
YKP3089C017 
Study 
Dose 
200mg 
100mg 
200mg 
400mg 
Median Percent 
Reduction 
34.1 
11.5 
31.0 
31.0 
50% Responder 
Rate 
28.2 
19.0 
35.2 
38.7 
P values in all comparisons were <0.01
Table 3:  Seizure free Rates (Completer Population) at 200mg in YKP3089C013
Responder Type
6 Week Maintenance Phase
% Responders  
placebo
N = 99
% Responders YKP3089
N = 102
P value
100%
9.1
27.5
0.0003
Table 4:  Seizure Free Rates (Completer Population) in YKP3089C017
Responder 
Type
12 Week Maintenance Phase
% Responder
s
% Responders
(YKP3089 100 mg)
% Responders 
% Responders 


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 73 of 135
There have been three cases of DRESS syndrome in YKP3089 clinical studies.
Rash and hypersensitivityDuring the YKP3089 development program there have been other 
reports of rash and hypersensitivity reactions, some resulting in hospitalization and/or 
discontinuation. An aggregate analysis of the rate of rash/hypersensitivity and DRESS in subjects 
exposed to multiple doses of YKP3089 was performed Table 5.
Table 5:  Rate of rash/hypersensitivity and DRESS in subjects exposed to multiple doses of 
YKP3089  
Starting Dose 50 mg 
with 50 mg Increase 
Every 2 Weeks
Starting dose 50 mg 
with 50 mg Increase 
Every 1 Week
Starting dose  100 mg 
or more with 100 mg 
Increase Every 5 to 7 
Days
Total
Active
Placebo
Active
Placebo
Active
Placebo
Active
Placebo
Subjects 
Exposed
120
112
363
152
350
37
833
301
Rash/hyper
sensitivity
N (%)
1 (0.8%)
3 (2.7%)
18(5.0%)
4(2.6%)
19 (5.4%)
3 (8.1%) 38 (4.6%)
10
(3.3%)
Dropouts  
1 (0.8%)
0
8 (2.2%)
1 (0.6%)
9 (2.5%)
0
18 (2.2%) 1 (0.3%)
DRESS
0
0
1
0
2
0
3
0
The results of the aggregate analysis suggest that lower YKP3089 starting dose and slower 
titration rate are associated with lower risk of rash/hypersensitivity.  
x
When YKP3089 dosing was increased weekly or faster, the rate of rash/hypersensitivity 
reactions was approximately 5%.  When YKP3089 was increased by 50 mg increments 
every 2 weeks, only one case (0.8%) of hypersensitivity reactions was observed.  
Two cases DRESS occurred when the first dose of YKP3089 was 100 mg (epilepsy study) or 
200 mg (healthy volunteer) followed by rapid titration.  The third case, in a healthy volunteer, 
occurred in a study where the initial dose of YKP3089 was 50 mg/day for 1 week followed by 50 
mg weekly increments. 


4.5
Rationale
4.5.1
Study Rationale
Approximately 30% of epilepsy cases, particularly those with partial seizures, are refractory to 
treatment. Many of these patients are taking multiple antiepileptic drugs. It is important to 
understand any interaction that occurs between them as well as the long term safety profile of 
YKP3089 when given as adjunctive therapy. 
Based on healthy volunteer studies with phenytoin and phenobarbital, YKP3089 increases plasma 
levels of phenobarbital and phenytoin levels. A portion of this open label safety and 
pharmacokinetic study is designed to understand the impact of adding YKP3089 to an AED 
regimen including either phenytoin or phenobarbital in subjects with partial epilepsy.
In addition this open label and pharmacokinetic study will enroll subjects taking concomitant 
AEDs other than phenytoin or phenobarbital to study long term safety and obtain population 
pharmacokinetic data.
A review of the YKP3089 safety database confirmed three cases of DRESS syndrome among the 
953 subjects exposed to the drug. 
In order to further characterize the safety profile of YKP3089 while minimizing risk to patients, 
the following plan was developed:
1. Low starting dose (12.5 mg) and slower titration (dose increase every two weeks) 
2. Close monitoring (visits every two weeks) during the first 4 months of treatment to allow 
early detection of suspected cases of hypersensitivity reaction  
3. Evaluation of suspected cases of hypersensitivity reaction to facilitate accurate diagnosis 
4. Care of subjects with hypersensitivity reactions to minimize consequences 


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 75 of 135
4.5.2
Dose Justification
The target dose of 200 mg/day is based on the efficacy, safety, and tolerability of YKP3089 in 
previously completed and ongoing studies.  
Initiating treatment with YKP3089 at 12.5 mg and then increasing the dose every two weeks is 
likely to further reduce the risk of many side effects including hypersensitivity reactions. Slowing 
the titration rates of pharmaceuticals is a well-known procedure for mitigating risk of adverse 
reactions. Reducing the initial dose and slowing the titration can reduce many central nervous 
system or gastrointestinal side effects.   It has been demonstrated that lowering the initial dose and 
slowing the titration rate can mitigate the occurrence of rash and possibly the rate of more serious 
and potentially life threatening adverse cutaneous reactions (Zaccara G, 2007). 
After initiating treatment with YKP3089 for two weeks at 12.5 mg and then for two weeks at  
25mg YKP3089, subjects taking phenytoin or phenobarbital will titrate YKP3089 upward at a rate 
of 50mg every other week to a target dose of 200mg/day. This titration is appropriate for this 
portion of the study because of the known interactions between YKP3089 200mg and phenytoin 
and phenobarbital. Titrating by 50mg of YKP3089 every other week to steady state will allow 
better understanding of the clinical impact of any interaction and allow for dosage adjustment of 
phenytoin or phenobarbital.
Subjects taking concomitant AEDs other than phenytoin or phenobarbital will titrate YKP3089 
upward at the same rate to a target dose of 200mg/day.
After reaching a target dose of 200mg, all subjects will be allowed to titrate up to a maximum dose 
of 400mg/day of YKP3089. A maximum dose of 400mg/day is justified by the additional efficacy 
seen in the subjects randomized to 400mg/day in the completed dose response study. Seizure free 
rate effect size in this group approached 20% during the maintenance phase.  
4.6
Potential Risks and Benefits
Cumulatively, 953 subjects have been exposed to YKP3089 in a total of 14 Phase 1 and 3 Phase 2 
clinical studies.
The potential risks in this study includes,


1.
Phenytoin dose related toxicity
2.
Risk of phenytoin hypersensitivity syndrome
3. Phenobarbital dose related toxicity 
4. Rash / hypersensitivity related to YKP3089 exposure
5.
DRESS syndrome related to YKP3089 exposure
6. YKP3089 dose related toxicities
Uncontrolled partial epilepsy is a life threatening disease with significant morbidity and elevated 
standard mortality rates.
The early signs and symptoms associated with hypersensitivity reaction that may progress to 
DRESS are readily identifiable by patients and clinicians. When detected and adequately 
managed, progression to DRESS can be prevented or reversed.   The potential benefits of
YKP3089 include significant partial seizure frequency reduction and substantial seizure free 
rates (~18%) in patients who continue to suffer seizures despite history of treatment with 
multiple AEDs. The current benefit/risk profile in conjunction with the risk minimization 
measures support the enrollment of partial epilepsy patients into this open-label study to assess 
the profile of YKP3089 as a potential antiepileptic drug
5
STUDY OBJECTIVES 
The objective is to evaluate the safety and pharmacokinetics of YKP3089 and concomitant AEDs 
when administered as adjunctive therapy for the treatment of partial seizures. The evaluations will 
include:
1. Phenytoin-YKP3089 interaction
2. Phenobarbital-YKP3089 interaction 
3. Long term safety of YKP3089 as adjunctive therapy in subjects with partial onset seizures 
4. Population pharmacokinetics of YKP3089 and concomitant AEDs


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 77 of 135
6
STUDY DESIGN
6.1
Overview
This multicenter, open label study in subjects with poorly controlled partial seizures will consist 
of a screening period, open-label titration phase, open label maintenance phase and a taper and 
follow up. At least 20 subjects taking phenytoin and at least 20 subjects taking phenobarbital will 
be enrolled. Additional subjects taking AEDs other than phenytoin or phenobarbital, will be 
enrolled in order to expose at least 1,000 subjects for 6 months to further evaluate long term safety.
6.1.1
Screening Period
The screening period for subjects on stable doses of phenytoin or stable doses of phenobarbital or 
stable doses of other concomitant AEDs will be up to 21 days. 
During Screening, assessments will be performed according to the study assessments listed in 
Table 1 to determine eligibility for the study. Each subject will be informed of his or her rights, 
and the subject or his or her legally authorized representative must sign an informed consent 
document indicating understanding of the purpose of the study and required procedures and 
indicating willingness to participate in the study.
6.1.2
Open label Treatment Period
The open label treatment period will consist of a 12 week titration phase followed by an open label 
maintenance phase.
6.1.2.1
Titration Phase
Subjects taking phenytoin or phenobarbital
The titration phase for subjects on stable doses of phenytoin or stable doses of phenobarbital will 
be 12 weeks. During the 12-week up-titration phase, subjects will increase YKP3089 dose every 
2 weeks to a target dose of 200mg/day as described in Table 6.
Table 6. YKP3089 Initial Up-Titration for subjects on phenytoin and phenobarbital
YKP3089 dose (mg/day)


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 79 of 135
To improve tolerability, the investigator may instruct the subject to take the dose of YKP3089 in 
the evening. The investigator may alter the timing or amount of an individual dose of any other 
concomitant AED, but the total daily dose and dosing frequency of any other concomitant AED
must remain unchanged during the titration phase.
Subjects taking concomitant AEDs other than phenytoin or phenobarbital
The titration phase for subjects on stable doses of other concomitant AEDs will be 12 weeks. 
Increasing doses of YKP3089 will be administered (50, 100, 150 and 200mg/day) at 2-week 
intervals as described in Table7.
Table7. YKP3089 Initial Up-Titration for subjects on concomitant AEDs other than 
phenytoin or phenobarbital
YKP3089 dose (mg/day)
Week 1 & 2 
Week 3 & 4
Week 5 & 6
Week 7 & 8
Week 9 & 10
Week 11 & 12
12.5
25
50
100
150
200
Prior to initiating YKP3089, subjects at US sites only will have trough concomitant AED levels
(oxcarbazepine, topiramate, lamotrigine, lacosamide, clobazam, perampanel and levetiracetam
only) drawn at Visit 2. Sites must instruct the subject and schedule the visit accordingly to obtain 
a trough level. Also the blood must be collected before first dose of YKP3089.  To improve 
tolerability, the investigator may instruct the subject to take the dose of YKP3089 in the evening. 
The investigator may add, remove, or adjust the dosage of any concomitant AEDs, as clinically 
indicated (see Table 8 below). Monotherapy with YKP3089 will not be allowed. If clinically 
indicated, titration can be stopped below 200mg/day. A minimum dose of 50mg/day is necessary 
to continue in the study.
Table 8. Dose Adjustment Rules during Titration Phase
Cohort Æ
Subjects taking Phenytoin or 
Phenobarbital
Subjects taking AEDs other 
than Phenytoin or 
Phenobarbital
Adjustments of any 
Concomitant AEDs
Not Allowed
Allowed
Adjustments of YKP3089
Not Allowed
Allowed


the dose of study medication in the evening or divide the total daily dose into 2 doses. Subjects 
will follow the schedule of study visits and assessments detailed in Table 1.
After 12 months of participation in the open-label treatment period, subjects will be re-evaluated. 
Those who are benefiting from treatment with YKP3089 may continue use of the drug at the
discretion of the investigator, until development is stopped by SK Life Science Inc or the product 
is approved for marketing, or anytime at the discretion of SK Life Science Inc.
Table 9. Dose Adjustment Rules during Maintenance Phase
Cohort Æ
Subjects taking Phenytoin or 
Phenobarbital
Subjects taking AEDs other 
than Phenytoin or 
Phenobarbital
Adjustments of any 
Concomitant AEDs
Allowed
Allowed
Adjustments of YKP3089
Allowed
Allowed
Adjustment of Phenytoin or 
Phenobarbital 
Allowed
Not Applicable
6.1.2.3
Taper and follow up
Subjects who are withdrawn from the open-label treatment period will taper YKP3089 according 
to the schedule described in Table 10, unless for safety reasons the investigator judges it necessary 
to discontinue study drug immediately. For subjects taking phenytoin or phenobarbital, 
discontinuing YKP3089 may reduce the plasma concentration of these AEDs. Doses of phenytoin 
or phenobarbital may need to be adjusted as clinically indicated.
Table 10. Study Drug Taper Schedule for Subjects Completing Open-Label Treatment 
Final open-label dose of 
YKP3089 (mg/day)
YKP3089 Dose During Taper (mg/day)
Week 1
Week 2
Week 3
50 or 100
None
150 or 200
100
None
None
250 or 300 
200
100
None
350 or 400
300
200
100


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 83 of 135
The follow up visit will take place 14 days after the subject’s last dose, following taper and 
discontinuation of YKP3089; at any time during the open-label treatment; or after 12 months of 
open-label treatment if there is no additional treatment beyond that point.
6.2
Study Endpoints
6.2.1
Pharmacokinetic Endpoints
Sparse PK blood samples will be collected to evaluate YKP3089 and relevant concomitant AED 
exposure using a population pharmacokinetics approach. This will allow for the investigation of 
potential effects of covariates on the pharmacokinetics of YKP3089 or other concomitant AEDs. 
YKP3089 and other concomitant plasma concentration data collected from this study will be 
pooled with relevant data from other YKP3089 clinical studies for population PK analysis.
6.2.2
Safety Endpoints
Safety will be assessed by the nature, frequency, and severity of treatment-emergent spontaneously 
reported AEs, dropouts due to AEs, overall dropout rates, and changes from baseline in vital signs, 
physical exams, clinical laboratory evaluations, C-SSRS and 12-lead ECGs, in YKP3089-treated 
subjects.
7
SELECTION OF STUDY POPULATION
7.1
Study Population and Sites
This trial will be sponsored by SK Life Science Inc. in the United States and other countries.
7.2
Subject Recruitment
Subjects will be selected from the investigator’s existing patient population or may be referred by 
another physician. Sites may also advertise beyond their practice. All advertisements must be
approved by the Sponsor and governing ethics committee. Subjects who have provided signed 
informed consent will need to complete the Screening visit assessments to confirm eligibility for 
the study.


7.3
Inclusion Criteria
Subjects must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female and greater than or equal to 18 years of age at the time of signing the informed 
consent. The upper age limit is 70 years inclusive.
2.
Weight at least 40 kg
3.
Written informed consent signed by the subject or legal guardian prior to entering the study in 
accordance with the ICH GCP guidelines. If the written informed consent is provided by the legal 
guardian because the subject is unable to do so, a written or verbal assent from the subject must 
also be obtained. In Germany, only the subject may sign the informed consent form in accordance 
with ICH guidelines.
4.
A diagnosis of partial epilepsy according to the International League Against Epilepsy’s 
Classification of Epileptic Seizures. Diagnosis should have been established by clinical history 
and an electroencephalogram (EEG) that is consistent with localization related epilepsy; normal 
interictal EEGs will be allowed provided that the subject meets the other diagnosis criterion (ie, 
clinical history).
5.
Have uncontrolled partial seizures and require additional AED therapy despite having been treated 
with at least one AED within approximately the last 2 years. 
6.
Currently on stable antiepileptic treatment regimen: 
g) Subject must have been receiving stable doses of 1 to 3 AEDs for at least 3 weeks prior to 
Visit 2.
h) Vagal nerve stimulator (VNS) or deep brain stimulator (DBS) will not be counted as an 
AED; however, the parameters must remain stable for at least 4 weeks prior to baseline.
The VNS or DBS must have been implanted at least 5 months prior to Visit 1.
i)
Benzodiazepines taken at least once per week during the 1 month prior to Visit 1 for 
epilepsy, or for anxiety or sleep disorder, will be counted as 1 AED and must be 
continued unchanged throughout the study. Therefore only a maximum of 2 additional 
approved AEDs will be allowed.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 85 of 135
7.
Computed tomography (CT) or magnetic resonance imaging (MRI) scan performed within the past 
10 years that ruled out a progressive cause of epilepsy. If a CT or MRI has not been performed 
within the past 10 years, one must be performed prior to dosing.
8.
Ability to reach subject by telephone.
9.
Use of an acceptable form of birth control by female subjects of childbearing potential (see Section 
7.5).
Any potential exception to inclusion criteria allowing de minimis (clinically trivial and 
meaningless) variations must be approved by the medical monitor. 
7.4
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the study:
1.
History of any serious drug-induced hypersensitivity reaction (including but not limited to Stevens 
Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic 
symptoms) or any drug-related rash requiring hospitalization.
2.
History of any drug-induced rash or hypersensitivity reaction with documented nature of the rash 
or hypersensitivity reaction.
3.
History of a first degree relative with a serious cutaneous drug-induced adverse reaction.
4.
History of serious systemic disease, including hepatic insufficiency, renal insufficiency, a 
malignant neoplasm, any disorder in which prognosis for survival is less than 3 months, or any 
disorder which in the judgment of the investigator will place the subject at excessive risk by 
participation in a controlled trial.
5.
Subjects taking phenytoin must not be taking phenobarbital or primidone; subjects taking 
phenobarbital must not be taking phenytoin or primidone.
6.
Subjects taking concomitant AEDs other than phenytoin or phenobarbital, must not be taking 
phenytoin or phenobarbital or primidone.
7.
Subjects with clinical evidence of phenytoin or phenobarbital toxicity.


