A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose-Response Trial of YKP3089 as Adjunctive Therapy in Subjects With Partial Onset Seizures, With Optional Open-Label Extension
Phase: PHASE2
Conditions: Partial Epilepsy
Sponsor: SK Life Science, Inc.

SK Life Science Inc 
CONFIDENTIAL 
Protocol YKP3089C017 
June 17, 2019 
Page 1 of 163 
 
SK Life Science Inc 
461 From Road, 5th floor 
Paramus, NJ  07652  
 
 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose-
Response Trial of YKP3089 as Adjunctive Therapy in Subjects with Partial 
Onset Seizures, with Optional Open-Label Extension 
 
 
Clinical Study Protocol 
June 12, 2013 
Amendment 1, January 7, 2014 
Amendment 2, March 20, 2015 
Amendment 3, June 17, 2019 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of SK Life Science Inc. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written 
authorization from the Sponsor. 
 
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Type of document: 
 Protocol 
 
 Protocol Amendment 
Protocol title: 
A Multicenter, Double-Blind, Randomized, Placebo-
Controlled, Dose-Response Trial of YKP3089 as 
Adjunctive Therapy in Subjects with Partial Onset 
Seizures, with Optional Open-Label Extension 
Protocol number: 
YKP3089C017 
EudraCT number:  
2013‐001858‐10 
Original protocol date: 
June 12, 2013 
Amendment 2 date: 
March 20, 2015 
 
Amendment 3 date: 
 
IND number (if applicable): 
June 17, 2019 
 
76,809 
NDA number (if applicable): 
Not applicable 
Sponsor's name: 
SK Life Science Inc 
Sponsor's address: 
461 From Road, 5th floor 
Paramus, NJ  07652 
Project medical officer: 
Marc Kamin, MD 
 
 
 
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SK Life Science Inc 
Protocol YKP3089C017 
PROTOCOL SIGNATURE PAGE 
Type of document: 
D Protocol 
~ Protocol Amendment 
CONFIDENTIAL 
June 17, 2019 
Protocol title: 
A Multicenter, Double-Blind, Randomized, Placebo-
Controlled, Dose-Response Trial of YKP3089 as Adjunctive 
Therapy in Subjects with Partial Onset Seizures with Optional 
Open-Label Extension 
Original protocol date: 
June 12, 2013 
Amendment 2 date: 
March 20, 2015 
Amendment 3 date: 
June 17, 2019 
Protocol number: 
YKP3089C0 17 
EudraCT number: 
2013-001858-10 
SPONSOR APPROVAL: 
Marc Kamin, MD 
Chief Medical Officer, 
SK Life Science, Inc. 
Page 3 of 163 
Date 

SK Life Science Inc 
CONFIDENTIAL 
Protocol YKP3089C017 
June 17, 2019 
Page 4 of 163 
 
INVESTIGATOR SIGNATURE PAGE 
 
Type of document: 
 Protocol 
 
 Protocol Amendment 
 
Protocol title: 
 
A Multicenter, Double-Blind, Randomized, Placebo-
Controlled, 
Dose-Response 
Trial 
of 
YKP3089 
as 
Adjunctive Therapy in Subjects with Partial Onset Seizures 
with Optional Open-Label Extension 
Original protocol date: 
June 12, 2013 
Amendment 2 date: 
March 20, 2015 
Amendment 3 date: 
 
Protocol number: 
June 17, 2019 
 
YKP3089C017 
 
EudraCT number:  
 
2013‐001858‐10 
 
 
 
 
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 
 
 
 
______________________________ 
 
 
 
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PROTOCOL AMENDMENTS 
 
Amendment 3 
 
 
 
Reasons for amendment 
 
1. Administrative changes to update the Sponsor’s address. 
 
 
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Amendment 3 
Summary of 
Change 
Section 
Old Text 
Amended Text 
Rationale 
Title Page 
22-10 Route 208 South 
Fair Lawn, NJ  07410 
461 From Road, 5th floor 
Paramus, NJ  07652 
Address change 
 
 
 
 
 
 
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PROTOCOL AMENDMENTS 
 
Amendment 2 
 
 
 
Reasons for amendment 
 
2. To remove interim analysis 
3. To provide details of proposed statistical procedures  
4. To add Lacosamide as one of the concomitant AED in the pharmacokinetic analysis 
 
 
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Section 
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Amended Text 
Rationale 
 
1.PROTOCOL 
SYNOPSIS 
 
Design and 
methodology 
An interim analysis will be performed on available data 
from the first 160 to 240 subjects randomly assigned to 
study drug (approximately 40 to 60 per group) who have 
completed or discontinued early during the double-blind 
treatment period of the study to obtain necessary efficacy 
and safety information on YKP3089 only for the purpose 
of planning of future studies. The results of the interim 
analysis will not be revealed to the investigators, subjects, 
or SK Life Science Inc or designated staff who are directly 
involved in the conduct of the study. The results will not 
be used to revise the trial design or the analysis methods. 
 
 
 
-text deleted- 
 
Management 
decided not to 
conduct 
interim 
analysis  for 
planning of 
future studies 
1.PROTOCOL 
SYNOPSIS 
Statistics and 
analyses 
Primary efficacy analysis: The primary efficacy variable 
is the percent reduction in seizure frequency (average 28-
day seizure rate) of complex partial and/or secondarily 
generalized and/or simple partial motor seizures during the 
double-blind phase relative to the pretreatment baseline.  
An analysis of covariance (ANCOVA) model will be fit to 
the ranked values of the primary efficacy variable. If the 
coefficient of the ranked baseline variable is statistically 
significant, then the final ranked analysis will be 
considered the primary analysis. If the baseline coefficient 
is not statistically significant, then a Wilcoxon rank-sum 
test will serve as the primary analysis.  
Secondary Efficacy Analyses: The secondary efficacy 
variable will be the response to treatment, defined as a 
The primary efficacy endpoint to be evaluated for 
registration in the United States and the Rest of the World is 
the percent change from the pretreatment baseline phase in 
seizure frequency (average monthly seizure rate per 28 days) 
of all simple partial motor, complex partial, or secondarily 
generalized seizures compared with the double-blind 
treatment phase. The primary efficacy endpoint to be 
evaluated for registration in the countries of Europe, 
Australia, New Zealand, and South Africa is the responder 
rate defined as a 50% or greater reduction during the 
maintenance phase of the double blind period in the seizure 
frequency from baseline. 
 