7.5
Birth Control Methods Allowable for Enrollment of Subjects
Sexually active female subjects of reproductive potential must practice 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”. Women not 
of childbearing potential are defined as women who are postmenopausal or permanently sterilised 
(e.g. tubal occlusion, hysterectomy, bilateral salpingectomy).
Acceptable methods include: 
x
Hormonal contraception (for at least 3 months prior to Visit 1) in combination with a barrier 
method.
x
Intrauterine device (placement at least 3 months prior to Screening visit)
x
Diaphragm with spermicide
x
Cervical cap
x
Condoms with contraceptive gel/foam or cream 
x
Surgical sterilization (tubal ligation at least 6 months prior to screening or partner who has had 
vasectomy at least 6 months prior to screening)
x
Postmenopausal (as defined by absent menses for at least 12 months)
x
Abstinence; however, if the subject becomes sexually active, 1 of the above methods must be 
utilized.
There is no need for male subjects enrolled in YKP3089C021 study to use contraception with 
partners of childbearing potential during their participation in the study.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 89 of 135
8
TREATMENTS
8.1
Study Medication Information
8.1.1
Description of Study Medication 
8.1.1.1
Physical Description of the Drug
 
12.5mg 
 
25mg 
 
50mg 
 
100mg 
 
¼ inch in diameter, 
round biconvex, 
tablets debossed 
with “SK” on one 
side and “12” on 
the other side.
 
 
10mm in diameter, 
round, biconvex 
plain-faced tablets 
scored on one side. 
 
10mm in diameter, 
round, biconvex 
plain-faced tablets 
scored on one side. 
 
10mm in diameter, 
round, biconvex 
plain-faced tablets 
scored on one side. 
8.1.1.2
Testing
The sponsor is responsible for testing investigational product to establish stability and storage 
conditions. The storage specification provided on the labeling reflect results of this testing.
8.1.1.3
Packaging and Labeling
YKP3089 will be packaged in high density polyethylene (HDPE) bottles each containing 30 tablets 
of either 12.5mg or 25mg or 100 tablets of either 50 mg or 100 mg.
8.1.2
Supply, Storage, Accountability, and Disposition of Study Medication
The Sponsor’s manufacturing facility will ship a sufficient supply of study medication to each 
study site directly or from a local depot. The clinical investigator has the responsibility for 
confirming that all study drug treatment supplies received by the site are inventoried and accounted 
for throughout the study. A drug receipt log is to be filled out and signed by the person accepting 
the shipment. It is important that the designated study staff count and verify that the shipment 
contains all the items noted in the shipment inventory. Any damaged or unusable study drug in a 


given shipment will be documented in the study files. The investigator must notify the study 
Sponsor of any damaged or unusable study treatments that were supplied to the investigator’s site.
Subjects or their legal representatives must be told to return all original containers (empty or 
containing study drug), which will be stored and disposed of according to Sponsor's instructions. 
Subjects or their legal representatives must also be told to keep study drugs in their original 
containers and not to combine the contents of different containers.
All study medication must be kept in a secure, locked area or locked cabinet with access restricted 
to designated study personnel. The tablets will be stored at room temperature in a dry area,
protected from light.
Study personnel will keep accurate records of the study medication dispensed to and used by each 
subject and be available for verification for the Sponsor's site monitor during on-site monitoring 
visits. The site monitor will periodically check the supplies of study medication held at the site to 
ensure accountability of all study medication used throughout the study.
At the conclusion of the study, a final inventory will be performed. Any discrepancies will be 
investigated, resolved, and documented prior to return to the Sponsor for destruction of study drug 
that has not been dispensed and study drug that has been dispensed and returned.
8.2
Screening and Study Drug Distribution
8.2.1.1
Screening Number
The subject will be assigned a screening number by IWRS after signing the informed consent form.
The screening number will be an 8-digit number in which the first 2 digits will signify the country, 
the third, fourth, and fifth digits will signify the site number in that country, and the last 3 digits 
will be a consecutive number, starting 101, assigned to subjects in the order in which they are 
screened. Thus, the third screened subject in the second site in the country given number 01 will 
have screening number 01002103. Screening number should not be reused. Re-screening is not 
allowed.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 91 of 135
8.2.1.2
Drug Dispensing
At each visit, the investigator will access the IWRS, enter his or her own user ID and PIN, and 
provide requested subject details (eg, subject’s year of birth). The IWRS will identify open label
bottles of tablets to be dispensed. Returned bottles may be re-dispensed to the same subject after 
drug accountability is performed.
Prior to dispensing, the investigator will record on each open label bottle label the subject number,
date dispensed, site number, phone contact, and investigator name.
In addition, the investigator will review the electronic case report form (eCRF) to make sure the
medication number printed on each bottle dispensed is populated in the system correctly.
At each visit, the investigator will record the exact dates and exact doses taken since the last visit 
in the case report form (eCRF). All dosing changes should be recorded in details.
8.3
Prior and Concomitant Treatments
Subjects must be on their current stable daily dosage of phenytoin or phenobarbital or any other 
concomitant AEDs for at least 3 weeks before Visit 2. They must continue taking the same brand 
of phenytoin or phenobarbital throughout the titration phase. 
Those subjects taking phenytoin every 24 hours will be instructed to take the dose at approximately 
8:00 a.m. beginning at least 7 days before Visit 2 and continue this regimen throughout the titration 
phase. On the day of Visit 2, subject should delay the morning dose until the trough phenytoin 
plasma sample is obtained. Subjects who are taking phenytoin every 24 hours at bedtime will need 
to switch to morning dosing at least 7 days before Visit 2. Subjects who take phenytoin every 12 
hours will be instructed to take their doses at approximately 8:00 a.m. and 8:00 p.m. beginning at 
least 7 days before Visit 2 and continue this regimen throughout the titration phase.
Those subjects taking phenobarbital every 24 hours will be instructed to take the dose at 
approximately 8:00 a.m. beginning at least 7 days before Visit 2 and continue this regimen 
throughout the titration phase. On the day of Visit 2, subject should delay the morning dose until 
the trough phenobarbital plasma sample is obtained. Subjects who are taking phenobarbital every 
24 hours at bedtime need not switch to morning dosing. Subjects who take phenobarbital every 12 


hours will be instructed to take their doses at approximately 8:00 a.m. and 8:00 p.m. beginning at 
least 7 days before Visit 2 and continue this regimen throughout the titration phase.
Intermittent rescue medication can be used during the open-label treatment period.
Subjects taking AEDs other than phenytoin or phenobarbital at the beginning of the study cannot 
add phenytoin or phenobarbital to the existing regimen.
8.4
Prohibited Medications or Devices
Medication
Not allowed
Allowed
x
Clopidogrel, fluvoxamine, 
amitriptyline, clomipramine, 
bupropion, methadone, 
ifosfamide, cyclophosphamide, 
efavirenz, natural progesterone
fosphenytoin, ethotoin, 
mephenytoin, primidone,  and 
diazepam
During the study and 
within 30 days prior to 
Visit 1
If taken any time before 30 days 
prior to Visit 1
x
Subjects taking phenytoin must 
not be taking phenobarbital or 
primidone; 
During the study and 
within 30 days prior to 
Visit 1
x
Subjects taking phenobarbital 
must not be taking phenytoin or 
primidone
During the study and 
within 30 days prior to 
Visit 1
x
Vigabatrin and ezogabine
During the study and 
within 1 year prior to 
Visit 1
If taken anytime 1 year before 
Visit 1 (see exclusion criteria for 
other restrictions specific to 
Vigabatrin and ezogabine)
x
Felbamate
During the study if 
felbamate was initiated 
within 18 months prior 
to Visit 1
If felbamate was initiated more 
than18 months prior to Visit 1
x
Investigational medications or
devices other than YKP3089 
During the study and 
within 30 days prior to 
Visit 1
If taken or used anytime 30 days 
before Visit 1
8.5
Dosing Instructions for Study Medication


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 93 of 135
x
It is recommended that the study medication is taken once daily in the morning.  
x
In the event of poor tolerability, the investigator may instruct the subject to take the dose of 
study medication in the evening.
x
During maintenance phase, in the event of poor tolerability, the investigator may instruct the 
subject to divide the total daily dose of study medication into 2 doses.
x
Study medication can be taken with or without food.
x
Study medication must be swallowed, not chewed.
9
STUDY PROCEDURES AND ASSESSMENTS
Visit windows of ± 2 days allowed for Visits 3 through 10.
Visit windows of ± 7 days allowed for all other open-label visits.
9.1
Screening 
9.1.1
Visit 1, Day -21
As shown in Table 1, the following will be performed during Visit 1: 
x
Obtain informed consent (obtained from the subject prior to any study-related procedures)
x
Review and record inclusion and exclusion criteria
x
Record medical and seizure history and demographics
x
Record vital signs
x
Conduct full physical examination (see Appendix A), including height and weight
x
Conduct full neurologic examination (see Appendix B)
x
Administer C-SSRS (Baseline/Screening version) (see Appendix D: COLUMBIA SUICIDE 
SEVERITY RATING SCALE (Baseline/Screening))
x
Perform 12-lead ECG once
x
Perform serum pregnancy test (female subjects of childbearing potential; if positive, subject 
will not be enrolled)
x
Draw blood for laboratory safety assessment
x
Obtain urine for urinalysis


x
An MRI or CT scan will be performed during screening if the subject has not had a 
neuroimaging study within 10 years of Visit 1. This will be used to document the absence of 
an active brain lesion, and a copy of the report will be made available to the Sponsor
x
Include the EEG report in the source document. If an EEG report cannot be obtained, and the 
subject is otherwise eligible, an EEG may be performed during screening.
x
Record concomitant medications
x
Schedule Visit 2 to occur within 3 weeks of Visit 1
9.1.2
Visit 2, Day 1
All subjects who have not discontinued will be scheduled to appear at the clinic for Visit 2. At
Visit 2, subjects who continue to meet all of the inclusion criteria and none of the exclusion criteria 
will receive study drug.
As shown in Table 1, the following will be performed at Visit 2:
x
Review and record inclusion and exclusion criteria 
x
Record vital signs
x
Conduct brief neurologic examination if required (Appendix C)
x
Administer C-SSRS (Since Last Visit version) (Appendix E)
x
Perform urine pregnancy test (for female subjects of childbearing potential)
x
Record concomitant medications
x
Record AEs
x
For subjects taking phenytoin or phenobarbital, draw blood for phenytoin or phenobarbital
trough levels
x
For subjects taking concomitant AEDs other than phenytoin or phenobarbital at US sites only,
draw blood for concomitant AEDs (oxcarbazepine, topiramate, lamotrigine, lacosamide, 
clobazam, perampanel and levetiracetam only) levels
x
Dispense study drug as instructed by IWRS if all of the inclusion criteria and none of the 
exclusion criteria are met


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 95 of 135
x
The subject may take the first dose of the study medication the same day or the next morning.
If the investigator wants to observe the subject after the first dose at the clinic, the first dose 
can be administered at the site after all other Visit 2 procedures have been completed
x
Schedule a return to occur in 2 weeks for Visit 3
x
Dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events
9.1.3
Visit 3, Day 15
As shown in Table 1, the following will be performed at Visit 3:
x
Record vital signs
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Draw blood for laboratory safety assessment
x
Administer C-SSRS (Since Last Visit version)
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS
x
Schedule a return to occur in 2 weeks for Visit 4
x
Check and dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events
9.1.4
Visit 4, Day 29
As shown in Table 1, the following will be performed at Visit 4:
x
Record vital signs
x
Measure weight
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever


x
Conduct brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)
x
Draw blood for laboratory safety assessment
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
For subjects taking phenytoin or phenobarbital, draw blood for phenytoin or phenobarbital
levels. Two blood samples will be collected: For subjects taking phenytoin or phenobarbital in 
the morning and coming into the visits in the morning, the first blood draw will be collected 
upon subjects’ arrival to the study unit; the second blood draw should be collected within 30 
minutes to 2 hours after the medication is taken. 
x
Dispense study drug as instructed by IWRS
x
Schedule a return to occur in 2 weeks for Visit 5
x
Check and dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events
9.1.5
Visit 5, Day 43
As shown in Table 1, the following will be performed at Visit 5:
x
Record vital signs
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Draw blood for laboratory safety assessment
x
Administer C-SSRS (Since Last Visit version)
x
Perform urine pregnancy test (for female subjects of childbearing potential)
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
For subjects taking phenytoin or phenobarbital, draw blood for phenytoin or phenobarbital 
levels. Two blood samples will be collected: For subjects taking phenytoin or phenobarbital in 


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 97 of 135
the morning and coming into the visits in the morning, the first blood draw will be collected 
upon subjects’ arrival to the study unit; the second blood draw should be collected within 30 
minutes to 2 hours after the medication is taken. 
x
Dispense study drug as instructed by IWRS
x
Schedule a return to occur in 2 weeks for Visit 6
x
Check and dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events
9.1.6
Visit 6, Day 57
As shown in Table 1, the following will be assessed at Visit 6:
x
Record vital signs
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)
x
Draw blood for laboratory safety assessment
x
For subjects taking phenytoin or phenobarbital, draw blood for phenytoin or phenobarbital 
levels. Two blood samples will be collected: For subjects taking phenytoin or phenobarbital in 
the morning and coming into the visits in the morning, the first blood draw will be collected 
upon subjects’ arrival to the study unit; the second blood draw should be collected within 30 
minutes to 2 hours after the medication is taken. 
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS.
x
Schedule a return to occur in 2 weeks for Visit 7
x
Check and dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events


9.1.7
Visit 7, Day 71
As shown in Table 1, the following will be assessed at Visit 7:
x
Record vital signs 
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)
x
Draw blood for laboratory safety assessment
x
For subjects taking phenytoin or phenobarbital, draw blood for phenytoin or phenobarbital 
levels. Two blood samples will be collected: For subjects taking phenytoin or phenobarbital in 
the morning and coming into the visits in the morning, the first blood draw will be collected 
upon subjects’ arrival to the study unit; the second blood draw should be collected within 30 
minutes to 2 hours after the medication is taken. 
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS.
x
Schedule a return to occur in 2 weeks for Visit 8
x
Check and dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events
9.1.8
Visit 8, Day 85
As shown in Table 1, the following will be assessed at Visit 8:
x
Record vital signs 
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)