To clarify the 
efficacy 
analyses based 
on country 
specific 
regulatory 
requirements 
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50% or greater reduction during the double blind phase in 
the seizure frequency from baseline for the ITT subjects. 
The data will be summarized using frequencies and 
percentages. The data will also be analyzed with a logistic 
regression model predicting the probability of response. 
Dose level will be the only covariate in the model. 
Other Efficacy and Safety Analyses: The percentage of 
subjects who become seizure-free (all seizure types) 
during the maintenance phase of the double-blind 
treatment period will also be analyzed. Responder rates for 
partial seizure subtypes (including simple partial with 
motor component, complex partial, and secondarily 
generalized tonic-clonic seizures) will be summarized. 
Outcome measurements such as quality of life and clinical 
global impression change will be analyzed. Safety will be 
assessed by the frequency, severity, and timing 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). 
Open-Label Extension: 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. 
Interim Analysis: An interim analysis will be conducted 
to obtain efficacy and safety information for planning of 
The primary Efficacy Analysis for United States, and the 
Rest of the World:  
The primary efficacy analysis of the primary endpoint will 
be based on the MITT population. 
The testing strategy for the primary efficacy endpoint is to 
compare each of the YKP3089 dosage groups with the 
placebo group.  Due to multiple treatment comparisons, a 
step-down procedure will be used to ensure the overall type I 
error rate is controlled at the 5% level. Each of the YKP3089 
dosage groups will be compared with the placebo group 
according to the following hierarchy: 
1. 200-mg dosage group versus placebo group 
2. 400-mg dosage group versus placebo group 
3. 100-mg dosage group versus placebo group 
The 200-mg dosage group will be compared with the 
placebo group at a 2-sided 0.05 level as the first step. If no 
statistically significant difference is detected between the 
200-mg dosage group and the placebo group, the procedure 
will stop and it will be concluded that none of the YKP3089 
dosages are efficacious. If a statistically significant 
difference is detected between the 200-mg dosage group and 
the placebo group in favor of the 200-mg dosage group, the 
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Amended Text 
Rationale 
new YKP3089 studies. Demographic and baseline 
characteristics, efficacy, and safety data from the first 160 
to 240 subjects randomly assigned to study drug and who 
have completed or discontinued early from the double-
blind treatment period will be analyzed. 
procedure will proceed to the next step to compare the 400-
mg dosage group with the placebo group at a 2-sided 0.05 
level. If a statistically significant difference is detected 
between the 400-mg dosage group and the placebo group in 
favor of the 400-mg dosage group, the procedure will 
proceed to the next step to compare the 100-mg dosage 
group with the placebo group at a 2-sided 0.05 level.  
An analysis of covariance (ANCOVA) model will be fit to 
the ranked values of the primary efficacy endpoint. The 
ANCOVA will have terms for ranked baseline seizure rate 
and randomized treatment group. 
The Primary Efficacy Analysis for Europe, Australia, 
New Zealand, and South Africa:  
The primary efficacy analysis of the primary endpoint will 
be based on the MITT-M population.   
The testing strategy for the primary efficacy endpoint 
(responder rate) is to compare each of the YKP3089 dosage 
groups with the placebo group. A step-down procedure will 
be used to ensure the type I error rate due to multiple 
treatment comparisons is controlled at the 5% level. Each of 
the YKP3089 dosage groups will be compared with the 
placebo group according to the following hierarchy: 
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1. 200-mg dosage group versus placebo group 
2. 400-mg dosage group versus placebo group 
3. 100-mg dosage group versus placebo group 
The 200-mg dosage group will be compared with the 
placebo group at a 2-sided 0.05 level as the first step. If no 
statistically significant difference is detected between the 
200-mg dosage group and the placebo group, the procedure 
will stop and it will be concluded that none of the YKP3089 
dosages are efficacious. If a statistically significant 
difference is detected between the 200-mg dosage group and 
the placebo group in favor of the 200-mg dosage group, the 
procedure will proceed to the next step to compare the 400-
mg dosage group with the placebo group at a 2-sided 0.05 
level. If a statistically significant difference is detected 
between the 400-mg dosage group and the placebo group in 
favor of the 400-mg dosage group, the procedure will 
proceed to the next step to compare the 100-mg dosage 
group with the placebo group at a 2-sided 0.05 level.  
The data will be summarized using frequencies and percents 
of subjects achieving at least a 50% response to treatment, 
the responder rate. The responder data will be analyzed 
using a chi-square test.   
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Other Efficacy and Safety Analyses:  
The percentage of subjects who have a 75%, 90% and 100% 
seizure reduction during the double blind period and the 
maintenance phase. Responder rates for partial seizure 
subtypes (including simple partial with motor component, 
complex partial, and secondarily generalized tonic-clonic 
seizures) will be summarized. Outcome measurements such 
as quality of life and clinical global impression change will 
be analyzed. Safety will be assessed by the frequency, 
severity, and timing 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). 
Open-Label Extension:  
The results of the open-label extension will be reported at a 
later date using summary tables, figures, and data listings. 
Summaries will be presented for demographic information 
and safety information only. 
6.2 Study 
Endpoints 
6.2.1 
Primary Efficacy Variable 
The primary efficacy variable is the percentage reduction 
in seizure frequency (average 28-day seizure rate) of 
 The primary efficacy endpoints reflect the United States 
Food and Drug Administration (FDA) recommendation of 
percent reduction in seizure frequency for registration which 
is adopted by many countries in the rest of the world, and the 
To clarify the 
efficacy 
endpoints 
based on 
country 
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complex partial and/or secondarily generalized and/or 
simple partial motor seizures during the double blind 
treatment period, relative to the pretreatment baseline 
period. The frequency of seizures will be calculated by the 
actual seizure count multiplied by 28, divided by the 
number of days in the period; in effect, frequency count is 
normalized to 28 days. The percent reduction is calculated 
as 100 * [B-D]/B, where B is the seizure frequency during 
baseline, D is seizure frequency in the double-blind 
treatment period, and reductions in seizure frequency yield 
a positive value. 
6.2.2 
Secondary Efficacy Variable 
The secondary efficacy variable is the response to 
treatment, which is defined as at least a 50% reduction in 
the average 28-day seizure rate during the double blind 
treatment period relative to the pretreatment baseline 
period.  
6.2.3 
Other Efficacy Variables 
Other efficacy variables include: 
• 
Seizure 
freedom 
during 
the 
double-blind 
maintenance phase 
• 
Percentage reduction in: 
European Agency for the Evaluation of Medicinal Products 
(EMEA) recommendation of the responder rate for 
registration in Europe, which is also adopted by Australia, 
New Zealand, and South Africa.  
6.2.1 
Primary Efficacy Endpoint in the United States 
and the Rest of the World 
The primary efficacy endpoint to be evaluated for 
registration in the United States and the Rest of the World is 
the percent change from the pretreatment baseline phase in 
seizure frequency (average monthly seizure rate per 28 days) 
of all simple partial motor, complex partial, or secondarily 
generalized seizures compared with the double-blind 
treatment phase.  
The baseline rate (B) is calculated by counting the number of 
seizures over the baseline period and dividing by the number 
of days in the interval with non-missing seizure data and 
then multiplying by 28. The double-blind rate (D) is 
calculated in a similar manner. The percent change is equal 
to 100*(D-B)/B. Simple partial seizures without a 
motor/visual component will not be counted. 
This value will be undefined if B=0. For the primary efficacy 
analysis, there will not be any baseline values with zero 
seizures. However, for the analysis of seizure sub-types, 
specific 
regulatory 
requirements 
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o 
Complex partial and/or secondarily generalized 
tonic-clonic and/or simple partial motor seizures  
o 
Secondarily generalized tonic-clonic seizure only 
 
there is a possibility that B may be zero. In this case, B will 
be set to a value of 1. 
6.2.2 
Primary Efficacy Endpoint in the countries of 
Europe, Australia, New Zealand, and South Africa 
The primary efficacy endpoint to be evaluated for 
registration in the countries of Europe, Australia, New 
Zealand, and South Africa is the responder rate defined as a 
50% or greater reduction during the maintenance phase of 
the double blind period in the seizure frequency from 
baseline. 
The responder endpoint is a binary indicator endpoint 
defined as 1 if the primary endpoint is <= -50%, and 0 
otherwise. 
6.2.3 
Secondary Efficacy Endpoint in the countries of 
Europe, Australia, New Zealand, and South Africa 
The secondary efficacy endpoint to be evaluated for 
registration in the countries of Europe, Australia, New 
Zealand and South Africa is the percent change from the 
pretreatment baseline phase in seizure frequency (average 
monthly seizure rate per 28 days) of all simple partial motor, 
complex partial, or secondarily generalized seizures 
compared with the maintenance phase of the double-blind 
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treatment phase.  
The baseline rate (B) is calculated by counting the number of 
seizures over the baseline period and dividing by the number 
of days in the interval with non-missing seizure data and 
then multiplying by 28. The double-blind rate (D) is 
calculated in a similar manner. The percent change is equal 
to 100*(D-B)/B. Simple partial seizures without a 
motor/visual component will not be counted. 
This value will be undefined if B=0. For the primary efficacy 
analysis, there will not be any baseline values with zero 
seizures. However, for the analysis of seizure sub-types, 
there is a possibility that B may be zero. In this case, B will 
be set to a value of 1. 
6.2.4 
Secondary Efficacy Endpoint in the United 
States and the Rest of the World 
The secondary efficacy endpoint to be evaluated for 
registration in the United States and the Rest of the World is 
the responder rate defined as a 50% or greater reduction 
during the double blind period in the seizure frequency from 
baseline.   The responder endpoint is a binary indicator 
endpoint defined as 1 if the primary endpoint is <= -50%, 
and 0 otherwise. 
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6.2.5 
Additional Secondary Efficacy Endpoints 
• 
Higher response rates of (defined by cutoffs of -
75%, -90% and -100%) simple partial seizures with motor 
component plus complex partial seizures plus secondarily 
generalized tonic clonic seizures during the double-blind 
period and maintenance phase.  
• 
Percentage change in other seizure types will be 
calculated in the same way as the primary endpoint except 
for selecting the specific seizure types:  
o  Complex partial  
o  Secondarily generalized tonic-clonic  
o  Simple partial motor 
6.2.7 
Pharmacokinetic 
and 
Pharmacodynamic 
Endpoints 
 
Pharmacokinetic and Pharmacodynamic Endpoints 
 
Trough AED levels (oxcarbazepine [OXC], topiramate 
[TPM], carbamazepine [CBZ], valproate [VPA], 
lamotrigine [LTG], and levetiracetam (LEV) only) during 
the baseline will be compared to those during the 
treatment period in subjects randomized to 100, 200, or 
400 mg/day YKP3089 or placebo to determine potential 
drug interactions. In addition, YKP3089 blood levels of 
Pharmacokinetic Endpoints 
 