9.1.9
Visit 9, Day 99
As shown in Table 1, the following will be assessed at Visit 9:
x
Record vital signs 
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)
x
Perform urine pregnancy test (for female subjects of childbearing potential)
x
Draw blood for laboratory safety assessment
x
For subjects taking phenytoin or phenobarbital globally and concomitant AEDs other than 
phenytoin or phenobarbital in US, draw blood for YKP3089 levels. Two blood samples will 
be collected: For subjects taking YKP3089 in the morning and coming into the visits in the 
morning, the first blood draw will be collected upon subjects’ arrival to the study unit; the 
second blood draw should be collected within 30 minutes to 2 hours after the medication is 
taken. 
x
For subject taking concomitant AEDs other than phenytoin or phenobarbital at US sites only,
draw blood for concomitant AED levels (oxcarbazepine, topiramate, lamotrigine, lacosamide, 
clobazam, perampanel and levetiracetam only). Two blood samples will be collected: For 
subjects taking concomitant AEDs in the morning and coming into the visits in the morning, 
the first blood draw will be collected upon subjects’ arrival to the study unit; the second blood 
draw should be collected within 30 minutes to 2 hours after the medication is taken. For 
patients that are taking concomitant AEDs in the afternoon and/or coming into the visits in the 
afternoon, the first blood draw will be collected upon subjects’ arrival to the study unit; the 
second blood draw should be collected within 30 minutes to 2 hours after the first blood draw 
with timing of the dose, blood draws and strength of previous dose clearly documented.
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 101 of 135
x
Schedule a return to occur in 2 weeks for Visit 10
x
Check and dispense laminated Hypersensitivity Information safety card
x
Call subject in approximately one week to check for any adverse events
9.1.10
Visit 10, Day 113
As shown in Table 1, the following will be assessed at Visit 10:
x
Record vital signs
x
Perform limited physical exam for signs of hypersensitivity such as rash, swelling, 
lymphadenopathy and fever
x
Conduct brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)
x
Draw blood for laboratory safety assessment
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS.
x
Schedule a return to occur in 4-5 weeks for Visit 11
9.1.11
Visit 11, Day 143
As shown in Table 1, the following will be performed at Visit 11:
x
Record vital signs
x
Conduct brief neurologic exam if required
x
Administer C-SSRS (Since Last Visit version)
x
Perform urine pregnancy test (for female subjects of child-bearing potential)
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS.
x
Schedule a return to occur in 8-9 weeks for Visit 12


9.1.12
Visit 12, Day 203
As shown in Table 1, the following will be performed at Visit 12:
x
Record vital signs
x
Measure weight
x
Perform brief neurologic examination if required
x
Administer C-SSRS (Since Last Visit version)
x
Perform urine pregnancy test (for female subjects of child-bearing potential)
x
Draw blood for laboratory safety assessment
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS
x
Schedule a return to occur in 8-9 weeks for Visit 13
9.1.13
Visit 13, Day 263
As shown in Table 1, the following will be performed at Visit 13:
x
Record vital signs 
x
Conduct brief neurologic exam if required
x
Administer C-SSRS (Since Last Visit version)
x
Perform urine pregnancy test (for female subjects of child-bearing potential)
x
Draw blood for laboratory safety assessment
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense study drug as instructed by IWRS.
x
Schedule a return to occur in 14-15 weeks for Visit 14


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 103 of 135
9.1.14
Visit 14 or Termination from study—Taper Visit
As shown in Table 1, the following will be performed at Visit 14 or at the time of early termination 
from the study.
x
Record vital signs
x
Measure weight
x
Conduct full physical examination
x
Conduct full neurologic examination
x
Administer C-SSRS (Since Last Visit version)
x
Perform 12-lead ECG once
x
Perform urine pregnancy test (for female subjects of childbearing potential)
x
Draw blood for laboratory safety assessment
x
Obtain urine for urinalysis
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
For subjects who completed 1 year of open-label treatment, determine whether the subject is 
benefitting from open-label treatment with YKP3089 
For subjects who are benefitting from open-label treatment:
x
Dispense open-label medication 
x
Schedule a return to occur in 3 months for next visit
x
See section 9.1.16 for further instructions
For subjects who are not benefitting from open-label treatment or leaving the open-label 
treatment due to any reasons at any time:
x
Dispense taper open-label study drug bottles as instructed by IWRS if needed
x
Schedule a return to occur in 2 weeks of the last dose for Visit 15 if tapered
x
Schedule a return to occur in 2 weeks for Visit 15 if not tapered


9.1.15
Visit 15, End of Study Follow-up (14 days from the last dose)
Visit 15 represents the Follow-up Visit after discontinuation of study drug. This final visit will 
take place 14 days after the subject’s last dose of YKP3089—at any time during the open-label 
treatment or after 12 months of open-label treatment if there is no additional treatment beyond that 
point.
As shown in Table 1, the following assessments will be performed at Visit 15:
x
Record vital signs 
x
Measure weight
x
Conduct full neurologic examination
x
Administer C-SSRS (Since Last Visit version)
x
Serum pregnancy test (for female subjects of child-bearing potential)
x
Draw blood for laboratory safety assessment
x
Record concomitant medications
x
Perform drug accountability if tapered
x
Record AEs
No study drug will be dispensed.
9.1.16
Open-Label Extension Beyond Year One
Subjects who complete Visit 14 and will continue in the open-label treatment beyond year one will 
adhere to the following visit schedule. The investigator will schedule a return visit in 3 months. 
Subjects will have study visits every 3 months for a total of 4 visits per study year. The investigator
will perform some or all of the following assessments depending up on the visits.
Perform the following every 3 months from Visit 14
x
Record vital signs 
x
Conduct brief neurologic examination  if required
x
Administer C-SSRS (Since Last Visit version)
x
Perform urine pregnancy test (for female subjects of childbearing potential)


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 105 of 135
x
Record concomitant medications
x
Perform drug accountability
x
Record AEs
x
Dispense open-label study drug bottles as instructed by IWRS
Perform the following every 6 months from Visit 14
x
Measure weight 
x
Draw blood for laboratory safety assessment
Perform the following every 12 months from Visit 14
x
Perform full physical exam
x
Perform 12-lead ECG once
x
Obtain urine for urinalysis 
This pattern will continue at the discretion of the investigator until development is stopped by SK 
Life Science Inc, the product is approved for marketing, or anytime at the discretion of SK Life 
Science Inc. 
After the first year of open-label treatment, the visits will be numbered sequentially beginning with 
Visit 16.
For subjects who discontinue any time after the first year of the open-label treatment, the subject 
should be brought to the clinic as soon as possible and the investigator will perform the assessments 
listed under Visit 14. The data collected at this visit will be entered in the Termination Visit page 
in eCRF. After this visit, the subject will be scheduled to return for Visit 15 (end-of-study follow-
up, 14 days after the last dose of study medication). 
9.2
Unscheduled Visit
At any time during the study, the subject may have an additional study visit/phone call if the 
investigator or the subject feels it is necessary. All information, including reason for visit/phone 
call, AEs, and any procedures performed should be collected in the source documents and recorded 
in the appropriate section of the eCRF.


9.3
Safety Assessments
Safety will be assessed by the nature, frequency, and severity of treatment-emergent spontaneously 
reported AEs, dropouts due to AEs, overall dropout rates, and changes from baseline in vital signs, 
physical and neurologic exams, clinical laboratory evaluations, 12-lead ECGs, and Columbia-
Suicide Severity Rating Scale (C-SSRS).
Study subjects will receive the following Hypersensitivity information on a laminated card to carry 
with them:    
x
Rash may occur and may progress to Drug Reaction with Eosinophilia and Systemic 
Symptoms (DRESS).
x
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.
x
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.
x
Reminder to check skin daily for evidence of rash for the first four months of therapy
If a subject reports a rash by telephone, an unscheduled visit should be performed promptly. Any 
patient with a rash or manifestation of hypersensitivity reaction such as lymphadenopathy, fever, 
facial swelling must be seen immediately at the study site. If it can definitely be determined that 
the rash or other symptoms are unrelated to study drug, then the subject can be maintained on 
YKP3809.  If the cause of the rash or other symptoms cannot be definitely determined 
immediately, then YKP3089 must be discontinued immediately. 
The initial physical/rash assessment for hypersensitivity reaction at the investigative site will 
include the following:
x
Measure body temperature


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 109 of 135
9.4
Pharmacokinetic Evaluations
Time and date of each blood draw and dosing records (time/date/dose) of YKP3089 and AEDs 
prior to each blood draw will be recorded on the eCRF and other appropriate forms.
Plasma samples will be assayed for YKP3089 and AEDs at a specified bioanalytical laboratory 
using previously validated methods. Assay methodology will be detailed in separate assay 
protocols.
For subject taking phenytoin or phenobarbital
These samples will be obtained from subjects taking phenobarbital or phenytoin at any global sites.
At Visit 2, a single trough level of phenytoin or phenobarbital will be obtained. At Visits , 4, 5, 6, 
7 and 8, two blood samples will be collected for the determination of phenobarbital or phenytoin 
plasma levels: For the subjects taking phenytoin or phenobarbital in the morning and coming into 
the visits in the morning, the first blood draw will be collected upon subjects’ arrival to the study 
unit; the second blood draw should be collected within 30 minutes to 2 hours after the medication 
is taken. At Visits 8 and 9, two blood samples will be collected for YKP3089 depending on stability 
of dosing (stable dose all AEDs including YKP3089 for prior 2 weeks).                                                                
For subject taking concomitant AEDs other than phenytoin or phenobarbital
These samples will be obtained from subjects taking concomitant AEDs other than phenobarbital 
or phenytoin at US sites only.
At Visit 2, a single blood sample will be drawn to determine trough level if the subject is taking 
one of the followings, oxcarbazepine, topiramate, lamotrigine, lacosamide, clobazam, perampanel 
and levetiracetam. At Visit 8 and/or 9, two blood samples will be drawn from the same subjects to
determine plasma levels of YKP3089, oxcarbazepine, topiramate, lamotrigine, lacosamide, 
clobazam, perampanel and levetiracetam.  Collect at visit 8 and/ or 9 depending on stability of 
dosing (stable dose all AEDs including YKP3089 for prior 2 weeks). At Visit 8 and 9, for the 
subjects that are taking concomitant AEDs in the morning and coming into the visits in the 
morning, first blood draw will be collected upon subjects’ arrival to the study unit; the second 
blood draw should be collected within 30 minutes to 2 hours after the medication is taken. For 


patients that are taking concomitant AEDs in the afternoon and/or coming into the visits in the 
afternoon, the first blood draw will be collected upon subjects’ arrival to the study unit; the second 
blood draw should be collected within 30 minutes to 2 hours after the first blood draw with timing 
of the dose, blood draws and strength of previous dose clearly documented.
The collection schedule is summarized in Table 11 below.
Table 11. Blood Collection Schedule* for YKP3089 and AED Levels
Cohort Æ
Subjects taking Phenytoin or 
Phenobarbital
Subjects taking AEDs other 
than Phenytoin or 
Phenobarbital –US sites only
Blood collection for 
YKP3089 levels
Visits 8 and/or 9
Visits 8 and/or 9
Blood collection for 
phenytoin or phenobarbital 
levels
Visits 2*, 4, 5, 6, 7 and 8
Not Applicable
Blood collection for 
concomitant AEDs (other 
than phenytoin or 
phenobarbital) levels
None
Visits 2*, 8 and/or 9
* At Visit 2, one sample will be collected; at all other visits, two samples will be collected
Additional Samples
Additional blood samples may be drawn for levels of concomitant AEDs during the open label
maintenance phase if the investigator believes that symptoms of toxicity may be related to 
concomitant AEDs.
10 SAFETY AND ADVERSE EVENTS 
10.1
Definitions
10.1.1
Adverse Events
An adverse event (AE) is any symptom, sign, illness, or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as AEs.
Abnormal results of diagnostic procedures are considered to be AEs if the abnormality:


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 111 of 135
x
Results in study withdrawal
x
Is associated with an SAE
x
Is associated with clinical signs or symptoms
x
Leads to additional treatment or to further diagnostic tests
x
Is considered by the investigator to be of clinical significance
10.1.2
Serious Adverse Event
AEs are classified as serious or non-serious. A serious adverse event is any AE that is:
x
Fatal
x
Life-threatening
x
Requires or prolongs hospital stay
x
Results in persistent or significant disability or incapacity
x
A congenital anomaly or birth defect
x
An important medical event
Important medical events are those that may not be immediately life threatening but are clearly of 
major clinical significance. They may jeopardize the subject and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in inpatient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.
10.1.3
Suspected Adverse Reaction
Suspected adverse reaction means any AEs for which there is a reasonable possibility that the drug 
cause the AE. For the purpose of investigational new drug (IND) safety reporting, “reasonable
possibility” means there is evidence to suggest a causal relationship between the drug and AE.
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
All AEs that do not meet any of the criteria for seriousness should be regarded as non-serious 
AEs.


10.1.4
Adverse Event Reporting Period
The study period during which AEs must be reported is normally defined as the period from the 
initiation of any study procedures (Visit 1) to the end of the study treatment follow-up. For this 
study, the AE reporting period is defined as 30 days following the last administration of study 
treatment for SAEs. For all other AEs, reporting period is defined as 14 days following the last 
administration of study treatment.
10.1.5
Preexisting Condition
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an AE if the frequency, intensity, or the character of the condition worsens 
during the study period.
At Visit 1 any clinically significant abnormality should be recorded as a preexisting condition. 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.
Post-study Adverse Events
All unresolved AEs should be followed by the investigator until the events are resolved, the subject
is lost to follow-up, or the AE is otherwise explained. At the last scheduled visit, the investigator
should instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.
The investigator should notify the study Sponsor of any death or AE occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this 
study. The Sponsor should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring of a 
subject who has participated in this study.
Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an AE if any one of the following
conditions is met:


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 113 of 135
x
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality.
x
The abnormality suggests a disease and/or organ toxicity.
x
The abnormality is of a degree that requires active management (eg, change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation).
Hospitalization, Prolonged Hospitalization, or Surgery
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious AE unless specifically instructed otherwise in this protocol. Any condition 
responsible for surgery should be documented as an AE if the condition meets the criteria for an 
AE.
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances:
x
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.
x
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study.
x
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator.
x
An Emergency Room visit is not considered hospitalization.
10.2
Adverse Event Recording and Assessing
All AEs occurring during this clinical trial will be recorded. The investigator will review each 
event and assess its relationship to drug treatment (unrelated, remote, possible, probable, or
definite). Each sign or symptom reported will be graded on a 3-point severity scale (mild, 
moderate, or severe), and the date of onset, time of onset, and outcome of each event will be noted.
The relationship of each AE to study drug will be assessed using the following definitions:


Definite
x
Distinct temporal relationship with drug treatment
x
Known reaction to agent or chemical group, or predicted by known 
pharmacology
x
Event cannot be explained by subject’s clinical state or other factors
Probable
x
Reasonable temporal relationship with drug treatment
x
Likely to be known reaction to agent or chemical group, or predicted by 
known pharmacology
x
Event cannot easily be explained by subject’s clinical state or other factors
Possible
x
Reasonable temporal relationship with drug treatment
x
Event could be explained by subject’s clinical state or other factors
Remote
x
Poor temporal relationship with drug treatment
x
Event easily explained by subject’s clinical state or other factors
Unrelated
x
Event occurring before dosing
x
Event or intercurrent illness due wholly to factors other than drug treatment
The following definitions for rating severity will be used:
x
Mild: The AE is easily tolerated and does not interfere with daily activity.
x
Moderate: The AE interferes with daily activity, but the subject is still able to function.
x
Severe: The AE is incapacitating and requires medical intervention.
10.3
Reporting of Adverse Events
At each contact with the subject, the investigator must seek information on AEs by specific 
questioning and, as appropriate, by examination. Information on all AEs should be recorded 
immediately in the source document and also in the appropriate AE module of the eCRF. All
clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded in 
the source document, though they should be grouped under one diagnosis.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 115 of 135
All AEs occurring during the study period must be recorded on the appropriate eCRFs. The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious AEs that are still 
ongoing at the end of the study period must be followed up to determine the final outcome. Any 
serious AE that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately no later than 24 
hours after awareness of the event.
10.3.1
Study Sponsor Notification by Investigator
In the event of any fatal or life-threatening SAE, the investigator must inform SK Life Science, 
Inc. (SKLSI) designee QDS by telephone immediately.  Any non-fatal or non-life-threatening 
SAE, regardless of expectedness or causality, must be reported on the SAE Report Form by 
scanned and emailed to SKLSI’s designee QDS within 24 hours of the investigator’s or any other 
study center personnel’s knowledge of the event as described below. 
A completed SAE Report Form, the AE record, pertinent medical records, and the Concurrent 
Medication record from the source documents should be scanned and emailed to SKLSI’s 
designee QDS within 24 hours of the investigator’s or any study center personnel’s knowledge of 
a serious event.  An updated SAE Report Form should be forwarded to SKLSI’s designee QDS 
within 24 hours of receipt of new/updated information.  The SAE Reporting Requirements and 
contact information are outlined in Table 12.
Seizures in this subject population are anticipated.  Therefore, seizures, in and of themselves, will 
not be considered adverse events.  Seizures to be considered adverse events will include those 
occurring with a measurable increase over the subject’s typical seizure frequency or duration; or 
multiple seizures in a pattern distinguishable from the usual seizure pattern. 
Table 12. Serious Adverse Event Reporting Requirements
Type of SAE
Reporting
Reporting
Email address, Telephone Number,


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 117 of 135
x
Study center
x
Subject number
x
A description of the event
x
Date of onset
x
Current status 
x
Whether study treatment was discontinued
x
The reason why the event is classified as serious
x
Investigator assessment of the association between the event and study treatment
Within the following 48 hours, the investigator must provide further information on the serious 
AE in the form of a written narrative. This should include a copy of the completed SAE form, and 
any other diagnostic information that will assist the understanding of the event. Significant new 
information on ongoing serious AEs should be provided promptly to the study Sponsor.
10.3.2
Ethics Committee/Institutional Review Board Notification by Investigator
Reports of all serious AEs (including follow-up information) must promptly be submitted to the 
Ethics Committee/Institutional Review Board (EC/IRB). Copies of each report and documentation 
of EC/IRB notification and receipt will be kept in the clinical investigator’s binder.
10.3.3
Regulatory Authority Notification of IND Safety Reports by Sponsor
The study Sponsor must notify the FDA and all participating investigators in an IND safety report 
of potential serious risks from clinical trials as soon as possible but in no case later than 15 calendar 
days after the Sponsor determines that the information qualifies for reporting. This includes any 
suspected adverse reaction that is both serious and unexpected (SUSAR).
The study Sponsor must notify the FDA of any unexpected fatal or life-threatening suspected 
adverse reaction as soon as possible but no later than 7 calendar days from the Sponsor’s initial 
receipt of the information.
If a previous AE that was not initially deemed reportable is later found to fit the criteria for 
reporting, the study Sponsor will submit the AE in a written report to the FDA as soon as possible, 
but no later than 15 calendar days from the time the determination is made.