Trough AED levels (oxcarbazepine [OXC], topiramate 
[TPM], carbamazepine [CBZ], valproate [VPA], lamotrigine 
[LTG], lacosamide (LMD) and levetiracetam (LEV) only) 
during the baseline will be compared to those during the 
treatment period in subjects randomized to 100, 200, or 400 
mg/day YKP3089 or placebo to determine potential drug 
interactions.  
Lacosamide 
was added as 
additional 
AED to be 
analyzed and 
text modified 
to clarify PK 
end points 
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subjects randomized to 100, 200, or 400 mg/day will be 
used to assess whether or not there are any correlations 
between the levels and reduction in seizure frequency. 
6.4 
Interim 
Analysis 
An interim analysis will be conducted to obtain efficacy 
and safety information for planning of future YKP3089 
studies. Details of the statistical analysis plan for the 
interim analysis are provided in Section 12.11 
No interim analysis will be performed. 
Management 
decided not to 
conduct 
interim 
analysis  for 
planning of 
future studies 
9.5 Clinical 
Laboratory & 
Pharmacokinetic 
Evaluations 
…… blood samples will be drawn to determine plasma 
levels of concomitant AED (OXC, TPM, CBZ, VPA, 
LTG, and LEV only) prior to study drug administration 
(Visit 3)… 
…… blood samples will be drawn to determine plasma 
levels of concomitant AED (OXC, TPM, CBZ, VPA, LTG, 
LMD and LEV only) prior to study drug administration 
(Visit 3)… 
Lacosamide 
was added as 
additional 
AED to be 
analyzed 
12.2 Statistical 
Methods 
Summary statistics and analyses will include the data from 
the dose-titration period and will be presented by 
randomized treatment group. Categorical variables will be 
summarized as frequencies and percentages. Descriptive 
statistics for continuous variables will include sample size, 
mean, median, standard deviation, and minimum and 
maximum values. SAS® version 9.2 or later will be used 
for all data summaries, statistical analyses, and data 
listings. Inferential statistical tests will be 2-sided and will 
employ a tolerance for type I error (alpha, α) of 0.05. Data 
will be used as collected. If an observation is missing, then 
Summary statistics and analyses will be presented by the 
treatment group category assigned to the subject regardless 
of the dosage of drug administered. Categorical variables 
will be summarized as frequencies and percentages. 
Descriptive statistics for continuous variables will include 
sample size, mean, median, standard deviation, and 
minimum and maximum values. SAS® version 9.2 or later 
will be used for all data summaries, statistical analyses, and 
data listings. Inferential statistical tests will be 2-sided and 
will employ a tolerance for type I error (alpha, α) of 0.05. 
To add details 
of handling of 
missing data 
and 
definitions of 
various 
analysis 
populations 
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the missing value will be imputed using the last 
observation carried forward (LOCF) method. 
Data will be used as collected. Full details of the analysis 
plan will be included in the Statistical Analysis Plan (SAP) 
and finalized prior to any un-blinding of efficacy data. 
Analyses of Missing Data 
The primary efficacy endpoint definition in the United States 
and Rest of the world states that seizure rates will be 
calculated using days with non-missing seizure data.  The 
definition does not explicitly account for days with missing 
data, i.e., days during which the presence or absence of 
seizures was not recorded in personal diaries.  However the 
definition implicitly accounts for missing data in that it is 
identical to a definition in which days with missing data are 
assumed to have the same seizure rate as days with non-
missing data.    
Similar to the United States definition of the primary 
efficacy endpoint, the primary endpoint (responder) 
definition in the countries of Europe, Australia, New 
Zealand and South Africa implicitly accounts for missing 
data during maintenance phase in that it is identical to a 
definition in which days with missing data are assumed to 
have the same seizure rate as days with non-missing data. An 
additional analysis will be performed in which subjects who 
dropped out during the titration phase will be included in the 
analysis by having their maintenance phase data imputed 
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using the available titration data. 
The same approach will be used for missing data in the 
analysis of all secondary efficacy end points. 
12.3 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. 
Intention-to-treat (ITT): All subjects randomly assigned to 
study drug will be considered intention-to-treat subjects.  
Modified intention-to-treat (MITT) subjects: All subjects 
randomly assigned to study drug who have taken at least 1 
dose of YKP3089 (or placebo) and have a post-dose 
evaluation will be considered modified intention-to-treat 
subjects.  
Per protocol population: All subjects randomly assigned to 
study drug who have no major protocol violations and 
have at least 80% drug compliance will be considered per-
protocol subjects. 
Safety evaluable subjects (SE): All MITT subjects will be 
considered safety evaluable subjects. 
For all populations, subjects will be analyzed according to 
the target (randomized) dosage group including subjects who 
fail to achieve the target dosage during the titration phase. 
Enrolled subjects: All subjects who have given informed 
consent to participate in this study will be considered 
enrolled subjects. 
Intention-to-treat (ITT): All randomized subjects will be 
considered intention-to-treat subjects.  
Modified intention-to-treat (MITT) subjects: All randomized 
subjects who have taken at least one dose of YKP3089 (or 
placebo) and have any post-baseline seizure data will be 
considered modified intention-to-treat subjects.  
Modified 
intention-to-treat 
(MITT-M) 
subjects 
in 
Maintenance phase: All randomized subjects who have 
completed the titration phase and have taken at least one 
dose of YKP3089 (or placebo) in the maintenance phase and 
have any maintenance phase seizure data will be considered 
modified intention-to-treat subjects in the maintenance 
phase.  
To add details 
regarding  
various 
analysis 
populations 
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Per protocol population (PP): All randomized subjects who 
have no major protocol violations and have at least 80% 
drug compliance will be considered per-protocol subjects. 
Safety evaluable subjects (SE): All ITT subjects. 
12.5 Primary 
Efficacy Analyses 
The primary efficacy analysis will be performed after all 
randomized subjects who have completed or discontinued early 
from the double-blind treatment period. It will be based on the 
ITT population. 
The primary efficacy variable is percent change in seizure 
frequency per 28 days for the ITT subjects during the double-
blind treatment period relative to the baseline period. Seizure 
frequency will be calculated as the number of seizures during the 
maintenance phase divided by the number of days treated in the 
maintenance phase multiplied by 28.  
The cumulative distribution functions for each dose group will 
be presented as a descriptive summary.  
An analysis of covariance (ANCOVA) model will be fit to the 
ranked values of the primary efficacy variable. If the coefficient 
on the ranked baseline variable is statistically significant, then 
the final ranked analysis will be considered the primary analysis. 
If the baseline coefficient is not statistically significant, then a 
Wilcoxon rank-sum test will serve as the primary analysis.  
The primary efficacy variable will be analyzed using a 
12.5.1 Primary Efficacy Analysis in the United States and the 
Rest of the World: 
The primary efficacy analysis of the primary endpoint will be based 
on the MITT population. 
The testing strategy for the primary efficacy endpoint (percent 
change in seizure frequency) is to compare each of the YKP3089 
dosage groups with the placebo group.  Due to multiple treatment 
comparisons, a step-down procedure will be used to ensure the 
overall type I error rate is controlled at the 5% level. Each of the 
YKP3089 dosage groups will be compared with the placebo group 
according to the following hierarchy: 
1. 
200-mg dosage group versus placebo group 
2. 
400-mg dosage group versus placebo group 
3. 
100-mg dosage group versus placebo group 
The 200-mg dosage group will be compared with the placebo group 
at a 2-sided 0.05 level as the first step. If no statistically significant 
difference is detected between the 200-mg dosage group and the 
 
To clarify the 
primary 
efficacy 
analyses based 
on country 
specific 
regulatory 
requirements 
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hierarchical step-down approach to provide control of the type 1 
error rate. The first comparison will be 400 mg/day vs placebo. If 
this test is significant at the 0.05 level, then the next lower dose 
200 mg/day will be compared with placebo. If that test is also 
statistically significant, the lowest dose 100 mg/day will be 
tested. The sequential testing will stop if a dose fails to be shown 
superior to placebo at the 0.05 level of statistical significance. 
placebo group, the procedure will stop and it will be concluded that 
none of the YKP3089 dosages are efficacious. If a statistically 
significant difference is detected between the 200-mg dosage group 
and the placebo group in favor of the 200-mg dosage group, the 
procedure will proceed to the next step to compare the 400-mg 
dosage group with the placebo group at a 2-sided 0.05 level. If a 
statistically significant difference is detected between the 400-mg 
dosage group and the placebo group in favor of the 400-mg dosage 
group, the procedure will proceed to the next step to compare the 
100-mg dosage group with the placebo group at a 2-sided 0.05 
level.  
An analysis of covariance (ANCOVA) model will be fit to the 
ranked values of the primary efficacy endpoint. The ANCOVA will 
have terms for ranked baseline seizure rate and randomized 
treatment group. Ties will be handled using the default option in 
SAS. 
It should be noted that the primary efficacy analysis uses a non-
parametric approach. Because of this, effect sizes are not estimated 
and tested directly, since testing is made on the rank of the primary 
efficacy value. However, summary tables for the actual (not the 
ranked) primary efficacy endpoint will be presented.   
Descriptive results of the primary efficacy end point will be 
provided for the subjects who were titrated under the original 
protocol.   
12.5.2 
Primary Efficacy Analyses in the countries of Europe, 
Australia, New Zealand, and South Africa 
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The primary efficacy analysis of the primary endpoint will be based 
on the MITT-M population.   
The testing strategy for the primary efficacy endpoint (responder 
rate) is to compare each of the YKP3089 dosage groups with the 
placebo group. A step-down procedure will be used to ensure the 
type I error rate due to multiple treatment comparisons is controlled 
at the 5% level. Each of the YKP3089 dosage groups will be 
compared with the placebo group according to the following 
hierarchy: 
1. 
200-mg dosage group versus placebo group 
2. 
400-mg dosage group versus placebo group 
3. 
100-mg dosage group versus placebo group 
The 200-mg dosage group will be compared with the placebo group 
at a 2-sided 0.05 level as the first step. If no statistically significant 
difference is detected between the 200-mg dosage group and the 
placebo group, the procedure will stop and it will be concluded that 
none of the YKP3089 dosages are efficacious. If a statistically 
significant difference is detected between the 200-mg dosage group 
and the placebo group in favor of the 200-mg dosage group, the 
procedure will proceed to the next step to compare the 400-mg 
dosage group with the placebo group at a 2-sided 0.05 level. If a 
statistically significant difference is detected between the 400-mg 
dosage group and the placebo group in favor of the 400-mg dosage 
group, the procedure will proceed to the next step to compare the 
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100-mg dosage group with the placebo group at a 2-sided 0.05 
level.  
The data will be summarized using frequencies and percents of 
subjects achieving at least a 50% response to treatment, the 
responder rate. The responder data will be analyzed using a chi-
square test.   
12.6 Secondary 
Efficacy Analyses 
The secondary efficacy variable is the response to 
treatment, which is defined as at least a 50% reduction in 
the average 28-day seizure rate during the double blind 
treatment period relative to the pretreatment baseline 
period for the ITT subjects. The data will be summarized 
using frequencies and percents of subjects achieving at 
least a 50% response to treatment, the responder rate. The 
data will also be modeled using a logistic regression 
model predicting the probability of response. Dose level 
will be the only covariate in the model. 
12.6.1 
Secondary Efficacy Analysis in the countries of 
Europe, Australia, New Zealand, and South Africa 
The secondary efficacy analysis will be based on the MITT-
M population. 
The secondary efficacy analysis is to compare each of the 
YKP3089 dosage groups with the placebo group for the 
percent reduction in seizure frequency.  
An analysis of covariance (ANCOVA) model will be fit to 
the ranked values of the change in seizure frequency during 
the maintenance phase. The ANCOVA will have terms for 
ranked baseline seizure rate and randomized treatment 
group. Ties will be handled using the default option in SAS.  
It should be noted that the efficacy analysis uses a non-
parametric approach. Because of this, effect sizes are not 
estimated and tested directly, since testing is made on the 
rank of the change in seizure frequency. However, summary 
tables for the actual (not the ranked) change in seizure 
To clarify the 
secondary 
efficacy 
analyses based 
on country 
specific 
regulatory 
requirements 
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frequency will be presented.   
12.6.2 
Secondary Efficacy Analysis in the United States 
and the Rest of the World 
The secondary efficacy analysis will be based on the MITT 
population. 
The secondary efficacy analysis is to compare each of the 
YKP3089 dosage groups with the placebo group for the 
responder rate.  
The data will be summarized using frequencies and percents 
of subjects achieving at least a 50% response to treatment, 
the responder rate. The responder data will be analyzed 
using a chi-square test. 
12.7 Additional 
Efficacy Analyses 
 