The notification of other Regulatory Authorities follows the same procedure and timeframe, per 
ICH Guidance, as for the FDA.
10.4
Withdrawal of Subject from Study 
Subjects may be withdrawn from the study prior to completion of the study if:
x
Consent is withdrawn by the subject
x
The subject fails to adhere to the protocol requirements
x
An intolerable AE is experienced
x
The subject becomes pregnant
x
The subject is lost to follow-up
When a subject is withdrawn, the discharge procedures must be performed. The reason(s) for the 
withdrawal must be documented in the subject’s eCRF.
11 DATA HANDLING PROCEDURES
11.1
Data Handling and Record Keeping 
11.1.1
Confidentiality
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following:
x
What protected health information (PHI) will be collected from subjects in this study
x
Who will have access to that information and why
x
Who will use or disclose that information
x
The rights of a research subject to revoke their authorization for use of their PHI
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected and that all personal 
information made available for inspection will be handled in strictest confidence and in accordance 
with local data protection laws.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 119 of 135
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject
authorization. For subjects who have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (ie, that the subject is alive) at the end 
of his or her scheduled study period.
11.1.2
Source Documents
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents. Examples of these original documents and data records include 
hospital records; clinical and office charts; laboratory notes; memoranda; subjects’ diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from automated instruments;
copies or transcriptions certified after verification as being accurate and complete; microfiches;
photographic negatives; microfilm or magnetic media; x-rays; subject files; and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial.
11.1.3
Electronic Case Report Forms
The eCRF is the primary data collection instrument for the study. All data requested on the eCRF 
must be recorded. All missing data must be explained. Details of the completion of the eCRF will 
be included in a data entry manual.
11.1.4
Records Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s).
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. Essential documents must be retained until at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 121 of 135
12 STATISTICAL METHODS AND PLANNED ANALYSES
12.1
Statistical Methods
Categorical variables will be summarized as frequencies and percentages. Descriptive statistics for 
continuous variables will include number of subjects, mean, median, standard deviation, and 
minimum and maximum values. SAS® version 9.2 or later will be used for all data summaries.
Data will be used as collected.  
12.2
Analysis Data Sets
Enrolled subjects: All subjects who successfully meet their entry criteria and who have given 
informed consent to participate in this study will be considered enrolled subjects.
Safety evaluable subjects (SE): All subjects enrolled in the study who received at least one dose of 
study drug medication will be considered safety evaluable subjects. 
Three safety evaluable subgroups of subjects will be defined: 
o
Subjects taking phenytoin and YKP3089
o
Subjects taking Phenobarbital and YKP3089
o
Subjects taking concomitant AEDs other than phenytoin or Phenobarbital and 
YKP3089
12.3
Baseline Characteristics
All demographic measurements (age, gender, race, ethnicity, height, and weight) and all baseline 
safety measurements (medical and seizure history, MRI, CAT, ECGs, vital signs, clinical 
laboratory values, physical and brief neurologic exam, and C-SSRS) will be summarized for all 
enrolled subjects, for all safety evaluable subjects and by the 3 subgroups of subjects defined in 
Section 12.2.


12.4
Safety Variable Analyses
All enrolled subjects who took at least one dose of study drug medication will be evaluable for 
safety. The number and percent of subjects reporting AEs (including treatment-emergent 
laboratory abnormalities) will be tabulated for all safety evaluable subjects and by the 3 subgroups 
of subjects defined in Section 12.2. All serious AEs (SAEs) will be tabulated separately as well as 
included with all reported AEs. 
Physical and neurologic assessments, laboratory results, vital signs (including orthostatic 
measurements, weight and height), concomitant medications, ECGs, and C-SSRS will be 
summarized using descriptive statistics.
Extent of exposure and dose modifications will be tabulated.
12.5
Pharmacokinetics and Pharmacodynamics Analysis
YKP3089 plasma concentration data collected from this study will be pooled with data from other 
YKP3089 clinical trials for possible population pharmacokinetic and pharmacodynamic analysis. 
An integrated population pharmacokinetic model for YKP3089 will be developed. Standard 
population pharmacokinetic parameters (eg, total body clearance, CL/F) in epilepsy patients and 
their inter- and intra-individual variability will be estimated. The effects of demographic 
characteristics, concomitant medication including AEDs, laboratory values, and other subject 
covariates on YKP3089 pharmacokinetics will be evaluated. 
For phenytoin, phenobarbital plasma concentrations obtained during titration phase (Visits 3-6)
will be compared with that taken at baseline (Visit 2) to assess the effect of YKP3089 on these two 
AEDs. The timing of AED sampling in relation to the subject’s AED dosing schedule will be 
factored into the analysis.
For each concomitant AED (oxcarbazepine, topiramate, lamotrigine, lacosamide, clobazam, 
perampanel and levetiracetam only), plasma concentrations obtained at Visits 8 and or 9 will be 
compared with that taken at baseline (Visit 2) to assess the effect of YKP3089 on these 7 AEDs. 
The timing of AED sampling in relation to the subject’s AED dosing schedule will be factored 
into the analysis. 


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 123 of 135
If warranted, the AED plasma concentration data collected from this study will be pooled with 
data from other YKP3089 studies to assess the potential for an interaction with YKP3089. Results 
will be displayed descriptively in tabular form.
13 LEGAL ASPECTS, ETHICAL AND ADMINISTRATIVE ISSUES 
13.1
Good Clinical Practice
This study is to be conducted according to US and international standards of GCP (FDA Title 21
parts 50 and 312 and ICH guidelines), applicable government regulations, and institutional 
research policies and procedures. This protocol and any amendments will be submitted to a 
properly constituted independent EC/IRB, in agreement with local legal prescriptions, for formal 
approval of the study conduct. The decision of the EC/IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be provided to the 
Sponsor before commencement of this study. The investigator should provide a list of EC/IRB 
members and their affiliate to the Sponsor.
13.2
Documentation of Consent
Written consent of a subject, using the EC/IRB-approved consent form, will be obtained before 
that subject undergoes any study procedure. The individual who consents the subject must be listed 
on the delegation log and be authorized to obtain consent. All subjects will have adequate time to 
ask questions and will be provided with a signed copy of the consent for his/her records. The 
consenting process will be clearly documented in the subject’s chart. The principal investigator is 
responsible for ensuring that valid consent is obtained and documented for all subjects.
13.3
Delegation of Investigator Responsibilities
The qualified investigator will ensure that all persons assisting the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-
related duties and functions. The qualified investigator will maintain a list of sub-investigators and 
other appropriately qualified persons to whom he delegates significant trial-related duties.


13.4
Conflict of Interest
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study Sponsor prior to 
participation in this study.
13.5
Publication Plan
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the Sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study Sponsor. Any 
investigator involved with this study is obligated to provide the Sponsor with complete test results 
and all data derived from the study.
13.6
Protocol Amendments
Protocol Amendments will not be implemented without agreement from the Sponsor and prior 
submission to and written approval from the EC/IRB, except when necessary to eliminate an 
immediate hazard to the subject. 
13.7
Study Monitoring, Auditing, and Inspecting
13.7.1
Study Monitoring Plan
This study will be monitored according to the monitoring plan and in accordance with 21 CFR 
312.53(d) and ICH guidelines. The investigator will allocate adequate time for such monitoring 
activities. The investigator will also ensure that the monitor or other compliance or quality 
assurance reviewer is given access to all the above noted study-related documents and study related 
facilities (eg, pharmacy, diagnostic laboratory), and has adequate space to conduct the monitoring 
visit.


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 125 of 135
13.7.2
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
Sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (eg, source documents, regulatory documents, data collection 
instruments, study data). The investigator will ensure the capability for inspections of applicable 
study-related facilities (eg, pharmacy, diagnostic laboratory).
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices.


APPENDIX A: FULL PHYSICAL EXAMINATION
FULL PHYSICAL EXAMINATION
BODY SYSTEM
Normal
Abnormal, 
NCS 
Abnormal, 
CS 
Not Done
If Abnormal, Specify Findings
General Appearance




Head




EENT




Neck




Cardiovascular




Abdominal




Respiratory




Musculoskeletal




Extremities




Neurological




Skin




Other, specify:
________________




Other, specify:
________________






SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 127 of 135
APPENDIX B: FULL NEUROLOGIC EXAMINATION
FULL NEUROLOGIC EXAMINATION
GENERAL
Normal
Abnormal, 
NCS
Abnormal, 
CS
Not Done
If Abnormal,
Specify Findings – including 
laterality, as applicable
1. Level of Consciousness




2. Mental Status




3. Visual Fields (II)




4. Eye Movements (III, IV, VI)




5. Jaw Movement and Facial Sensation (V)




6. Facial Motion (VII)




7. Hearing (VIII)




8. Swallowing, pharynx, larynx (IX, X)




9. SCM, trapezius (XI)




10. Tongue (XII)




11. Biceps Reflexes




12. Triceps Reflexes




13. Patellar Reflexes




14. Achilles Reflexes




15. Plantar Reflexes




16. Gait




17. Romberg




18. Nystagmus




19. Tremor




20. Finger-Nose




21. Heel-Shin




22. Rapid Alternating Movements




23. Muscle Strength




24. Pin




25. Vibration






APPENDIX C: BRIEF NEUROLOGIC EXAMINATION
BRIEF NEUROLOGIC EXAMINATION
GENERAL
Normal
Abnormal, 
NCS
Abnormal, 
CS
Not Done
If Abnormal,
Specify Findings – including 
laterality, as applicable
1. Level of consciousness




2. Mental status




3. Biceps reflexes




4. Knee reflexes




5. General movement




6. Gait




7. Romberg




8. Nystagmus




9. Tremor




10. Finger-nose




11. Heel-shin




12. Rapid alternating movements






SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 129 of 135
APPENDIX D: COLUMBIA SUICIDE SEVERITY RATING SCALE (BASELINE/SCREENING)


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


SK Life Science Inc
CONFIDENTIAL
Protocol YKP3089C021, Amendment 5 
June 20, 2019 
Page 135 of 135
14 REFERENCES
1. World Health Organization. Epilepsy: Aetiogy, epidemiology and prognosis. WHO Fact Sheet 
No. 165, February 2001.
2. Guidelines for the clinical evaluation of antiepileptic drugs. Epilepsia 1989;30:400-406.
3. European Agency for the Evaluation of Medicinal Products, Committee for Proprietary 
Medicinal Products. Note for guidance on clinical investigation of medicinal products in the 
treatment of epileptic disorders. CPMP/EWP/566/98 rev 1, 2000.
4. Food and Drug Administration, Guidelines for the clinical evaluation of antiepileptic drugs 
(adults and children). HHS (FDA) 81-3110, 1981. 

SAP_001.pdf: 
SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 1 of 50 
 
 
 
STATISTICAL ANALYSIS PLAN 
An Open Label, Multicenter, Safety and Pharmacokinetic Study of YKP3089 
As Adjunctive Therapy in Subjects with Partial Onset Seizures 
(Phase 3) 
PROTOCOL YKP3089C021 Amendment 4  
28 July 2017 
Statistical Analysis Plan Version 5.0 
05 September 2018 
 
 
SPONSOR: 
 
SK Life Science Inc. 
22-10 Route 208 South 
Fair Lawn, NJ 07410 
 
 
 
 
 
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 2 of 50 
 
 
1 
REVISION HISTORY 
Versi
on 
Date 
Author 
Description 
1.0 
25Sep2017 
QDS 
Based on Protocol Amendment  3 
2.0 
19Jun2018 
QDS 
Updated per Protocol Amendment 4 and 
additional requests from SKLSI after meeting 
with FDA 
3.0 
26Jul2018 
QDS 
Clarifications for Physical Exam, C-SSRS 
visit windows. 
Updated definition for duration of epilepsy. 
Removed analyses for overall compliance. 
Administrative changes for subjects 
disposition, clinical laboratory tests, vital 
signs analyses 
4.0 
23Aug2018 
QDS 
Removed reference to Screen Failures as an 
analysis population. 
Removed all analyses by country and region. 
PK Section: AED plasma concentration 
analysis will be based on Central Lab results 
Included Study Assessment Flowchart from 
Protocol Amendment 4 in Appendix 1 
5.0 
05Sep2018 
QDS 
Updated analyses for LFTs to include all 
baseline values (ie, not restricted to normal 
baseline) 
 


SK Life Science Inc Protocol YKP3089C02I 
Statistical Analysis Plan - V5.0
2 SIGNATURE 
' 
APPROVAL PAGE
AUTHORS
Dana L Creanga, PhD
Statistician, Quality Data Services, lnc.
Date
APPROVERS
Head, $tatistics and Data Management, SK Life
Science, lnc
)*Xztz* t
Date
Chief Medical Officer, SK Life Science, lnc.
Marc Kamin, MD
Page 3 of 50


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 4 of 50 
 
 
TABLE OF CONTENTS 
1 
REVISION HISTORY ................................................................................. 2 
2 
SIGNATURE / APPROVAL PAGE ............................................................ 3 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................... 6 
4 
INTRODUCTION ....................................................................................... 8 
5 
STUDY OBJECTIVES ............................................................................... 9 
6 
STUDY DESIGN AND VISIT SCHEDULE ................................................. 9 
7 
STUDY ENDPOINTS ............................................................................... 12 
8 
STUDY PROCEDURES AND ASSESSMENTS ...................................... 13 
8.1 
Screening and Baseline ........................................................................... 13 
8.2 
Safety and Tolerability Measures ............................................................. 14 
8.2.1 
Adverse Events ........................................................................................ 14 
8.2.2 
Other Safety Measures ............................................................................ 15 
8.3 
Study Drug Exposure and Compliance .................................................... 16 
9 
STUDY SUBJECTS................................................................................. 17 
9.1 
Determination of Sample Size and Randomization .................................. 17 
9.2 
Analysis Populations ................................................................................ 17 
10 
STATISTICAL METHODS ....................................................................... 18 
10.1 
General Methods ..................................................................................... 18 
10.2 
Handling Missing Data ............................................................................. 18 
10.3 
Visit Windows for Safety Analyses ........................................................... 18 
10.4 
Baseline Value and Change from Baseline .............................................. 22 
11 
SUBJECT DISPOSTION, BASELINE CHARACTERISTICS, AND 
EXPOSURE ............................................................................................. 23 
11.1 
Subject Disposition .................................................................................. 23 
11.2 
Protocol Deviations .................................................................................. 23 
11.3 
Demographic and Baseline Characteristics ............................................. 24 
11.4 
Drug Exposure, Dosing, and Compliance ................................................ 24 
11.4.1 
Exposure to YKP3089 study drug ............................................................ 25 
11.4.2 
Phenytoin and Phenobarbital Dosing during Titration Phase ................... 26 
11.5 
Prior and Concomitant Medications and Procedures ............................... 30 
11.6 
Medical and Seizure/Epilepsy History ...................................................... 31 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 5 of 50 
 