12.7 Additional Efficacy Analyses 
The primary efficacy variable will also be analyzed based 
on the MITT population (if this population differs 
appreciably from the ITT population) and the per-protocol 
population. In addition, the maintenance phase data will be 
analyzed for the ITT population. This analysis will use all 
available double-blind period data for subjects who 
withdraw before reaching the maintenance phase. The 
maintenance phase data will also be used to test for a 
12.7 
Additional Secondary Efficacy Analyses 
These secondary efficacy analyses will be based on the 
MITT or MITT-M population. 
• 
Higher response rate of (75, 90 and 100%) of 
simple partial seizures with motor component plus complex 
partial seizures plus secondarily generalized tonic clonic 
seizures during the double-blind period and maintenance 
phase will be summarized.  
To provide 
details of 
additional 
secondary 
efficacy 
analyses  
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dose-response relationship and to compare the YKP3089 
doses to each other. 
The percentage of subjects who become seizure free (all 
seizure types) during the maintenance phase of the double-
blind treatment period will also be analyzed. 
Seizure frequency reductions and responder rates for 
partial seizure subtypes including simple partial with 
motor component, complex partial, and secondarily 
generalized tonic-clonic seizures will also be analyzed. 
Outcome measurements will be summarized by visits or 
analyzed by appropriate models. 
• 
Median percent change for partial seizure subtypes 
(including simple partial with motor component, complex 
partial, and secondarily generalized tonic-clonic seizures) 
will be summarized.   
• 
Seizure rate over time  will be analyzed using 
following scheme 
o A moving average for each dose group will be 
computed using 4 week periods with 2 week 
overlap beginning from Visit 3 (V3-V5, V4-V6, 
V5-V6+2 weeks and so on) 
• 
For the QOLIE-31 analysis, changes from baseline 
(Visit 3) to the the final value (defined as the last observation 
obtained in the double-blind phase) (Visit 9) for each 
treatment group will be summarized using descriptive 
statistics. Differences between each treatment group and the 
placebo group in the change from baseline will also be 
summarized using descriptive statistics. The minimally 
important change (MIC) was defined as a change from 
baseline ≥11.8 at the End Point for the weighted overall 
QOLIE-31 score. The incidence of subjects meeting the MIC 
criteria will be summarized by treatment group. 
• 
CGIC will be summarized using descriptive 
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statistics for each treatment group and the placebo group. 
12.8 Safety 
Variable Analyses 
All MITT subjects will be evaluable for safety. The number and 
percent of subjects reporting AEs (including treatment-emergent 
laboratory abnormalities) will be tabulated by randomized 
treatment group. 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), ECGs, and C-SSRS 
will be summarized using descriptive statistics. 
All ITT subjects will be evaluable for safety. The number and 
percent of subjects reporting AEs (including treatment-emergent 
laboratory abnormalities) will be tabulated by randomized 
treatment group. 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), ECGs, and C-SSRS will be 
summarized using descriptive statistics. 
 
To clarify 
safety analysis  
population 
12.9 
Pharmacokinetic 
and 
Pharmacodynamic 
Analysis 
 
12.9 
Pharmacokinetic and Pharmacodynamic 
Analysis 
Individual plasma concentrations of YKP3089 will be 
tabulated with the corresponding time related to study 
drug administration by dose group.  
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 
12.9 
Pharmacokinetic Analysis 
Individual plasma concentrations of YKP3089 will be 
tabulated with the corresponding time related to study drug 
administration by dose group.  
Descriptive statistical analyses will be performed on the 
plasma concentrations of the YKP3089 obtained during 
steady-state treatment (Visit 7 and 8). 
Descriptive statistical analyses will be performed on the 
plasma concentrations of the concomitant AEDs obtained 
during steady-state concomitant treatment (Visit 7 and 8) 
and those at baseline (Visit 3) to assess the effect of 
YKP3089 on these AEDs. 
To clarify PK 
analysis plan 
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effects of demographic characteristics, concomitant 
medication including AEDs, laboratory values, and other 
subject covariates on YKP3089 pharmacokinetics will be 
evaluated.  
For each concomitant AED (OXC, TPM, CBZ, VPA, 
LTG, LEV only), plasma concentrations obtained during 
steady-state concomitant treatment (Visits 7 and 8) will be 
compared with that taken at baseline (Visit 3) to assess the 
effect of YKP3089 on these 6 AEDs. The timing of AED 
sampling in relation to the subject’s AED dosing schedule 
will be factored into the analysis. The difference between 
subjects receiving active and placebo treatments will be 
assessed. 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 by individual study drug 
dose. 
12.10 
Open-
Label 
Extension 
Analyses 
 
The results of the open-label extension will be reported 
using summary tables, figures, and data listings. 
The results of the open-label extension will be reported at a 
later date using summary tables, figures, and data listings. 
To clarify the 
timing of 
reporting of 
the open label  
data 
12.11 
Interim 
Analysis 
The objective of the interim analysis is to obtain necessary 
efficacy and safety information on YKP3089 for planning 
No interim analysis will be performed. 
Management 
decided not to 
conduct 
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future studies. There is no plan for stopping the study 
based on the interim analysis of efficacy. The study will 
proceed without changes in the protocol, as the interim 
analysis results will not be used to revise the trial design 
or method of analysis. Therefore, in theory no type 1 error 
rate spending should be necessary. 
This interim analysis will be based on the available data 
from the first 160 to 240 randomized subjects 
(approximately 40 to 60 per group) from a total of 400 
subjects. The size of this cohort will depend upon a 
number of considerations, including the rate of enrollment. 
The cutoff will be the time point that the last subject of 
this cohort completes the 18-week double-blind treatment, 
or the time at which the last subject from this group drops 
out of the study. 
The demographics and baseline characteristics, efficacy, 
and safety data from these subjects will be analyzed. An 
independent statistician who is not involved with any other 
trial activity will analyze the interim data. The interim 
analysis results will be available to and reviewed by an 
interim analysis committee consisting of clinicians and 
statisticians who are not directly involved with any other 
trial activity. The decisions or recommendations from the 
interim analysis committee will be communicated only to 
interim 
analysis  for 
planning of 
future studies 
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limited individuals who are involved with planning future 
studies. All decisions or recommendations that are 
communicated outside of the committee will be properly 
documented. In addition, these results may be made 
available to regulatory agencies. The results of the interim 
analysis will not be revealed to the investigators, subjects, 
or SK Life Science Inc or designated staff who are directly 
involved in the conduct of the study. 
Details of the following aspects will be pre-specified in 
the interim analysis plan: 
• 
Timing of the interim analysis 
• 
Data to be analyzed 
• 
Level of unblinding 
• 
Possible actions based on the interim analysis 
• 
The role and composition of the interim analysis 
committee and interim analysis statistician 
• 
Communication of the interim analysis results 
• 
Data analysis methods 
 
The amendment must be reviewed and approved or have a favorable opinion from the Institutional Review Board/ Ethics Committee, prior to 
being implemented. 
 