11.7 
EEG, MRI or CT Scan Results ................................................................. 31 
12 
PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS 
AND ANALYSIS ...................................................................................... 31 
13 
SAFETY ANALYSIS................................................................................ 33 
13.1 
Analysis of Adverse Events (treatment-emergent, non-serious, 
serious, and deaths) ................................................................................ 33 
13.2 
Analysis of Clinical Laboratory parameters .............................................. 35 
13.3 
Analysis of Electrocardiograms ................................................................ 36 
13.4 
Analysis of Vital Signs.............................................................................. 37 
13.5 
Analysis of Physical and Neurologic Examination Results....................... 38 
13.6 
Columbia Suicide Symptoms and Signs Rating Scale (CSSRS) ............. 39 
14 
INTERIM ANALYSIS ............................................................................... 40 
15 
GENERAL PROGRAMMING SPECIFICATIONS ................................... 41 
15.1 
Format ..................................................................................................... 41 
15.2 
Validation ................................................................................................. 42 
16 
CHANGES FROM PROTOCOL SPECIFIED ANALYSES ...................... 42 
17 
APPENDIX 1: STUDY ASSESSMENT FLOWCHART: .......................... 44 
18 
APPENDIX 2: DATA HANDLING RULES FOR MISSING OF 
PARTIAL START/STOP DATES FOR CONCOMITANT 
MEDICATIONS, CONCOMITANT AEDS, AND BASELINE AEDS ........ 48 
19 
REFERENCES ........................................................................................ 50 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 6 of 50 
 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical classification system 
AUC 
Area under the plasma concentration versus time curve 
β-hCG 
β-human chorionic gonadotropin 
CBZ 
Carbamazepine 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
Computed tomography 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEG 
Electroencephalograph 
EMEA 
Evaluation of Medicinal Products 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
IWRS 
Interactive Web response system 
kg 
Kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
mg 
Milligrams 
mg/day 
Milligrams per Day 
mg/day/week 
Milligrams per Day per Week 
mg/week 
Milligrams per Week 
MRI 
Magnetic resonance imaging 
PK 
Pharmacokinetic 
QC 
Quality Control 
QDS 
Quality Data Services 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Safety evaluable 
SKLSI 
SK Life Science Inc. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 7 of 50 
 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, listings, figures 
VPA 
Valproic acid (divalproex sodium) 
WHO DD 
World Health Organization Drug Dictionary 
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 8 of 50 
 
4 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methodology to be 
used for the reporting and statistical analysis of safety and pharmacokinetic (PK) 
clinical data as collected under SK Life Science clinical study protocol 
YKP3089C021 (amendment 4, 28 July 2017).   
All statistical methods in this SAP are in regulatory compliance with the 
specifications as detailed in the International Conference on Harmonization (ICH) 
Guidelines: 
• E3: Structure and Content of Clinical Study Reports; 
• E6: Guideline for Good Clinical Practice; and 
• E9: Statistical Principles for Clinical Trials. 
Table, listing and figure templates (TLFs) for this study are presented in separate 
TLF documents. 
All analyses described, statistical populations and TLFs programmed mentioned 
in this SAP are to be included in sections 14 and 16 of the clinical study report 
(CSR). All computer outputs detailing the statistical computations are to appear 
in an appendix: Statistical Documentation in the CSR as specified in the ICH E3 
Guidance. 
The signatures on this statistical analysis plan indicate approval of the safety and 
PK statistical analyses as detailed in each section of this SAP.  These sections 
are agreed upon by SK Life Science (the Sponsor) and QDS (the Vendor).  
This SAP may be revised at the end of the clinical investigation and prior to 
database lock to reflect specific details regarding protocol deviations and/or other 
data analysis clarifications (if needed).  
This SAP supersedes any statistical considerations which were identified in the 
study protocol. Substantial differences from the study protocol are identified in 
this plan.  If additional analyses are required to supplement the planned analyses 
then they will be performed and identified in the appropriate section of the CSR.   
Computer program validation methods are to be agreed upon by the Sponsor 
and Vendor. Quality Control (QC) of all statistical components including derived 
SAS analysis datasets and TLFs will be performed by the Vendor prior to delivery 
to the Sponsor. All computational methods will be checked for accuracy. All “SAS 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 9 of 50 
 
Notes generated from the computers programs will be checked for 
appropriateness. 
. 
5 
STUDY OBJECTIVES 
The objective of this Phase 3 study is to evaluate the safety and 
pharmacokinetics of YKP3089 and concomitant anti epileptic drugs (AEDs) when 
administered as adjunctive therapy for the treatment of partial seizures.  
 
The evaluations will include: 
1. Phenytoin-YKP3089 interaction 
2. Phenobarbital-YKP3089 interaction 
3. Long term safety of YKP3089 as adjunctive therapy in subjects with partial 
onset seizures 
4. Population pharmacokinetics of YKP3089 and concomitant AEDs 
 
6 
STUDY DESIGN AND VISIT SCHEDULE 
This is a multicenter, open label study in subjects with poorly controlled partial 
seizures.  The study will consist of a:  
• screening period,  
• open-label titration phase,  
• open label maintenance phase  
• taper and follow up.  
The study will enroll: 
• Subjects on stable doses of phenytoin 
• Subjects on stable doses of phenobarbital 
• Subjects on stable doses of other concomitant AEDs 
from approximately 80-110 sites (US and other countries)t 
At least 20 subjects taking phenytoin and at least 20 subjects taking 
phenobarbital are to be enrolled.  Additional subjects taking AEDs other than 
phenytoin or phenobarbital are to be enrolled in order to expose at least 1,000 
subjects for 6 months to further evaluate long term safety. 
Details about inclusion / exclusion criteria are included in Protocol Sections 7.3 
and 7.4.   


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 10 of 50 
 
The screening period for subjects on stable doses of phenytoin or stable doses of 
phenobarbital or stable doses of other concomitant AEDs will be up to 21 days.   
The open label treatment period will consist of a 12 week titration phase followed 
by an open label maintenance phase.   
The titration phase for subjects on stable doses of phenytoin or stable doses of 
phenobarbital will be 12 weeks.  During the 12-week up-titration phase, subjects 
will increase YKP3089 dose every 2 weeks to a target dose of 200 mg/day as 
described in the table below: 
Table 1. YKP3089 Initial Up-Titration for subjects on phenytoin and phenobarbital 
 
The titration phase for subjects on stable doses of other concomitant AEDs will 
be 12 weeks.  Increasing doses of YKP3089 will be administered (50, 100, 150 
and 200 mg/day) at 2-week intervals as described in the table below: 
Table 2. YKP3089 Initial Up-Titration for subjects on concomitant AEDs other than 
phenytoin or phenobarbital 
 
During titration phase, the investigator may add, remove, or adjust the dosage of 
any concomitant AEDs, as clinically indicated: 
Table 3. Dose Adjustment Rules during Titration Phase 
 
Monotherapy with YKP3089 will not be allowed. If clinically indicated, titration can 
be stopped below 200 mg/day.  A minimum dose of 50 mg/day is necessary to 
continue in the study.   


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 11 of 50 
 
During open label maintenance phase:  
(1) For subjects taking phenytoin or phenobarbital, the initial target dose will 
be 200 mg/day. If the investigator feels that a subject requires a dose that 
is higher than 200 mg/day, the dose can be increased to a maximum of 
400 mg/day once the target dose of 200 mg/day was reached.  The 
upward dose adjustments should occur every other week in increments of 
50-mg/day.  If the investigator feels that a subject requires a dose that is 
lower than 200 mg/day, the dose can be reduced to a minimum of 
50 mg/day once the target dose of 200 mg/day was reached.  The 
downward dose adjustments may occur weekly by 100 mg/day or 
50 mg/day. 
(2) For subjects taking other concomitant AEDs, the initial target dose will be 
200 mg/day. If the investigator feels that a subject requires a dose that is 
higher than 200 mg/day, the dose can be increased to a maximum of 400 
mg/day once the target dose of 200 mg/day was reached. The upward 
dose adjustments should occur every other week in increments of 
50 mg/day.  If the investigator feels that a subject requires a dose that is 
lower than 200 mg/day, the dose can be reduced to a minimum of 
50 mg/day once the target dose of 200 mg/day was reached.  The 
downward dose adjustments may occur weekly by 100 mg/day or 
50 mg/day. 
(3) The investigator may add (except phenytoin or phenobarbital), remove, or 
adjust the dosage of any concomitant AEDs, as clinically indicated: 
Table 4. Dose Adjustment Rules during Maintenance Phase 
 
Subjects who are withdrawn from the open-label treatment period will taper 
YKP3089 according to the schedule described in Table 5, unless for safety 
reasons the investigator judges it necessary to discontinue study drug 
immediately.   
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 12 of 50 
 
Table 5. Study Drug Taper Schedule for Subjects Completing Open-Label 
Treatment 
 
Details about scheduled procedures during titration phase, open label 
maintenance phase and taper follow-up  are included in Protocol Section 6.1.2.1.   
Study schedule and assessments flow chart is included in Appendix 1.   
 
7 
STUDY ENDPOINTS 
7.1 
Pharmacokinetic Endpoints
 
Population pharmacokinetic analyses of potential effects of covariates on the 
pharmacokinetics of YKP3089 including other concomitant AEDs will be based 
on the sparse PK blood sample approach.  The results for population PK 
analyses will be reported in a separate document.  Summary results for plasma 
concentration are discussed in the SAP and will be included in the CSR. 
7.2 
Safety Endpoints  
Safety endpoints will include: 
• Exposure (YKP3089 and concomitant phenytoin /phenobarbital AEDs) 
• Adverse events (treatment emergent, serious adverse events, 
discontinuations due to adverse events) 
• Overall discontinuation rates 
• Concomitant Medications  
• Vital signs 
• Physical exams  
• Clinical laboratory evaluations  


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 13 of 50 
 
• Columbia Suicide Severity Rating Scale (C-SSRS)  
• 12-lead ECGs 
 
8 
STUDY PROCEDURES AND ASSESSMENTS 
The study will include multiple study visits during the 3 years duration.  Titration 
phase will include 7 study visits (Visit 2 to Visit 8), Maintenance phase will 
include up to 5 visits (Visit 9 to Visit 14).  Visit 15 is considered 14-days after last 
dose follow-up visit.  Subjects who benefit  from treatment, may continue in an 
Open-Label Extension beyond year one with visits occurring every 3 months.   
8.1 Screening and Baseline 
At the time of enrollment in the study, all subjects will sign the informed consent.   
Demographic data  (Date of Birth, Sex, Race and Ethnicity), characterizing 
enrolled subjects will be collected on the Demographics eCRF.   
Height and weight at baseline will be recorded on the Vital Signs eCRF.   
The subject’s date of past and present medical conditions, prior to study 
enrollment, will be recorded on a Medical History eCRF. Medical history data will 
include the Body System, verbatim text, start date, and end date or ongoing.   
The subject’s epilepsy/seizure history including past and current seizures will be 
recorded on an Epilepsy/Seizure History eCRFs. Seizure identification and 
Etiology data will also be collected.   
Physical Examination at screening  (full examination) will be recorded on the 
Physical Exam eCRF. These data will include Body System, a normal/abnormal 
indication, and a description of the abnormality.   
All non-AED medications taken by the subject up to the first dose of the study 
drug will be recorded on the Prior and Concomitant Medications eCRF.  These 
data will include the verbatim medication name, indication for use, dose, route, 
frequency, start date, and end date or ongoing indication.   
A full neurologic evaluation examination will also be performed at screening and 
recorded on the eCRF.  If the subject has not had a recent (within the last 10 
years) CT or MRI, one will be performed and entered on the eCRF.  An 
electrocardiogram (EEG) may also be performed and entered on the eCRF.  At 
baseline visit, a brief neurologic examination may be performed (if needed).   


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 14 of 50 
 
Twelve-lead ECGs overall interpretation and results will be collected at screening 
and will be entered on an eCRF.   
Clinical laboratory evaluations (including blood and urine) will be collected at 
screening and results will be returned electronically for inclusion in the clinical 
database.   
Serum or urine pregnancy test results, where applicable, will be entered into the 
eCRF.   
The baseline version of the Columbia Suicide Rating Scale (C-SSRS) will be 
assessed at Visit 1 and entered on the eCRF.   
8.2 Safety and Tolerability Measures 
8.2.1 Adverse Events 
Adverse event (AE) assessments will be recorded on the Adverse Events eCRF. 
The term AE is used to include both serious and non-serious AEs.   
Adverse events will be assumed to be treatment emergent unless (through 
comparison of full or partial dates) the onset date of the adverse event is 
specified as outside the treatment period or its exclusion from the treatment 
emergent period can be definitely ascertained from the end date or available 
month and year components of either of the start or end dates.  An AE is also 
considered treatment emergent if the onset date is before the start of study 
treatment [Visit 2 /Day 1 + 1] but the severity worsened following that.  If the AE 
onset date is missing or partial, the date will be compared as far as possible with 
the date of first dose of study treatment.  Treatment emergent AEs (TEAEs) 
occurring during the study treatment period from the first dose of study drug 
medication up to and including 14 days after the end of treatment (i.e., not 
present at baseline or worsened in severity following start of treatment) will be 
reported as TEAEs.   
For each AE, the following will be collected: the verbatim term for the AE, start 
date, end date or indication of ongoing, severity, indication of Serious AE, SAE 
criterion, relationship to study drug, action taken, and outcome. AEs will be 
coded using MedDRA version 20.0.   
The onset day of the AE will be the difference between the date of onset of the 
AE and the date the study drug medication was first dispensed + 1.  The duration 
of the AE will be the difference between the end date of the AE and its onset date 
+ 1. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 15 of 50 
 
AE relationship to study drug can be classified by the investigator as definite, 
probable, possible, remote or unrelated.  AEs severity can be rated as mild, 
moderate or severe.  
AEs are classified as serious or non-serious. A serious adverse event (SAE) is 
any AE that is: 
• Fatal 
• Life-threatening 
• Requires or prolongs hospital stay 
• Results in persistent or significant disability or incapacity 
• A congenital anomaly or birth defect 
• An important medical event 
Adverse events (including SAEs) are collected through the length of study for all 
enrolled subjects and for screen failures. 
8.2.2 Other Safety Measures 
Concomitant medications and concomitant procedures will be recorded on the 
Prior and Concomitant eCRF and Concomitant Procedures eCRF, respectively.   
Concomitant AED administration since last visit will be recorded on the eCRF 
page. 
Vital signs will be recorded on the Vital Signs eCRF. These data will include 
blood pressure, heart rate (supine for 5 minutes), temperature, respiratory rate, 
and weight. 
Physical examinations will be recorded on the Physical Exam eCRF. These data 
will include Body System, normal/abnormal indication, and a description of the 
abnormality. 
Routine 12-lead ECGs will be performed periodically during the study. 
Parameters including Heart rate, PR interval, QRS interval, RR interval, QT 
interval, and QTcF will be measured. These results will be recorded on the 
eCRF. 
A brief neurologic evaluation examination will be made and recorded on the 
eCRF. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 16 of 50 
 
Clinical laboratory evaluations will be collected and returned electronically and 
not entered on an eCRF. Clinical Laboratory Evaluations will include the 
following:  
• Hematology: hemoglobin, hematocrit, white blood count with differential, 
RBC count, platelet count, and calculated indices. 
• Serum chemistry: blood urea nitrogen (BUN), calcium, chloride, creatinine, 
glucose, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate 
transaminase (AST), alanine aminotransferase (ALT), total protein, 
albumin, globulin, sodium, potassium, phosphorus, and glucose. Serum 
creatinine will be used to calculate the creatinine clearance.  
• Urinalysis: pH, specific gravity, protein, glucose, ketone, bilirubin, blood, 
nitrite, urobilinogen, and microscopic examination 
• Pregnancy Tests – All females of child-bearing potential will undergo a 
serum pregnancy test for β-hCG (β-human chorionic gonadotropin). 
All safety laboratory samples will be analyzed by a central laboratory. 
The follow-up version of the Columbia Suicide Rating Scale (C-SSRS) will be 
assessed at Visit 2 and all subsequent visits throughout the study and entered on 
the eCRF. 
8.3 Study Drug Exposure and Compliance 
Information on subject drug compliance will be recorded on the study drug 
dispensing eCRF and the Study drug accountability eCRF.  These data will 
include the dates and amount of drug dispensed and returned. 
End of study data will be recorded on the End of Study eCRF. These data will 
include completion status, date of completion or discontinuation, primary reason 
for discontinuation, lost to follow-up information.   
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 17 of 50 
 
9 
STUDY SUBJECTS 
9.1 Determination of Sample Size and Randomization 
No formal sample size estimation was involved for this long-term safety study.  At 
least 20 subjects taking phenytoin and at least 20 subjects taking phenobarbital 
are planned to be enrolled.  Additional subjects taking AEDs other than phenytoin 
or phenobarbital will be enrolled in order to expose at least 1,000 subjects for 6 
months to further evaluate long term safety.   
9.2 Analysis Populations 
The following analysis populations (sets) will be defined: 
Enrolled Population: All subjects who successfully meet their entry criteria and 
who have given informed consent to participate in this study will be considered 
enrolled subjects.   
Safety Population: All subjects enrolled in the study who received at least one 
dose of study drug medication will be considered safety evaluable subjects. 
For reporting purposes, three safety evaluable subgroups of subjects  will be 
defined: 
• Subjects taking phenytoin and YKP3089 
• Subjects taking phenobarbital and YKP3089 
• Subjects taking concomitant AEDs other than phenytoin or Phenobarbital 
and YKP3089 
PK Population: All subjects enrolled in the study, who took at least one dose of 
study drug, and with at least one blood sample for PK. 
All subjects who have given informed consent to participate in this study but 
failed one or more of the entry criteria will be considered screen failures.  
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 18 of 50 
 
10 STATISTICAL METHODS 
10.1 General Methods 
Summary statistics and analyses will be presented by overall (YKP3089) and by 
safety evaluable subgroups.  Categorical variables will be summarized using 
counts and percentages.  Descriptive statistics for continuous variables will 
include mean, standard deviation, median, minimum, and maximum values.  No 
inferential analysis will be performed. 
SAS® version 9.4 or later will be used for all statistical analyses.  
10.2 Handling Missing Data  
All summary results will be based on observed data, unless otherwise specified 
in the next sections.  Data handling rules for missing or partial dates for 
concomitant and baseline AEDs and medication are included in Appendix 2. 
10.3 Visit Windows for Safety Analyses 
The table below presents the visits assigned for safety analyses corresponding to 
the range of treatment study days (window) during which an actual visit 
(scheduled or unscheduled) may occur. Note that the windows defined for 
statistical analysis are different from the ones defined in Protocol Section 9. 
Visit windows for laboratory tests, vital signs, and for Columbia Suicide 
Symptoms and Signs Rating Scale (CSSRS): 
 
Derived Visit  
Target  Study 
Day [1] 
Window  [2] 
Baseline (for laboratory 
tests and vitals) 
Day 1 
Days <= 1 
Baseline (for C-SSRS) 
Screening (Visit 
1) 
NA 
Visit 2 (for C-SSRS) 
Day 1 
Days = 1 
Visit 3  
Day 15 
>= Day 2 to <= Day 22 
Visit 4  
Day 29 
>= Day 23 to <= Day 36 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 19 of 50 
 
Visit 5  
Day 43 
>= Day 37 to <= Day 50 
Visit 6  
Day 57 
>= Day 51 to <= Day 64 
Visit 7  
Day 71 
>= Day 65 to <= Day 78 
Visit 8  
Day 85 
>= Day 79 to <= Day 92 
Visit 9  
Day 99 
>= Day 93 to <= Day 106 
Visit 10  
Day 113 
>= Day 107 to <= Day 128 
Visit 11  
Day 143 
>= Day 129 to <= Day 173 
Visit 12  
Day 203 
>= Day 174 to <= Day 233 
Visit 13  
Day 263 
>= Day 234 to <= Day 314 
Visit 14  
Day 365 
>= Day 315 to <= Day 410 
3 Months after 1 Year 
Treatment  
Day 456 
>= Day 411 to <= Day 501 
6 Months after 1 Year 
Treatment 
Day 547 
>= Day 502 to <= Day 592 
9 Months after 1 Year 
Treatment 
Day 638 
>= Day 593 to <= Day 684 
12 Months after 1 Year 
Treatment 
Day 730 
>= Day 685  to <= Day 775 
15 Months after 1 Year 
Treatment 
Day 821 
>= Day 776  to <= Day 866 
18 Months after 1 Year 
Treatment 
Day 912 
>= Day 867  to <= Day 957 
21 Months after 1 Year 
Treatment 
Day 1003 
>= Day 958 to <= Day 1049 
24 Months after 1 Year 
Treatment 
Day 1095 
>= Day 1050 to <= Day 1112 
Visit 15 (14-day follow-
up)  
Day of  the last 
dose of study 
>= day of the last dose of study 
drug+14 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 20 of 50 
 
drug+14 days 
Termination Visit [3] 
Termination Visit during treatment period 
[1] Relative to the date of the first dose of study drug.  For example, Day 1 
= the date of the first dose of study drug.   
[2] The study days evaluated for windows of visits during treatment period 
are on or prior to the last dose day. 
[3] For subjects who decide not to continue in the study at any time (i.e., 
eCRF check box for “Continuing” is answered ‘No’), the Termination Visit 
is performed (as per Protocol Section 9.1.14). This is available for entry at 
any time as a separate visit on eCRF. The study day for the termination 
visit will be assigned relative to the first dose of study drug. 
Visit windows for ECG measurements: 
Derived Visit  
Target  Study 
Day [1]  
Window [2]  
Baseline  
Day 1 
Days <= 1 
Visit 14 
Day 365 
>= Day 2  to <= Day 547 
12 Months after 1 Year 
Treatment 
Day 730 
>= Day 548  to <= Day 914 
24 Months after 1 Year 
Treatment 
Day 1095 
>= Day 915 to <= Day 1112 
Visit 15 (14-day follow-
up)  
Day of  the last 
dose of study 
drug+14 days 
>= day of the last dose of study 
drug+14 
Termination Visit [3] 
Termination Visit during treatment period 
[1] Relative to the date of the first dose of study drug.  For example, Day 1 
= the date of the first dose of study drug.   
[2] The study days evaluated for windows of visits during treatment period 
are on or prior to the last dose day. 
[3] For subjects who decide not to continue in the study at any time (i.e., 
eCRF check box for “Continuing” is answered ‘No’), the Termination Visit 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 21 of 50 
 
is performed (as per Protocol Section 9.1.14). This is available for entry at 
any time as a separate visit on eCRF. The study day for the termination 
visit will be assigned relative to the first dose of study drug. 
Visit windows for Physical Exam measurements: 
Derived Visit  
Target  Study 
Day [1]  
Window [2]  
Baseline  
Day 1 
Days <= 1 
Visit 3  
Day 15 
>= Day 2 to <= Day 22 
Visit 4  
Day 29 
>= Day 23 to <= Day 36 
Visit 5  
Day 43 
>= Day 37 to <= Day 50 
Visit 6  
Day 57 
>= Day 51 to <= Day 64 
Visit 7  
Day 71 
>= Day 65 to <= Day 78 
Visit 8  
Day 85 
>= Day 79 to <= Day 92 
Visit 9  
Day 99 
>= Day 93 to <= Day 106 
Visit 10  
Day 113 
>= Day 107 to <= Day 239 
Visit 14  
Day 365 
>= Day 240 to <= Day 547 
12 Months after 1 
Year Treatment 
Day 730 
>= Day 548  to <= Day 914 
24 Months after 1 
Year Treatment 
Day 1095 
>= Day 915 to <= Day 1112 
Visit 15 (14-day 
follow-up)  
Day of  the last 
dose of study 
drug+14 days 
>= day of the last dose of 
study drug+14 
Termination Visit [3] 
Termination Visit during treatment period 
[1] Relative to the date of the first dose of study drug.  For example, Day 1 
= the date of the first dose of study drug.   


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 22 of 50 
 
[2] The study days evaluated for windows of visits during treatment period 
are on or prior to the last dose day. 
[3] For subjects who decide not to continue in the study at any time (i.e., 
eCRF check box for “Continuing” is answered ‘No’), the Termination Visit 
is performed (as per Protocol Section 9.1.14). This is available for entry at 
any time as a separate visit on eCRF. The study day for the termination 
visit will be assigned relative to the first dose of study drug. 
Visit Day is calculated by (Visit date – date of the first dose of study drug + 1). 
The following conventions will be used for the derived visits with respect to safety 
variables: 
1. If more than one actual visit date (including the unscheduled visits) falls 
within the same window, the visit closest to the target study day will be 
considered for analysis. 
2. If 2 actual visit dates within a window are at the same distance from the 
target study day, the later visit with non-missing data will be considered for 
analysis. If repeated measurements are all taken on the same day, then 
the last measurement will be used. 
3. Values recorded at Termination Visit will be mapped to the derived visit 
based on the window where the actual visit date falls in per rules 1 and 2 
above. 
4. Given the rules for completing the Termination Visit on eCRF (as defined 
in Protocol Section 9.1.14), the results recorded at Termination Visit will 
be summarized in the safety tables at both derived visit based on rule 3 
above and at Termination Visit.  
10.4 Baseline Value and Change from Baseline
 
For all safety variables that involve eCRF data collected during study visits prior 
to the first dose of study drug, the baseline value is defined as the last non-
missing value obtained immediately prior to the first dose. 
Change from baseline variables will be calculated by subtracting the baseline 
value from the post-baseline derived visit (i.e., for derived Visit 3 to Visit 15 as 
per table in Section 11.4) for each subject. 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 23 of 50 
 
11 SUBJECT DISPOSTION, BASELINE CHARACTERIS TICS, AND 
EXPOSURE 
11.1 Subject Disposition  
Subject disposition will be summarized by safety evaluable subgroups, overall, 
and by country. 
The number and percentage of subjects who discontinued the study along with 
the distribution of the reasons for discontinuation will be presented overall and by 
safety evaluable subgroups. 
Since the protocol allows for subjects who are benefiting from treatment with 
YKP3089 to continue the use of the drug at the discretion of the investigator, until 
development is stopped by SK Life Science Inc or the product is approved for 
marketing, or anytime at the discretion of SK Life Science Inc., study completion 
is included as an option for reasons for discontinuation on eCRF. 
For any interim reporting of the results from this study, number of subjects 
ongoing at the time of interim date of data cut-off will be presented overall and by 
safety evaluable subgroups.   
The number and percentage of subjects in each analysis population will be 
presented overall, by safety evaluable subgroups (when applicable), by country, 
and by geographic region.  
For subjects who are screen failures, reason for screen failures will be listed in 
enrollment status listing.  
For summary tables the reasons for termination/withdrawal will be summarized 
for the following categories: adverse event, lost to follow-up, pregnancy, protocol 
deviation, withdrew consent for reason other than adverse event, other reason, 
and completed. 
By-subject data listings will include reason for termination/withdrawal as recorded 
on eCRF. 
11.2 Protocol Deviations 
Protocol deviations will be recorded by monitoring CRO (PPD) and recorded in 
their tracking system by deviation category. Protocol deviations will be included 
in a by-subject listing for subjects in safety population. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 24 of 50 
 
11.3 Demographic and Baseline Characteristics 
The following demographic and other baseline characteristics will be summarized 
overall and by safety evaluable subgroups in safety population:  
• Sex 
• Age (years) 
• Age groups (18-64 years, >=65 years) 
• Race 
• Ethnicity 
• Weight (kg) 
• Height (cm) 
• Body Mass Index (BMI) (kg/m2) 
 
Summary results will include number and percentages (sex, age groups, race, 
and ethnicity) and mean, standard deviation (SD), median, minimum, maximum 
(age, weight, height, BMI).  
By-subject listings of all baseline characteristics (including childbearing potential) 
will be generate for all enrolled subjects.  A separate listing for demographic 
characteristics (including childbearing potential) will be prepared for screen 
failures.   
 
11.4 Drug Exposure, Dosing, and Compliance  
The extent of exposure to study drug (YKP3089 and concomitant AED) as 
recorded on eCRF will be provided in a listing by-subject and by visit.   
Drug exposure will be summarized for exposure to YKP3089 (throughout the 
entire duration of the study for all 3 safety evaluable subgroups) and Phenytoin 
and Phenobarbital dosing during titration period (including only corresponding 
safety evaluable subgroups: subjects taking phenytoin and YKP3089, subjects 
taking phenobarbital and YKP3089, respectively). 
The following parameters will be derived for each subject in the ITT/safety 
population: 
• Number of days/weeks/months YKP3089 study drug medication was 
taken 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 25 of 50 
 
• Number of days on each YKP3089 dose level (12.5 mg up to an including 
400 mg or maximum reported daily dose) during the titration phase, the 
maintenance phase and overall during study. 
• Modal YKP3089 daily dose defined as the dose taken the most days 
during maintenance phase (Visit 9 to Visit 14); in case of ties (i.e., 2 
different dose levels taken the same number of days), modal dose will be 
defined as the highest dose between the two. 
• Daily phenytoin dose during titration phase (for subjects taking phenytoin 
and YKP3089 only) 
• Daily phenobarbital dose during titration phase (for subjects taking 
phenobarbital and YKP3089 only) 
 
11.4.1 Exposure to YKP3089 study drug  
The following will be summarized overall and by safety evaluable subgroups: 
• Length of exposure (weeks and months) 
• Number and percentages of subjects by time intervals (0-<1 weeks, 1-<2 
weeks, 2-<4 weeks, 4 - <12 weeks, 12 - <24 weeks, 24-<48 weeks, 48-
<96 weeks, >=96 weeks)  
• Number and percentage of subjects by exposure categories: >= 1 dose, 
>=6 months, >=12 months, >=18 months, >=24 months, >=36 months  
For any interim reporting of the results from this study, only applicable exposure 
categories based on maximum duration of exposure observed will be included in 
the summary tables). 
Derivation for length of exposure to YKP3089: 
• Length of exposure to YKP3089 (days) = (stop date – start date + 1). 
• Length of exposure to YKP3089 (weeks) = length of exposure to YKP3089 
(days)/7 
• Length of exposure to YKP3089 (months) = length of exposure to 
YKP3089 (days)/30.4 
Start and stop dates are define as per rules below: 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 26 of 50 
 
 
 
Analysis 
Period 
Subject Participation 
Enrolled and discontinued 
study  
Enrolled and ongoing at date of 
data cut-off 
Overall 
Start Date = First dose date 
Stop Date = last dose date 
Start date = First dose date 
Stop Date = date of data cut-off 
Titration 
Phase 
Start date = First dose date 
Stop Date = Visit 9 date OR 
Last dose date  
Start date = First dose date 
Stop Date = Visit 9 date OR date of 
data cut-off 
Maintenance 
Phase 
Start Date = Visit 9 date + 1 
Stop Date = Last dose date 
Start Date = Visit 9 date + 1 
Stop Date = date of data cut-off 
 
Descriptive statistics (mean, standard deviation, median, minimum, and 
maximum) will be provided to summarize the length of exposure (in weeks and in 
months) for each safety evaluable subgroup and overall.  Similar summary 
results will be prepared by modal dose within each safety evaluable subgroup. 
The number and percentage of subjects at each dose level will be summarized 
by safety evaluable subgroup and overall for the titration phase, the maintenance 
phase and overall during study.  The length of exposure to YKP3089 at each 
dose level (from 12.5 mg up to maximum daily dose reported in study) will be 
summarized using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum). 
Dosing duration will also be expressed in terms of total subject years of exposure 
to YKP3089, calculated as the sum of all subject exposure days, divided by 
365.25.  
 