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Amendment 1 
 
Reasons for amendment 
1. To provide the results of a completed Phase 1 multiple ascending  dose study targeting 
YKP3089 doses of 400mg, 500mg and 600mg/day 
2. To provide the results of a completed Phase 2 randomized, double-blind, placebo-
controlled study that evaluated the efficacy and safety of YKP3089 200mg as adjunctive 
therapy for partial seizures.  
3. To reduce the initial starting dose to 50mg and slow the titration rate to improve 
tolerability 
4. To clarify the definition of uncontrolled partial seizures 
5. To provide guidance on contraception for male subjects   
6. To allow the first dose of study drug to be given at the investigator’s site 
7. To revise the timelines for the data monitoring committee review of data 
8. To add a 50mg dosing card 
9. To make minor administrative changes 
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1.PROTOCOL 
SYNOPSIS 
 
Design and 
methodology 
Subjects will first enter a titration phase lasting up to 6 
weeks, during which the daily dose will be increased by 
100 mg every week until the target dose is reached. 
Subjects having tolerability issues for the first time during 
Weeks 2 to 5 will have their dose reduced by 100 mg once. 
Subsequent to this reduction, subjects will recommence the 
upward titration by 50 mg increments towards their target 
dose until Week 6. Subjects having tolerability issues for a 
second time until Week 8 or having tolerability issues for 
the first time during Week 6 will have their dose reduced 
by 50 mg once and must remain at that dose for the 
remainder of the study. 
Subjects will first enter a 6-week titration phase, during 
which the initial dose will be 50mg/day. The planned 
increase in the daily dose will be 50mg/day/week increments 
until 200mg is reached and after which the dose will be 
increased by 100mg/day/week in subjects randomized to 
400mg/day. Subjects having tolerability issues for the first 
time during Weeks 2 to 6 will have their dose reduced by 50 
or100 mg depending on their attained dose at the time 
(Reduce by 50mg if taking 100mg, 150mg or 200mg; reduce 
by 100mg if on 300mg or 400mg).Subsequent to this 
reduction, subjects may at the discretion of the investigator, 
recommence the upward titration by 50 mg weekly 
increments towards their target dose until Week 6. If the 
subject cannot tolerate the new upward titration, the daily 
dose can be reduced one time by 50 mg through the end of 
week 8.  
To improve 
tolerability, the 
dose and the 
titration rate is 
reduced 
Table 1. Study 
Assessment 
Flowchart for 
Double-Blind 
Study 
EEG or MRI or CT scan 
EEG and MRI or CT scan 
Text changed 
to correct 
typographical 
error 
4.4.4 Clinical 
safety 
Approximately 400 human subjects have been exposed to 
YKP3089 in 12 completed (11 Phase 1 and 1 proof-of-
concept) and 3 ongoing clinical studies (1 Phase 2a and 2 
Phase 1 studies).  
Approximately 400 human subjects have been exposed to 
YKP3089 in 15 completed (13 Phase 1, 1 proof-of-concept) 
and 1 Phase 2a).  
In a multiple ascending dose study in healthy volunteers, 
Text revised to 
update safety 
results from 
recently 
completed 
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In a multiple ascending dose study in healthy volunteers, 
when doses of 250 to 300 mg once daily were given from 
Day 1, somnolence, dizziness, and decreases in mean 
systolic blood pressure have been seen, but no serious AEs 
have been reported. Horizontal nystagmus, ataxia, and gait 
disturbance have also been observed in normal volunteers 
receiving 250 and 300 mg once daily. These reactions 
resolved after YKP3089 was discontinued at the end of the 
study. At 300 mg once daily, a mean shortening of the 
QTcF interval of 10 to 15 msec was observed.  
In an ongoing Phase 1 multiple ascending dose study that 
remains blinded, subjects are titrated from a starting dose 
of 200 mg once daily to a target dose of 400, 500, or 600 
mg once daily by 100-mg increments every 5 to 7 days. To 
date, adverse events in the first and second cohorts are 
generally mild, with no discernible pattern other than 
drowsiness. Two subjects taking YKP3089 discontinued 
from the cohort targeting 500 mg once daily because of an 
adverse event that was probably related to YKP3089. One 
subject discontinued for facial swelling and rash. The other 
subject 
discontinued 
because 
of 
an 
antiepileptic 
hypersensitivity syndrome with symptoms consistent with 
DRESS syndrome. Dosing was discontinued during the 
blinded phase of treatment with 600 mg once daily because 
when doses of 250 to 300 mg once daily were given from 
Day 1, somnolence, dizziness, and decreases in mean systolic 
blood pressure have been seen, but no serious AEs have been 
reported. Horizontal nystagmus, ataxia, and gait disturbance 
have also been observed in normal volunteers receiving 250 
and 300 mg once daily. These reactions resolved after 
YKP3089 was discontinued at the end of the study. At 300 
mg once daily, a mean shortening of the QTcF interval of 10 
to 15 msec was observed.  
In another, now completed Phase 1 multiple ascending dose 
study in healthy volunteers, YKP3089C018, subjects were 
titrated from a starting dose of 200 mg once daily to a target 
dose of 400, 500, or 600 mg once daily by 100-mg 
increments every 5 to 7 days. Adverse events in the first and 
second cohorts were generally mild, with no discernible 
pattern other than drowsiness. All subjects following daily 
administration of 600 mg YKP3089 experienced multiple 
neurological adverse events including somnolence, ataxia, 
and nystagmus. Many of these AEs were probably related to 
the study drug and at least 2 subjects had exceeded their 
maximum tolerated dose. Based on the overall condition of 
the remaining subjects, the study was stopped. Two subjects 
taking YKP3089 discontinued from the cohort targeting 500 
mg once daily because of an adverse event that was probably 
related to YKP3089. One subject discontinued for facial 
clinical studies 
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of ataxia. In addition, a 41-year-old male subject receiving 
600 once daily of YKP3089 was hospitalized because of 
head trauma subsequent to a fall and an altered state of 
consciousness. 
In an ongoing Phase 2a, double-blind, randomized, 
adjunctive therapy, placebo-controlled trial to evaluate the 
efficacy and safety of YKP3089 in subjects with treatment-
resistant partial-onset seizures, subjects start with a 50-mg 
daily dose, which is increased by 50 mg every 2 weeks to a 
target dose of 200 mg once daily. There is a 6-week 
titration and 6-week maintenance period, followed by a 1-
week taper period. Subjects who complete the double-blind 
period are eligible to enter an open-label extension. The 
sponsor remains blinded to results.  
A data monitoring committee has reviewed safety data 
from 100 subjects who have completed the double-blind 
period of the study and found no reason to alter the 
conduct of the study. Two suspected unexpected serious 
adverse reaction (SUSAR) have occurred:  an early 
manifestation 
of 
a 
drug 
hypersensitivity 
reaction 
characterized by flushed erythema of palms and soles with 
mild itching of ears and a status epilepticus during tapering 
of the study medication. During the open-label extension, 2 
notable serious adverse events occurred: one case of 
swelling and rash. The other subject discontinued because of 
an antiepileptic hypersensitivity syndrome with symptoms 
consistent with DRESS syndrome. In addition, a 41-year-old 
male subject receiving 600 once daily of YKP3089 was 
hospitalized for one day because of head trauma subsequent 
to a fall and an altered state of consciousness. 
A recently completed Phase 2a, randomized, double-blind, 
placebo-controlled study, YKP3089C013, evaluated the 
efficacy and safety of 200mg of YKP3089 as adjunctive 
therapy for the treatment of partial seizures. YKP3089 
treatment began with a 50-mg daily dose, which was 
increased by 50 mg every 2 weeks to a target dose of 200 mg 
once daily. There was a 6-week titration and 6-week 
maintenance period, followed by a 1-week taper period. 
Subjects who completed the double-blind period were 
eligible to enter an open-label extension.  
In the Phase 2a study, 113 subjects received YKP3089 and 
109 received placebo.  Comparison of the primary efficacy 
endpoint, median percent reduction in partial seizure 
frequency, demonstrated a highly statistically significant 
effect in favor of the YKP3089 group, 55% vs 21%, 
p<0.0001. Initial efficacy was observed at doses of 50-
100mg/day and maintained throughout the 12 week study.  
Review of the safety data indicated that 4% of subjects in the 
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sudden unexpected death in epilepsy (SUDEP) and one 
case of suicide. They were considered remotely related or 
unrelated to study drug. 
 
 
active and 4% of subjects in the placebo-group dropped out 
because of adverse events.  Two-thirds of subjects completed 
the study at the target dose of 200mg/day.  The most common 
central nervous system adverse events in the YKP3089 group 
were somnolence, dizziness, fatigue, and gait disorder 
Two suspected unexpected serious adverse reaction (SUSAR) 
occurred 
in 
YKP3089 
treated 
subjects: 
 an 
early 
manifestation 
of 
a 
drug 
hypersensitivity 
reaction 
characterized by flushed erythema of palms and soles with 
mild itching of ears and a status epilepticus during tapering. 
During the open-label extension, 2 notable serious adverse 
events occurred in YKP3089 treated subjects: one case of 
sudden unexpected death in epilepsy (SUDEP) and one case 
of suicide. They were considered remotely related or 
unrelated to study drug. 
4.5.1 Double-
Blind Dose 
Selection 
 
The primary objective of this study is to determine the 
effective dose range of YKP3089 as adjunctive therapy for 
the treatment of partial seizures. According to a blinded 
review of an ongoing Phase 2a double-blind, randomized, 
placebo-controlled trial involving subjects with partial 
epilepsy, few subjects dropped out and 2 serious adverse 
events were related to YKP3089. Some subjects did not 
reach the maximum target dose of 200 mg. However, a 
daily dose of up to 500 mg was generally well tolerated by 
healthy volunteers in a multiple ascending dose extension 
The primary objective of this study is to determine the 
effective dose range of YKP3089 as adjunctive therapy for 
the treatment of partial seizures. During the initial design of 
this protocol,  a blinded review of the ongoing Phase 2a 
randomized, double-blind, placebo-controlled study 
YKP3089C013, revealed that few subjects dropped out and 
that only the two previously described serious adverse events 
were related to YKP3089. Some subjects did not reach the 
maximum target dose of 200 mg. In the multiple ascending 
dose study, YKP3089C018, a daily dose of up to 500 mg was 
Text added to 
provide 
rationale for 
lower initial 
dose and 
slower titration 
rate 
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trial.  
In the open-label extension portion of the Phase 2a study, 
some subjects reportedly began to have clinically 
significant improvement in their seizure frequency only 
when they started taking a daily dose of 100 to 200 mg. A 
dose range of 200 to 400 mg/day should therefore be broad 
enough to identify efficacious doses. A 100-mg daily dose 
was chosen to determine the minimum effective dose. 
Although a dose of 500 mg once daily has generally been 
well tolerated by healthy volunteers, the maximum dose in 
this study will be 400 mg once daily, to account for 
potential adverse pharmacodynamic interaction with the 
concomitant antiepileptic drugs.  
The Phase 2a study titrated the daily dose upward by 50 
mg every 2 weeks. However, the healthy volunteers in the 
ongoing multiple ascending dose study started with a daily 
dose of 200 mg, titrated upward by 100 mg every 5 to 7 
days, and are tolerating the faster titration rate. Therefore, 
this study will begin with a daily dose of 100 mg, followed 
by weekly increments of 100 mg in the daily dose, to a 
target dose of up to 400 mg once daily. 
generally well tolerated by healthy volunteers.  
 
In the open-label extension portion of the Phase 2a study, 
some subjects reportedly began to have clinically significant 
improvement in their seizure frequency only when they 
started taking a daily dose of 100 to 200 mg. It was 
concluded that a dose range of 200 to 400 mg/day should 
therefore be broad enough to identify efficacious doses. A 
100-mg daily dose was chosen to determine the minimum 
effective dose. Although a dose of 500 mg once daily has 
generally been well tolerated by healthy volunteers, the 
maximum dose chosen for the study was 400 mg once daily, 
to account for potential adverse pharmacodynamic interaction 
with the concomitant antiepileptic drugs.  
Although the Phase 2a study titrated the daily dose upward 
by 50 mg every 2 weeks the healthy volunteers in the 
recently completed  multiple ascending dose study initiated 
therapy with a daily dose of 200 mg, titrated upward by 100 
mg every 5 to 7 days to 400 and 500mg/day, and generally 
well tolerated the faster titration rate. Therefore, it was 
initially decided that in the current study subjects would 
begin with a daily dose of 100 mg, followed by weekly 
increments of 100 mg in the daily dose, to the target dose. 
Recently, a blinded review of the tolerability profile in the 
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first 9 subjects randomized in this study, YKP3089C017, was 
performed. Three subjects had study drug dose reduction and 
subsequently discontinued because of adverse events within 
four weeks of randomization. One of these subjects, a 47 year 
old male with a history of partial epilepsy, head trauma and a 
right hemiparesis, developed significant somnolence and 
ataxia and was hospitalized for increasing right hemiparesis.  
Asymptomatic pulmonary emboli were found incidentally 
during the hospitalization. Two other subjects had study drug 
dose reductions because of adverse events and are continuing 
therapy. The adverse events reported by these subjects are 
consistent with the adverse event profile of YKP3089 
reported in previous studies of YKP3089, including 
somnolence, dizziness and ataxia; however the frequency of 
discontinuation and dose reductions is higher than initially 
expected. 
Although only a small number of subjects have been exposed 
to the new titration rate, to ensure that the results of this study 
can be interpreted correctly, the titration rate will be modestly 
slowed to provide for better tolerability and potentially fewer 
adverse event dropouts. The initial dose will be reduced to 
50mg/day and the titration rate will slow to 50mg/day/week 
until 200mg is reached and then the dose will be increased by 
100mg/week in subjects randomized to 400mg/day. If the 
subject experiences tolerability issues during the titration that 
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require intervention by the investigator, the  study drug dose 
will be reduced by 50 or 100mg depending on the attained 
dose at that time. (Reduce by 50mg if taking 100mg, 150mg 
or 200mg; reduce by 100mg if on 300mg or 400mg). The 
lower dose will be maintained for 7-13 days and then the 
investigator, at his/her discretion, may recommence an 
upward titration to the target dose.  
These changes are being made based on a blinded review of 
the data and will not impact the integrity of this double-blind 
placebo-controlled dose response study. 
4.6 Potential 
Risks and 
Benefits 
Approximately 400 human subjects have been exposed to 
YKP3089 in 12 completed (11 phase 1 and 1 proof-of-
concept) and 3 ongoing clinical studies (1 Phase 2a and 2 
Phase 1).  
In an ongoing Phase 2a proof-of-concept study involving 
subjects with partial-onset seizures, only 2 SAEs have been 
related to YKP3089: an early manifestation of a drug 
hypersensitivity 
reaction 
characterized 
by 
flushed 
erythema of palms and soles with mild itching of ears and 
a status epilepticus during tapering of the study 
medication. In the open-label extension, 1 case of SUDEP 
and 1 suicide have been observed.  
In an ongoing Phase 1 drug interaction study with 
YKP3089 and phenytoin, a case of antiepileptic-induced 
Approximately 400 human subjects have been exposed to 
YKP3089 in 15 completed (13 Phase 1, 1 proof-of-concept 
and 1 Phase 2a).  
In the completed Phase 2a randomized double-blind, placebo-
controlled study in subjects with partial-onset seizures, only 2 
SAEs have been related to YKP3089: an early manifestation 
of a drug hypersensitivity reaction characterized by flushed 
erythema of palms and soles with mild itching of ears and a 
status epilepticus during tapering of the study medication. In 
the open-label extension, one case of SUDEP and one case of 
suicide have been observed. No significant laboratory or 
electrocardiographic abnormalities were identified.  
In a completed Phase 1 drug interaction study with YKP3089 
and phenytoin, a case of antiepileptic-induced 
Text updated 
to provide 
results of 
recently 
completed 
clinical studies 
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hypersensitivity syndrome was observed. Rash and 
mucosal ulcers developed after 14 days of phenytoin 
treatment and 1 dose of YKP3089. The investigator 
deemed this SAE not related to YKP3089 and 
characterized it as phenytoin-induced hypersensitivity 
syndrome. 
As described previously, in an ongoing Phase 1 multiple 
ascending dose study, 1 subject developed fever, rash, 
leukocytosis, eosinophilia, and hepatic enzyme and 
electrolyte abnormalities. The drug was stopped and the 
signs and symptoms resolved thereafter. This was 
diagnosed as an antiepileptic hypersensitive syndrome with 
symptoms consistent with DRESS syndrome and probably 
related to YKP3089. 
In Phase 1 trials and in a Phase 2a proof-of-concept trial 
where treatment assignment is known, a total of 11 of 256 
(4.3%) YKP3089-treated subjects reported rashes and 2 of 
60 (3.3%) placebo treated subjects reported rashes. 
The preclinical antiepileptic profile of YKP3089 and a 
proof-of-concept study suggest that YKP3089 could 
provide additional seizure control in patients with poorly 
controlled epilepsy. 
hypersensitivity syndrome was observed. Rash and mucosal 
ulcers developed after 14 days of phenytoin treatment and 
one dose of YKP3089. The investigator deemed this SAE not 
related to YKP3089 and characterized it as phenytoin-
induced hypersensitivity syndrome. 
As described previously, in a completed Phase 1 multiple 
ascending dose study, one subject developed fever, rash, 
leukocytosis, eosinophilia, and hepatic enzyme and 
electrolyte abnormalities. The drug was stopped and the signs 
and symptoms resolved thereafter. This was diagnosed as an 
antiepileptic hypersensitive syndrome with symptoms 
consistent with DRESS syndrome and probably related to 
YKP3089. 
The incidence of rashes in YKP3089 and placebo treated 
subjects in completed Phase 1 trials and in a Phase 2a studies 
is approximately 4% in each group. 
At this time, the preclinical antiepileptic profile of YKP3089 
and the first Phase 2a randomized, double-blind, placebo-
controlled study suggest that YKP3089 could provide 
additional seizure control in patients with poorly controlled 
epilepsy with limited safety risks. 
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6.1 Overview 
 
Subjects will first enter a 6-week titration phase, during 
which the planned increase in the daily dose will be 100 
mg per week. Subjects will then enter a 12-week double-
blind maintenance phase. 
Subjects will first enter a 6-week titration phase, during 
which the initial dose will be 50mg/day. The planned 
increase in the daily dose will be 50mg/day/week increments 
until 200mg is reached and after which the dose will be 
increased by 100mg/day/week in subjects randomized to 
400mg/day 100 mg per week. Subjects will then enter a 12-
week double-blind maintenance phase. 
Text revised to 
lower the 
initial dose and 
the titration 
rate 
6.1.2.1 Titration 
Phase 
During the initial 6-week up-titration phase of the double-
blind treatment period, subjects assigned to receive 
YKP3089 will receive blinded study medication according 
to the dosage schedule shown in Table 3 
Table 3. YKP3089 Initial Double-Blind Up-Titration 
YKP3089  
target dose  
(mg/day) 
 
 
YKP3089 dose (mg/day) 
Week 1  
Week 
2 
Week 3  
Week 4 
Week 5 + 6 
100 
100 
100 
100 
100 
100 
200 
100 
200 
200 
200 
200 
400 
100 
200 
300 
400 
400 
During Week 1, no dose reduction will be permitted. 
Subjects who have significant tolerability issues should 
discontinue treatment with study drug. If study drug is not 
tolerated for the first time at any time during Weeks 2 
through 5, subjects may have one 100-mg reduction in 
their daily dose. For subjects in the 100-mg group, the 100-
mg dose reduction will only be simulated because the 
During the initial 6-week up-titration phase of the double-
blind treatment period, subjects assigned to receive YKP3089 
will receive blinded study medication according to the dosage 
schedule shown in Table 3 
Table 3. YKP3089 Initial Double-Blind Up-Titration 
YKP3089  
target 
dose  
(mg/day) 
 