11.4.2 Phenytoin and Phenobarbital Dosing during Titration Phase 
A by-subject data listing including phenytoin and phenobarbital dosing starting 
with baseline records up to an including end of titration (Visit 9) or early 
discontinuation for subjects who discontinue before Visit 9 will be prepared 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 27 of 50 
 
separately for the two safety evaluable subgroups: subjects taking phenytoin and 
YKP3089, subjects taking phenobarbital and YKP3089, respectively.  
Daily dose of phenytoin/phenobarbital will be computed using frequency and 
dose  as recorded on eCRF:  total daily dose (mg) = dose (mg) x frequency. 
At each visit post-baseline during titration phase (ie, for visits up to an including 
Visit 9) change in phenytoin/phenobarbital total daily dose will be assessed for 
each subject based on comparison to the daily dose at the previous visit.  The 
following variables will be derived: 
1. Change from previous visit total daily dose of phenytoin/phenobarbital =  
total daily dose at current visit – total daily dose at the previous visit.   
2. Change in total daily dose of phenytoin/phenobarbital categories: 
o no change, if total daily dose at current visit – total daily dose at the 
previous visit = 0.0 
o increase, if total daily dose at current visit – total daily dose at the 
previous visit > 0.0 
o decrease, if total daily dose at current visit – total daily dose at the 
previous visit < 0.0 
3. Change from baseline total daily dose of phenytoin/phenobarbital =  total 
daily dose at current visit – total daily dose at baseline.   
4. Percent 
change 
from 
previous 
visit 
total 
daily 
dose 
of 
phenytoin/phenobarbital = [(total daily dose at current visit – total daily 
dose at the previous visit)/( total daily dose at the previous visit)] x 100.  
Note: percent change will have negative values in the change represents 
a decrease, positive values if the change represents an increase and will 
be 0% if there is no change. 
5. Percent change from baseline total daily dose of phenytoin/phenobarbital 
= [(total daily dose at current visit – total daily dose at the baseline)/( total 
daily dose at the baseline)] x 100.  Note: percent change will have 
negative values in the change represents a decrease, positive values if 
the change represents an increase and will be 0% if there is no change 
Using 
baseline 
and 
end 
of 
titration 
phase 
total 
daily 
dose 
phenytoin/phenobarbital, the following variables will be derived: 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 28 of 50 
 
• Change from baseline to end of titration phase (Visit 9 or early 
discontinuation, whichever is earlier) will be computed as (total daily dose 
of phenytoin/phenobarbital at the end of titration – baseline total daily dose 
of phenytoin/phenobarbital.   
6. Change in total daily dose of phenytoin/phenobarbital categories: 
o no change, if total daily dose at end of titration phase – total daily 
dose at baseline = 0.0 
o increase, if total daily dose at end of titration phase – total daily 
dose at baseline > 0.0 
o decrease, if total daily dose at end of titration phase – total daily 
dose at baseline < 0.0 
• Percent change from baseline to end of titration phase (Visit 9 or early 
discontinuation, whichever is earlier) will be computed as [(total daily dose 
of phenytoin/phenobarbital at the end of titration – baseline total daily dose 
of 
phenytoin/phenobarbital)/ 
baseline 
total 
daily 
dose 
of 
phenytoin/phenobarbital] x 100. 
The following summary results will be prepared for the two safety evaluable 
subgroups: 
subjects 
taking 
phenytoin 
and 
YKP3089, 
subjects 
taking 
phenobarbital and YKP3089, respectively: 
• Summary statistics (n, mean, SD, standard error, median, minimum, 
maximum) for : 
o baseline total daily dose of phenytoin/phenobarbital  
o end of titration phase total daily dose of phenytoin/phenobarbital  
o change from baseline to end of titration in total daily dose of 
phenytoin/phenobarbital 
o increase from baseline to end of titration in total daily dose of 
phenytoin/phenobarbital (including only subjects with an increase in 
total daily dose of phenytoin/phenobarbital) 
o decrease from baseline to end of titration in total daily dose of 
phenytoin/phenobarbital (including only subjects with a decrease in 
total daily dose of phenytoin/phenobarbital) 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 29 of 50 
 
o percent change from baseline to end of titration in total daily dose 
of phenytoin/phenobarbital 
o total daily dose of phenytoin/phenobarbital by post-baseline visit. 
o change 
from 
previous 
visit 
total 
daily 
dose 
of 
phenytoin/phenobarbital (reported by visit) 
o increase 
from 
previous 
visit 
total 
daily 
dose 
of 
phenytoin/phenobarbital (reported by visit and including only 
subjects 
with 
an 
increase 
in 
total 
daily 
dose 
of 
phenytoin/phenobarbital for the respective visit) 
o decrease 
from 
previous 
visit 
total 
daily 
dose 
of 
phenytoin/phenobarbital (reported by visit and including only 
subjects 
with 
a 
decrease 
in 
total 
daily 
dose 
of 
phenytoin/phenobarbital for the respective visit) 
o percent 
change 
from 
previous 
visit 
total 
daily 
dose 
of 
phenytoin/phenobarbital (reported by visit) 
o change from baseline total daily dose of phenytoin/phenobarbital 
(reported by visit) 
o percent 
change 
from 
baseline 
total 
daily 
dose 
of 
phenytoin/phenobarbital (reported by visit) 
• Number and percentage of subjects: 
o no change from baseline to end of titration phase in total daily dose 
of phenytoin/phenobarbital 
o increase from baseline to end of titration phase in total daily dose of 
phenytoin/phenobarbital 
o decrease from baseline to end of titration phase in total daily dose 
of phenytoin/phenobarbital 
o reporting “no change from previous visit” during titration phase (ie, 
subjects 
with 
“no 
change” 
in 
total 
daily 
dose 
of 
phenytoin/phenobarbital for all post-baseline visits). 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 30 of 50 
 
o reporting at least one increase in total daily dose during titration 
phase (ie, subjects with at least one “increase” in total daily dose of 
phenytoin/phenobarbital for all post-baseline visits). 
o reporting at least one decrease in total daily dose during titration 
phase (ie, subjects with at least one “decrease” in total daily dose 
of phenytoin/phenobarbital for all post-baseline visits). 
o reporting decreases in total daily dose during titration phase: by 
number of decreases (1, 2, 3, >3) 
• Plots by visit for percent change from baseline in total daily dose of 
phenytoin/phenobarbital to each post-baseline visits during titration phase 
• Plots 
by 
visit 
for 
observed 
mean 
total 
daily 
dose 
of 
phenytoin/phenobarbital 
 
11.5 Prior and Concomitant Medications and Procedures 
Baseline AED medications are defined as AED medications that started prior to 
and are ongoing at the time of the first dose.   
Concomitant AED medications are defined as AEDs that started prior to and are 
ongoing at the time of the first dose of study medication or started after the first 
dose of study medication. 
Prior medications are defined as non-AED medications with a start date and stop 
date prior to the first dose of study medication. 
Concomitant medications are defined as non-AED medications with a start date on 
or after the first dose of study medication (Day 1) or started prior to and are 
ongoing at the time of the first dose of study medication. 
Concomitant procedures are defined as procedures with a start date on or after the 
first dose of study medication (Day 1).  
Prior and concomitant therapies will be coded to a World Health Organization Drug 
Dictionary (WHO DD) term including ATC classification (Version March 2016 or a 
later version available at the time of data cut-off).  A by-subject listing of baseline 
AEDs, concomitant AEDs, prior and concomitant non-AEDs use, and concomitant 
procedures will be produced.  


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 31 of 50 
 
The use of baseline and concomitant AEDs, prior non-AEDs, and concomitant 
non-AEDs will be summarized by safety evaluable subgroup and overall for 
subjects in the safety population.  The number and percentage of subjects taking 
each medication will be presented by ATC Classification. 
In addition, a summary table for: 
• Number of baseline AEDs (0, 1, 2, >2) 
• Number of baseline AEDs per subject (mean, standard deviation, median, 
minimum, and maximum number of AEDs)  
will be prepared for safety population (overall and by safety evaluable subgroups). 
11.6 Medical and Seizure/Epilepsy History 
Medical history will be summarized (number and percentage of subjects) by body 
system overall and by safety evaluable subgroups using safety population. The 
medical history data will also be presented in a by-subject listing. Female 
reproductive history will be presented in a by-subject listing. 
Epilepsy classification and history of seizures by type, current and past seizures  
will be summarized overall and by safety evaluable subgroups for safety 
population and will be included in  by-subject listings. 
Duration of epilepsy diagnosis (years) will be estimated as the number of years 
between year of diagnosis and date (year) of the informed consent  
11.7 EEG, MRI or CT Scan Results  
All EEG, MRI or CT Scan results will be listed by-subject. These results will also 
be summarized at baseline overall and by safety evaluable subgroups for the 
safety population. 
12 PHARMACOKINETIC AND PHARMACODYNAMIC ENDP OINTS AND 
ANALYSIS  
Time and date of each blood draw and dosing records (time/date/dose) of 
YKP3089 and AEDs prior to each blood draw will be recorded on the eCRF and 
other appropriate forms. 
Plasma samples will be assayed for YKP3089 and AEDs at a specified 
bioanalytical 
laboratories 
using 
previously 
validated 
methods. 
Assay 
methodologies will be detailed in separate bioanalytical reports. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 32 of 50 
 
Subjects receiving phenobarbital or phenytoin: Samples will be obtained from 
subjects taking phenobarbital or phenytoin at any global sites. At Visit 2, a single 
trough level of phenytoin or phenobarbital will be obtained. At Visits , 4, 5, 6, 7 
and 8, two blood samples will be collected for the determination of phenobarbital 
or phenytoin plasma levels. At Visits 8 and 9, two blood samples will be collected 
for YKP3089 depending on stability of dosing (stable dose all AEDs including 
YKP3089 for prior 2 weeks). 
Subjects taking other taking concomitant AEDs other than phenobarbital or 
phenytoin : Samples will be obtained from subjects taking concomitant AEDs 
other than phenobarbital or phenytoin at US sites. At Visit 2, a single blood 
sample will be drawn to determine trough level if the subject is taking one of the 
followings, oxcarbazepine, topiramate, lamotrigine, lacosamide, clobazam, 
perampanel and levetiracetam. At Visit 8 and/or 9, two blood samples will be 
drawn from the same subjects to determine plasma levels of YKP3089, 
oxcarbazepine, topiramate, lamotrigine, lacosamide, clobazam, perampanel and 
levetiracetam. Collect at visit 8 and/ or 9 depending on stability of dosing (stable 
dose all AEDs including YKP3089 for prior 2 weeks). 
The collection schedule is included in the table below: 
 
Plasma concentrations of YKP3089 and of concomitant AEDs measured in 
samples collected in this study will be combined with clinical data from previous 
studies to generate and validate population pharmacokinetic model for YKP3089. 
Relevant concomitant AEDs will be tested as covariates to evaluate their 
possible effect on YKP3089 PK.  In addition, the effect of YKP3089 on the PK of 
relevant AEDs (like lamotrigine or lacosamide for instance) will be assessed if 
deemed appropriate. These analyses will be included in the separate report. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 33 of 50 
 
For the CSR, summary tables including descriptive statistics (mean, SD, median, 
minimum, maximum) for plasma concentrations of the concomitant AEDs and for 
plasma concentrations of the YKP3089 as per Central Lab results will be 
prepared by the planned collection timepoints.   
 
13 SAFETY ANALYSIS  
Safety analyses will be performed using safety evaluable set. Separate by-
subject AEs and SAEs listings will be prepared for screen failures. 
Safety will be assessed by the frequency, severity of adverse events, as well as 
by clinical laboratory test values, 12-lead ECG recordings, vital sign 
measurements, physical and neurologic examinations, and the Columbia- 
Suicide Severity rating Scale (C-SSRS). 
 
13.1 Analysis of Adverse Events (
treatment -emergent, non -serious, 
serious,  and deaths)  
Adverse events will be coded to a Medical Dictionary for Regulatory Activities 
Terminology (MedDRA) version 20.0 or later version available at the time of data 
cut-off. Verbatim description and the MedDRA System Organ Class (SOC) and 
Preferred Term for all adverse events will be contained in the subject data listings 
of the clinical study report.   
For adverse events with partial start date (i.e., with only month and year are 
recorded), the following imputation rule will be applied: 15th of the month or fist 
dose date which one comes later.  The imputed date will be used to derive TEAE 
analysis flag.  The actual collected date will be displayed in all AE data listings. 
All reported adverse events (regardless of treatment-emergent or not) will be 
included in a by- subject adverse event listing, with separate by-subjects listings 
for adverse events and serious adverse events reported for screen failures.   
Only treatment-emergent adverse events will be included in summary tables.   
Treatment emergent adverse events (TEAE) are defined as AEs with onset after 
the start of study medication, up to last dose date of study medication + 14 days 
(or analysis cut-off date whichever comes first), or onset before study medication 
and worsened after starting study medication, up to last dose date of study 
medication + 14 days (or analysis cut-off date whichever comes first).   
An adverse event is regarded as related to study medication if the relationship to 
study medication is definite, probable, or possible. Adverse events with missing 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 34 of 50 
 
relationship will be assumed to be treatment related. Adverse events with 
missing severity will be assumed to be severe in order to perform the most 
conservative statistical analysis. 
Severe adverse events and adverse events related to treatment will be 
summarized overall and by safety evaluable subgroups. 
TEAE Incidence will be computed as number of subjects with AE/ number of 
subjects in each reporting group (%). 
Incidence of TEAEs leading to study drug discontinuation will report only TEAEs 
with Action Taken = study drug discontinuation. 
In TEAE summary tables, system organ classes (SOCs) will be presented in 
alphabetical order and preferred terms within each SOC will be presented in 
descending order of frequency in overall YKP3089 group within each SOC, 
unless specified otherwise. 
The planned summary of adverse events tables are listed below: 
• Incidence of treatment-emergent adverse events by MedDRA System 
Organ Class and Preferred Term 
• Incidence of treatment-emergent adverse events (TEAEs) in descending 
order of frequency in all YKP3089 group. 
• Incidence of severe treatment-emergent adverse events by MedDRA 
System Organ Class and Preferred Term 
• Incidence of treatment-emergent adverse events related to study 
medication by MedDRA System Organ Class and Preferred Term 
• Incidence of treatment-emergent adverse events by MedDRA System 
Organ Class, Preferred Term, and by maximum severity 
• Incidence of treatment-emergent adverse events leading to study drug 
discontinuation by MedDRA System Organ Class and Preferred Term 
• Incidence of treatment-emergent serious adverse events by MedDRA 
System Organ Class and Preferred Term 
 
Deaths, other serious adverse events, and adverse events leading to study drug  
discontinuation, will be listed including the safety evaluable subgroup and  
YKP3089 dose (if applicable) at onset, start and stop dates of the adverse event, 
and days on study relative to the start of the study.  Details of listings that will be 
provided for the safety evaluable analysis population are as follows: 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 35 of 50 
 
• Listing of subjects  who died; 
• Listing of subjects  with treatment-emergent serious adverse events; 
• Listing of subjects  with non treatment-emergent serious adverse events; 
• Listing of subjects  with treatment-emergent severe adverse events; 
• Listing of subjects with treatment-emergent adverse events leading to 
study drug discontinuation. 
 