 
YKP3089 dose (mg/day) 
Week 
1  
Week 
2 
Week 
3  
Week 
4 
Week 
5 
Week 
6 
100 
50 
100 
100 
100 
100 
100 
200 
50 
100 
150 
200 
200 
200 
400 
50 
100 
150 
200 
300 
400 
During Week 1, no dose reduction will be permitted. Subjects 
who have significant tolerability issues should discontinue 
treatment with study drug. If study drug is not tolerated for 
the first time at any time during Weeks 2 through 6, subjects 
may a reduction in their daily dose. The size of the reduction 
will depend on the dose at the time poor tolerability is noted 
(Reduce by 50mg if taking 100mg, 150mg or 200mg; reduce 
Table and text 
changed to 
provide lower 
starting dose 
and slower 
titration rate 
 
 
 
 
 
 
 
 
 
 
 
 
 
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minimum dose to be tested is 100 mg. Subjects will remain 
at the reduced dose level for a minimum of 7 days and up 
to 13 days. Thereafter, the subjects will recommence the 
upward titration at 50-mg increments in the daily dose 
once a week towards the target dose until week 6. If the 
subject cannot tolerate the new upward titration, the daily 
dose can be reduced one time by 50 mg through the end of 
week 8. Subjects having tolerability issues during Week 6 
for the first time will have their dose reduced by 50 mg 
once and will remain at that dose for the rest of the study. 
For the 100-mg group, the 50-mg dose reduction will only 
be simulated because the minimum dose to be tested is 100 
mg. No upward titration will be allowed after Week 6. No 
two consecutive dose reductions will be allowed. 
If a tolerability issue occurs, dosage adjustments need to be 
made at a scheduled visit or at an unscheduled visit at the 
discretion of the investigator. At the visit, the subject will 
be issued a new set of cards to be determined by interactive 
web response system (IWRS). 
To improve tolerability, the investigator may instruct the 
subject to take the dose of study medication in the evening. 
The investigator may alter the timing or amount of an 
individual dose of a concomitant AED, but the total daily 
dose and dosing frequency of the concomitant AED must 
by 100mg if on 300mg or 400mg). Subjects will remain at 
the reduced dose level for a minimum of 7 days and up to 13 
days.  
Thereafter, the subjects may at the discretion of the 
investigator, recommence the upward titration at 50-mg 
increments in the daily dose once a week towards the target 
dose until week 6. If the subject cannot tolerate the new 
upward titration, the daily dose can be reduced one time by 
50 mg through the end of week 8. No upward titration will be 
allowed after Week 6. No two consecutive dose reductions 
will be allowed.  
If a tolerability issue occurs, dosage adjustments need to be 
made at a scheduled visit or at an unscheduled visit at the 
discretion of the investigator. At the visit, the subject will be 
issued a new set of cards to be determined by the interactive 
web response system (IWRS).  
To improve tolerability, the investigator may instruct the 
subject to take the dose of study medication in the evening. 
The investigator may alter the timing or amount of an 
individual dose of a concomitant AED, but the total daily 
dose and dosing frequency of the concomitant AED must 
remain unchanged during the double-blind phase. 
During titration, the investigator may instruct the subject to 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Language 
added to 
provide an 
additional step 
to improve 
tolerability 
during titration 
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remain unchanged during the double-blind phase. 
 
hold the daily dose of the study drug up to a maximum of 2 
days per week. 
6.1.2.3 Blinded 
Study Drug 
Taper: 
Termination at 
End of Double-
Blind Phase 
Table 4. Blinded Study Drug Taper Schedule 
Final Double-Blind 
Dose of YKP3089 
(mg/day) 
YKP3089 Dose During Taper 
(mg/day) 
Week 1 
Week 2 
Week 3 
0 (placebo) or 100 
0 
0 
0 
150 or 200 
100 
0 
0 
250 or 300 
200 
100 
0 
350 or 400 
300 
200 
100 
Table 4. Blinded Study Drug Taper Schedule 
Final Double-Blind 
Dose of YKP3089 
(mg/day) 
YKP3089 Dose During Taper 
(mg/day) 
Week 1 
Week 2 
Week 3 
0 (placebo)/50/100 
0 
0 
0 
150 or 200 
100 
0 
0 
250 or 300 
200 
100 
0 
350 or 400 
300 
200 
100 
Table revised 
to provide 
taper schedule 
for subjects 
reaching only 
50mg/day 
6.1.4.1 Blinded 
Study Drug 
Conversion 
Period: Subjects 
Entering the 
Open-Label 
Phase 
Subjects will have a 2-week double-blind conversion 
period at the beginning of the open-label extension phase 
of the study. In order to keep the treatment blind, subjects 
from all four dose groups will be converted to a single dose 
group of 300 mg/day after two weeks of blinded 
conversion period. This conversion period will begin at 
Visit 9. Subjects will follow the study medication schedule 
shown in Table 5. The daily dose will consist of 4 tablets 
of YKP3089 or placebo (depending on the dose regimen 
assigned during the double-blind phase) from a blinded 
blister card plus tablets (1 for Week 1 and 2 for Week 2) 
from an open-label bottle of 100-mg YKP3089 tablets 
taken every morning. Starting at Visit 11, the subjects will 
take three 100-mg tablets from the open-label bottle every 
morning.  
 
Subjects will have a 2-week double-blind conversion period 
at the beginning of the open-label extension phase of the 
study. In order to keep the treatment blind, subjects from all 
four dose groups will be converted to a target dose of 300 
mg/day after two weeks of blinded conversion period. This 
conversion period will begin at Visit 9. Subjects will follow 
the study medication schedule shown in Table 5. The daily 
dose will consist of 4 tablets of YKP3089 or placebo 
(depending on the dose regimen assigned during the double-
blind phase) from a blinded blister card plus tablets (2 for 
Week 1 and 4 for Week 2) from an open-label bottle of 50-
mg YKP3089 tablets taken every morning. Starting at Visit 
11, the subjects will take three 100-mg tablets from the open-
label bottle every morning.  
 
 
Text 
revised/added 
to  provide 
50mg  open 
label tablets 
during blinded 
conversion to 
open label 
treatment 
 
 
 
 
 
 
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Table 5. Blinded Study Drug Conversion to Open-Label 
Target of 300 mg/day YKP3089 
YKP3089 
dose 
group 
(mg/day) 
during 
double-
blind 
period 
Dose of YKP3089 (mg/day)a 
Dispensed at Visit 9 
Dispensed at 
Visit 11 
Week 1 
Week 2 
Week 3 
From 
Card 
From 
Open-
Label 
Bottle 
From 
Card 
From 
Open-
Label 
Bottle 
From 
Card 
From 
Open-
Label 
Bottle 
0 
(placebo) 
0 
100 
0 
200 
No 
card 
300 
100 
100 
100 
100 
200 
No 
card 
300 
150/200 
100 
100 
100 
200 
No 
card 
300 
250/300 
200 
100 
100 
200 
No 
card 
300 
350/400 
200 
100 
100 
200 
No 
card 
300 
 
aThe total daily dose is the amount taken from the blister 
card plus the amount taken from the bottle of 100-mg 
tablets (eg, the placebo group from the double-blind phase 
receives placebo from the blister card and a 100-mg tablet 
from the bottle every day during Week 1 of the conversion 
period, placebo from the blister card and two 100-mg 
tablets from the bottle every day during Week 2 of the 
conversion period, and then three 100-mg tablets from the 
bottle per day starting in Visit 11).  
 
Table 5. Blinded Study Drug Conversion to Open-Label Target 
of 300 mg/day YKP3089 
YKP3089 
dose group 
(mg/day) 
during 
double-
blind period 
Dose of YKP3089 (mg/day)a 
Dispensed at Visit 9 
Dispensed at 
Visit 11 
Week 1 
Week 2 
Week 3 
From 
Card 
From 
Open-
Label 
Bottle 
From 
Card 
From 
Open-
Label 
Bottle 
From 
Card 
From 
Open-
Label 
Bottle 
0 
(placebo)/50 
0 
2X50 
0 
4X50 
No 
card 
300 
100 
100 
2X50 
100 
4X50 
No 
card 
300 
150/200 
100 
2X50 
100 
4X50 
No 
card 
300 
250/300 
200 
2X50 
100 
4X50 
No 
card 
300 
350/400 
200 
2X50 
100 
4X50 
No 
card 
300 
 
aThe total daily dose is the amount taken from the blister card 
plus the amount taken from the bottle of 50-mg tablets (eg, 
the placebo group from the double-blind phase receives 
placebo from the blister card and two  50-mg tablets from the 
bottle every day during Week 1 of the conversion period, 
placebo from the blister card and four 50-mg tablets from the 
bottle every day during Week 2 of the conversion period, and 
then three 100-mg tablets from the bottle per day starting in 
Visit 11).  
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Investigator can increase or decrease the open-label dosage 
by 100 mg if clinically indicated (ie, recurrence of 
seizures, adverse events) during the conversion period. 
 