13.2 Analysis of Clinical Laboratory parameters
 
Individual laboratory values (hematology, chemistry, and urinalysis) will be listed 
by subject and summarized using descriptive statistics (mean, standard 
deviation, median, minimum, and maximum) by safety evaluable subgroups and 
by visit.  Both SI and Conventional units will be used in reporting summary 
results. 
Baseline measurement is defined as the last available measurement prior to 
dosing. 
Post-baseline timepoints will be derived as per rules included in Section 10.3. 
Individual change from baseline (the last available measurement prior to dosing) 
in laboratory values will be calculated and summarized descriptively (mean, 
standard deviation, median, minimum and maximum) for each post-baseline visit.  
Summary results will be presented by post-baseline timepoints.  
Shift tables from baseline to each post-baseline timepoint will be prepared for all 
laboratory assessments based on the categories of Low, Normal, and High (for 
numerical results) or Abnormal and Normal (for categorical results).   
Overall summary tables for shift from normal/abnormal (low or high) baseline to 
normal or abnormal post-baseline accounting for all post-baseline results during 
study will also be prepared.  For these summary tables both scheduled and 
unscheduled post-baseline visits will be considered and subjects will be counted 
as shift to post-baseline normal if they do not have any abnormal (High or Low) 
post-baseline results during the treatment period; and as shift to post-baseline 
abnormal they have at least one post-baseline abnormal (High or Low) post-
baseline results. 
The following abnormality categories will be derived to evaluate liver function test 
results: 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 36 of 50 
 
• AST  
o >= 3 x ULN 
o > 5 x ULN 
o > 10 x ULN 
• ALT  
o >= 3 x ULN 
o > 5 x ULN 
o > 10X ULN 
• Total Bilirubin  
o > 1 x ULN 
o > 1.5 x ULN  
o >= 2 x ULN 
• Alkaline phosphatase  
o > 2 x ULN 
o > 3 x ULN 
The number and percentage of subjects with clinical laboratory test values in 
each category for the laboratory tests listed above will be summarized by each 
timepoint (including baseline) and overall (ie, anytime post-baseline), and by 
safety evaluable subgroups. 
Pregnancy test results will be listed by subject (females only) by visit. 
 
13.3 Analysis of Electrocardiograms
 
All ECG results will be listed on a by-subject basis. ECG parameters consist of 
heart rate (beats /min)), PR interval (msec), RR interval (msec), QRS Interval 
(msec), QT interval (msec), and QTcF interval (msec).  Individual ECG values 
(parameters) will be listed by subject and visit.  Baseline measurement is defined 
as the last available measurement prior to dosing. Post-baseline timepoints will 
be derived as per rules included in Section 10.3. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 37 of 50 
 
For the safety population the following summary tables will be generated for the 
ECG data: 
• Summary statistics (n, mean, standard deviation, median, minimum, and 
maximum) of the baseline value, the value at each post-baseline timepoint 
and the corresponding change from baseline for each continuous ECG 
parameter, 
• Count and percentage of subjects  with QTcF absolute value > 450 msec, 
>480 msec, >500 msec, <360 msec, <340 msec, <320 msec, and <300 
msec at each post-baseline timepoint, 
• Count and percentage of subjects  with a mean change from baseline in 
QTcF intervals >30 msec, >60 msec >90 msec, <30 msec, <60 msec, and 
<90 msec at each post-baseline timepoint, 
• Count and percentage of subjects  with absolute heart rate > 100 bpm at 
each post-baseline timepoint, 
• Count and percentage of subjects  with heart rate change from baseline 
>10 bpm, >20 bpm, and >30 bpm at each post-baseline timepoint, 
• ECG overall interpretation shift table from baseline to each post-baseline 
timepoint based on normal / abnormal categories. 
• List of abnormal ECG results by safety evaluable subgroups. 
 
13.4 Analysis of Vital Signs
 
All vital signs will be listed by-subject.  Baseline measurement is defined as the 
last available measurement prior to the first dose.  Post-baseline timepoints will 
be derived as per rules included in Section 10.3. For the safety population the 
following summary tables will be generated for vital signs by safety evaluable 
subgroups and overall for the safety population: 
• Summary statistics (n, mean, standard deviation, median, minimum, and 
maximum) of the baseline value, the observed value at each post-baseline 
timepoint and the corresponding change from baseline. 
• Number and percentage of subjects with at least one post-baseline 
(scheduled or unscheduled) vital sign measurement meeting any of these 
criteria: 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 38 of 50 
 
• Systolic Blood Pressure: <90 mmHg, >140 mmHg, >160 mmHg 
• Diastolic Blood Pressure: <50 mmHg, >90 mmHg, >100 mmHg 
• Pulse Rate: <60 bpm, >100 bpm 
• Body Weight: decrease of ≥7% from baseline and increase of ≥7% 
from baseline 
• Respiratory rate: <12 breaths/min, > 20 breaths/min 
• Temperature: >38.0 °C, <36.0 °C 
 
13.5 Analysis of Physi cal and Neurologic Examination R
esults  
Physical examination will be summarized by body system by safety evaluable 
subgroups and overall. The number and percentage of subjects will be 
presented. The physical exam findings will also be presented in a by-subject 
listing including the verbatim text for each physical exam event. 
Observations from the full physical, and brief/full neurological examinations will 
be listed on a by-subject basis. The full examination findings will also be 
summarized at baseline and follow-up for each body system for physical 
examination and neurologic parameter (level of consciousness, mental status, 
visual fields etc.) for the full neurologic examination by safety evaluable 
subgroups and overall for the safety population.  
Neurological examination results will be tabulated as number and percentage of 
subjects with normal, abnormal non-clinically significant, abnormal clinically 
significant for each one of the exams for each post-baseline visit.   
Physical examination results will be tabulated as number and percentage of 
subjects with normal, abnormal non-clinically significant, abnormal clinically 
significant for each one of the exams for each post-baseline timepoint.  Post-
baseline timepoints will be derived as per rules included in Section 10.3. 
In addition, a shift table of physical examination from baseline to post-baseline 
timepoint will be prepared using the normal, abnormal non-clinically significant, 
abnormal clinically significant categories for each one of the exams. 
A shift table displaying the changes from baseline to follow-up in physical 
examination findings will also be presented by body system by safety evaluable 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 39 of 50 
 
subgroups and overall. A similar table will be prepared for the brief neurologic 
exam findings. 
 
13.6 Columbia Suicide Symptoms and Signs Rating Scale (CSSRS)
 
C-SSRS Ideation, Intensity and Behavior are collected at baseline and all post-
baseline visits.  Summary results of response to each question (number and 
percentage of subjects) will be reported by safety evaluable subgroups and 
overall and by study visit.  The summary table will include all subjects in the 
safety population.  
At each visit, C-SSRS responses will be mapped into Columbia-Classification 
Algorithm of Suicide Assessment events on as follows: 
• Complete suicide = as captured in the safety database (adverse events 
and/or reason for discontinuation) 
• Suicide attempt: “Yes” on “Actual attempt” question 
• Preparatory acts towards imminent suicidal behavior: “Yes” on any of the 
following 
▪ “Aborted attempt”, or 
▪ “Interrupted attempt”, or 
▪ “Preparatory acts or behavior”. 
• Suicidal ideation: “Yes” on any of the following: 
▪ “Wish to be dead”, or 
▪ “Non-specific active suicidal thoughts”, or 
▪ “Active suicidal ideation with any methods (not plan) without 
intent to act”, or 
▪ “Active suicidal ideation with some intent to act without 
specific plan”, or 
▪ “Active suicidal ideation with specific plan or intent”. 
New onset suicidality and worsening suicidality during double-blind-phase will be 
assessed via a shift analysis from baseline to each post-baseline visit and to any 
post-baseline visit.  The following shift categories will be defined: 
Suicidality  
Baseline Event  
Any post -baseline and 
by visit event  
New onset 
No suicidal ideation and 
no 
behavior 
(i.e., 
no 
suicide attempt or no 
preparatory acts towards 
Any ideation (i.e., suicide 
ideation) or any behavior 
(i.e., complete suicide, 
suicide 
attempt, 
or 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 40 of 50 
 
imminent 
suicidal 
behavior) 
preparatory acts towards 
imminent 
suicidal 
behavior) 
Worsening 
Suicidal ideation 
Complete 
suicide, 
or 
suicide 
attempt, 
or 
preparatory acts towards 
imminent 
suicidal 
behavior 
 
Preparatory acts towards 
imminent 
suicidal 
behavior 
Complete 
suicide 
or 
suicide attempt 
 
Suicide Attempt 
Complete suicide 
 
The number and percentages of subjects in each of the shift categories defined 
above will be reported by safety evaluable subgroups and overall for all subjects 
included in the safety population. Missing C-SSRS responses will not be 
imputed. 
 
14 INTERIM ANALYSIS  
An early data cut-off may be applied for the purpose for regulatory safety 
reporting.  The date for the early data cut-off will be noted in the summary tables 
and in by-subject listings.   
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 41 of 50 
 
15 GENERAL PROGRAMMING SPECIFICATIONS 
15.1  Format 
Computer generated tables described in this analysis plan will adhere to the 
following specifications. 
(a) Summary tables displaying results by derived visit as defined in 
Section 10.3. 
(b) By-subject listing will display results in chronological order of visit dates 
and will include both scheduled and unscheduled visits. 
(c) The estimated mean and median for a set of values will be reported to 
one more decimal place than the raw (observed) data and rounded 
appropriately.  The standard errors (or standard deviations [SD]) will be 
reported to two additional decimal places than the raw (observed) data 
and rounded appropriately.  For example, for age (with raw data in 
whole years): 
N  
 
 
XX 
Mean (SD) 
 
XX.X (X.XX) 
LS Mean (SE) 
 
XX.X (X.XX) 
Median 
 
 
XX.X 
Range 
 
 
XX-XX 
 
(d) Data in columns of a table will be formatted as follows: 
i. Alphanumeric values will be left-justified (in mixed and upper- 
and lower-case) 
ii. Whole numbers (e.g., counts) will be right justified 
iii. Numbers containing fractional portions will be decimal aligned 
(e) All fractional numeric values will be reported with a zero to the left of 
the decimal point (e.g., 0.12-0.3). 
(f) Percents will be reported to one decimal place. 
(g) Dates will be reported in SAS DATE9. format (eg, 29MAR2007).  
Missing portions of dates should be represented on subject listings as 
dashes (--MAR2007).  Dates that are missing because they are not 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 42 of 50 
 
applicable for the subject should be listed as “N/A”, unless otherwise 
specified. 
(h) The table should be typed in Arial 10-point font.  The table title should 
be typed in Bold Initial Caps, Arial 10-point font, beginning with the 
word Table X, Title. 
(i) Header (or footer) information for all tables, figures, and listings (TFLs) 
will include the protocol number, table status (draft or final) and the 
date and time the table was created. 
(j) Any TFLs generated prior to database lock or completion of TFL 
validation will be marked “Draft”. 
 
15.2 Validation 
All programmed tables, listings, and figures will be validated with independent 
programming, to include checking the log for any errors or warnings, verifying 
format of output against the statistical analysis plan, reviewing program output for 
internal consistency, consistency with other output and accuracy against the 
source data.  Derived datasets will be independently programmed and compared 
using PROC COMPARE.   
 
16 CHANGES FROM PROTOCOL SPECIFIED ANALYSES  
Analysis populations names were revised to be “Enrolled Population” and “Safety 
Population” from protocol terminology: “Enrolled subjects” and “Safety evaluable 
subjects (SE). 
For the purpose of reporting selected baseline and safety summary results, the 
following geographic regions were defined in the SAP: United States, Europe, 
Asia, and Rest of the World.  The following parameters are to be reported by 
geographic 
regions: 
subject 
disposition, 
demographic 
and 
baseline 
characteristics, drug exposure, overall compliance, and overall summary of 
adverse events. 
Laboratory results are to be reported using both standard units and conventional 
units. 
Vital Signs: Protocol Section 12.4 indicates that for blood pressure and heart rate 
orthostatic results will be included.  However, according to Protocol Section 9.3, 
these vital signs are measured after the subjects have been supine for 5 minutes 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 43 of 50 
 
only. Therefore, SAP does not include specific summary tables for orthostatic 
results. 
The following analyses and summary results were included in the SAP:  
o Analyses for liver function test. 
o number and percentage of subjects with at least one post-treatment vital 
sign measurement meeting pre-specified criteria were included in the 
SAP. 
o phenytoin/phenobarbital total daily dose during titration phase by visit and 
overall, change and percent change from baseline, change and percent 
change from previous visit 
o number and percentage of subjects with no change, increase, decrease in 
phenytoin/phenobarbital total daily dose during titration phase 
. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 44 of 50 
 
17 APPENDIX 1: STUDY AS SESSMENT FLOWCHART: 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 45 of 50 
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 46 of 50 
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 47 of 50 
 
 
 
 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 48 of 50 
 
18 APPENDIX 2: DATA HANDLING RULES FOR MISSING OF PARTIAL 
START/STOP DATES FOR CONCOMITANT MEDICATIONS, 
CONCOMITANT AEDS, AN D BASELINE AEDS  
 
Concomitant Medications and Concomitant AEDs
 
If a concomitant medication or AED, as reported on the eCRF, has a partially or 
completely missing start or end date, use the following algorithm to impute 
missing components of the date(s). Imputed dates will be used in order to 
determine prior/concomitant status of a medication. 
If a medication has some missing components in both the start and end dates, 
first impute the end date as follows (only if the medication is not ongoing): 
1. 
If CMENDTC contains only year and month – impute the missing day 
to the last day of the corresponding month (e.g., 31 for January, or 30 
for April) or date of data cut-off (whichever comes first). 
2. 
If CMENDTC contains only year – impute the missing day and month 
to the 31st of December of the corresponding year or date of data cut-
off (whichever comes first). 
3. 
If CMENDTC is completely missing impute to the date of end of the 
last period/phase defined for the subject or date of data cut-off 
(whichever comes first). 
Note: The end date should remain null for medications that are ongoing. 
After having imputed the end date (if needed), impute the therapy start date if it is 
partial or missing as follows: 
4. 
If CMSTDTC contains only year and month – impute the missing day 
to the 1st day of the corresponding month. 
5. 
If CMSTDTC contains only year – impute the missing day and month 
to the 1st of January of the corresponding year. 
6. 
If CMSTDTC is completely missing impute to the date of start of the 
screening period (of IFC date) or to the medication end date 
(previously imputed if needed), whichever is earlier. 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 49 of 50 
 
Baseline AEDs  
Baseline AEDs are AEDs that started prior to and are ongoing at the time of the 
first dose of study medication.   
Any AEDs recorded as “prior” in eCRF will be evaluated if it is a baseline AED or 
not. 
(1) If both start and stop dates are missing, the medication will not be 
considered as Baseline AEDs and will not be counted in number of baseline 
AEDs. 
(2) If an AED is identified as Prior in eCRF and it is “not ongoing” and has 
partial end date, the following rules will be applied: 
• if CMENDTC contains only year or day -year and year < first 
dose date year, the medication will not be considered Baseline 
AED 
• if CMENDTC contains only year or day-year and year >= first 
dose date year, the medication will be considered Baseline AED 
• if CMENDTC contains only month-year and month-year < first 
dose date month-year, the medication will not be considered 
Baseline AED 
• if CMENDTC contains only month-year and month-year >= first 
dose date month-year, the medication will be considered 
Baseline AED 
• if CMEDTC contains only day-month (ie, no year), the 
medication will not be considered Baseline AED 
(3) If AEDs are not recorded as “prior” in eCRF, the following rules will be 
considered if start dates are missing or have partial dates: 
• If CMSTDTC contains only year and month – impute the 
missing day is the 1st day of the corresponding month.   
• If CMSTDTC contains only year – impute the missing day and 
month to the 1st of January of the corresponding year. 
• If CMSTDTC is completely missing impute to the date of start of 
the screening period (of IFC date). 
(4) After AED start date is imputed: 
• If the imputed start date > the first dose date, AED will not be 
considered “prior” AED and will not be considered Baseline 
AED 


SK Life Science Inc Protocol YKP3089C021 
Statistical Analysis Plan – V5.0 
 
 
Page 50 of 50 
 
• If the imputed start date <= the first dose date, AED will be 
considered “Prior” AED and will be evaluated as potential 
Baseline AED. The decision if AED is Baseline AED will be 
based on CMENDTC [as per rule (2) above]. 
 
19 REFERENCES 
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC. 
ICH Guidance for Industry: E9 Statistical Principles for Clinical Trials, 1998 
ICH Guidance for Industry: E3 Structure and Contents for Clinical Study Report, 
1996 
ICH Guidance for Industry:E6 Guideline for Good Clinical Practice