During the first week of the conversion period, the 
investigator can increase or decrease the open-label dosage 
by 50-100 mg if clinically indicated (ie, recurrence of 
seizures, adverse events). During the second week of the 
conversion period, the investigator can decrease the open-
label dosage by 50-200 mg or increase the open label dosage 
by a maximum of 100 mg if clinically indicated (ie, 
recurrence 
of 
seizures, 
adverse 
events). 
All 
dose 
adjustments must be made with tablets from the open 
label bottles.  All tablets from the cards must be taken on 
Week 1 and Week 2 during the conversion period.   
Although the target dose for subjects is 300mg at Visit 11, 
subjects may be taking 50-400 mg at Visit 11 depending 
upon tolerability and efficacy during the conversion period. 
Doses of concomitant AEDs may be adjusted during the 
conversion phase. 
6.1.4.2 Open-
Label Extension 
Treatment Phase 
The initial target dose for the open-label extension will be 
300 mg/day. However, if a subject is not tolerating the 300 
mg/day dose, YKP3089 dose may be reduced to a 
minimum of 100 mg/day. If the investigator feels that a 
subject requires a dose that is higher than 300 mg/day, the 
dose can be increased to a maximum of 400 mg/day once 
the target dose of 300 mg/day was reached. The dose 
adjustments may occur in weekly increments of 100 
The initial target dose for the open-label extension will be 
300 mg/day. However, if a subject is not tolerating the 300 
mg/day dose, YKP3089 dose may be reduced to a minimum 
of 50 mg/day. If the investigator feels that a subject requires a 
dose that is higher than 300 mg/day, the dose can be 
increased to a maximum of 400 mg/day once the target dose 
of 300 mg/day was reached. The dose adjustments may occur 
in weekly increments of 100 mg/day or 50-mg/day. However, 
Text added to  
allow 
minimum open 
label treatment 
dose of 
50mg/day 
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mg/day or 50-mg/day. However, the rate of change may be 
more rapid or slow as clinically indicated. No dose 
reductions are permitted if subject is taking 100 mg/day 
YKP3089. If 100 mg/day YKP3089 is not tolerated, the 
subject will withdraw from the study 
the rate of change may be more rapid or slow as clinically 
indicated. No dose reductions are permitted if the subject is 
taking 50 mg/day YKP3089. If 50 mg/day YKP3089 is not 
tolerated, the subject will withdraw from the study. 
6.1.4.3 Study 
Drug Taper: 
Subjects 
Leaving the 
Open-Label 
Extension 
Table 6. Study Drug Taper Schedule for Subjects Completing 
Open-Label Extension  
Final open-label 
dose of YKP3089 
(mg/day) 
YKP3089 Dose During Taper 
(mg/day) 
Week 1 
Week 2 
Week 3 
100 
None 
150 or 200 
100 
None 
None 
250 or 300 
200 
100 
None 
350 or 400 
300 
200 
100 
 
Table 6. Study Drug Taper Schedule for Subjects Completing 
Open-Label Extension  
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 
 
Text added to 
provide taper 
schedule for 
subject treated 
with 50mg/day 
YKP3089 
during open 
label treatment 
6.1.5 
Dose 
Adjustments of 
Study Drug and 
Concomitant 
AEDs 
During week 1, no dose reduction will be permitted. 
Subjects who have significant tolerability issues should 
discontinue treatment with study drug. If study drug is not 
tolerated at some point during weeks 2 through 5, subjects 
may have one (and only one) 100-mg reduction in the daily 
dose. For the 100-mg group, the 100-mg dose reduction 
will only be simulated because the minimum dose to be 
tested is 100 mg. Subjects will remain at the reduced dose 
level for a minimum of 7 days and up to 13 days. 
Thereafter, the subjects will recommence the upward 
titration to the target dose at 50-mg increments in the daily 
dose once a week until week 6. If the subject cannot 
tolerate the new upward titration, the daily dosage can be 
During week 1, no dose reduction will be permitted. Subjects 
who have significant tolerability issues should discontinue 
treatment with study drug. If study drug is not tolerated at 
some point during weeks 2 through 6, subjects may have a 
reduction in the daily dose. The size of the reduction will 
depend on the dose at the time poor tolerability is noted 
(Reduce by 50mg if taking 100mg, 150mg or 200mg; reduce 
by 100mg if on 300mg or 400mg). Subjects will remain at the 
reduced dose level for a minimum of 7 days and up to 13 
days. Thereafter, the subjects may, at the discretion of the 
investigator, recommence the upward titration to the target 
dose at 50-mg increments in the daily dose once a week until 
week 6. If the subject cannot tolerate the new upward 
Text revised to 
clarify dose 
adjustments 
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reduced once by 50 mg up through the end of Week 8. 
Subjects having tolerability issues during Week 6 for the 
first time will have their dose reduced by 50 mg once and 
will remain at that dose for the rest of the study. For the 
100-mg group, the 50-mg dose reduction will only be 
simulated because the minimum dose to be tested is 100 
mg. No upward titration will be allowed after Week 6. No 
two consecutive dose reductions will be allowed. 
Dosage adjustments related to tolerability issues need to be 
made at a scheduled visit or at an unscheduled visit at the 
discretion of the investigator. At the visit, the subject will 
be issued a new card or set of cards to be determined by 
IWRS. 
For further instruction on dose adjustments, please refer to 
study manual. 
The investigator may instruct the subject to take the dose 
of study medication in the evening if clinically indicated 
and consistent with other aspects of the protocol. The 
investigator may alter the timing or amount of an 
individual dose of a concomitant AED, but the total daily 
dose and dosing frequency of the concomitant AED must 
remain unchanged during the double-blind phase. 
The initial target dose for the open-label extension will be 
300 mg/day. However, if a subject is not tolerating the 300 
titration, the daily dosage can be reduced once by 50 mg up 
through the end of Week 8.. No upward titration will be 
allowed after Week 6. No two consecutive dose reductions 
will be allowed. 
Dosage adjustments related to tolerability issues need to be 
made at a scheduled visit or at an unscheduled visit at the 
discretion of the investigator. At the visit, the subject will be 
issued a new card or set of cards to be determined by IWRS. 
For further instruction on dose adjustments, please refer to 
study manual. 
The initial target dose for the open-label extension will be 
300 mg/day. However, if a subject is not tolerating the 300 
mg/day dose, YKP3089 dose may be reduced to a minimum 
of 50 mg/day. If the investigator feels that a subject requires 
higher than 300 mg/day, the dose can be increased to a 
maximum of 400 mg/day once the target dose of 300 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. 
No dose reductions are permitted if subject is taking 50 
mg/day YKP3089. If 50 mg/day YKP3089 is not tolerated, 
the subject will withdraw from the study. Monotherapy with 
YKP3089 will not be allowed. The investigator may add, 
remove, or adjust the dosage of concomitant AEDs, as 
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mg/day dose, YKP3089 dose may be reduced to a 
minimum of 100 mg/day. If the investigator feels that a 
subject requires higher than 300 mg/day, the dose can be 
increased to a maximum of 400 mg/day once the target 
dose of 300 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. No dose reductions are 
permitted if subject is taking 100 mg/day YKP3089. If 100 
mg/day YKP3089 is not tolerated, the subject will 
withdraw from the study. Monotherapy with YKP3089 will 
not be allowed. The investigator may add, remove, or 
adjust the dosage of concomitant AEDs, as clinically 
indicated. In the event of poor tolerability, the investigator 
may instruct the subject to take the dose of study 
medication in the evening or divide the total daily dose into 
2 doses. 
clinically indicated. In the event of poor tolerability, the 
investigator may instruct the subject to take the dose of study 
medication in the evening or divide the total daily dose into 2 
doses. 
 
7.3 Inclusion 
Criteria 
5. Have uncontrolled partial seizures despite having been 
treated with at least 2 different AEDs within approximately 
the last 2 years. 
5. Have uncontrolled partial seizures despite having been 
treated with at least one AED within approximately the last 2 
years. 
Text changed 
to define 
uncontrolled 
partial seizures 
7.5 Birth 
Control 
Methods 
Allowable for 
Enrollment of 
7.5 Birth Control Methods Allowable for Enrollment of 
Female Subjects 
 
 
 
7.5 Birth Control Methods Allowable for Enrollment of 
Subjects 
 
 
 
Title changed 
to provide 
contraception 
guidance for 
both male and 
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Female Subjects 
 
 
 
- 
 
 
 
 
 
 
 
- 
 
 
 
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). 
There is no need for male subjects enrolled in YKP3089C017 
to use contraception with partners of childbearing potential 
during their participation in the study. 
female 
subjects 
 
Text added to 
provide 
definition for 
women of 
child bearing 
potential 
 
Text added to 
provide 
contraception 
language for 
male subjects 
8.1.1.3 
Packaging and 
Labeling 
For the double-blind phase and the blinded conversion to 
open-label phase, 50 mg and 100 mg YKP3089 and 
matching placebo tablets will be packaged in 2-panel 
blister cards—one panel for the label and the other for the 
medication. There will be 8 blister card types, one for each 
of the possible daily doses in this study: placebo, 100, 150, 
200, 250, 300, 350, and 400 mg. Each medication panel of 
the blister card will contain nine rows and four columns of 
tablets for 7 days of treatment plus 2 extra days for a total 
of 9 days. Each row will contain the same total dose. 
For the double-blind phase and the blinded conversion to 
open-label phase, 50 mg and 100 mg YKP3089 and matching 
placebo tablets will be packaged in 2-panel blister cards—
one panel for the label and the other for the medication. 
There will be 9 blister card types, one for each of the possible 
daily doses in this study: placebo, 50, 100, 150, 200, 250, 
300, 350, and 400 mg. Each medication panel of the blister 
card will contain nine rows and four columns of tablets for 7 
days of treatment plus 2 extra days for a total of 9 days. Each 
row will contain the same total dose. 
Text added to 
include 50mg 
cards to the 
blister card 
types 
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8.1.2 Blinding 
of Study 
Medication 
Neither the investigator nor the site staff will know the 
contents of the tablets administered; however, this 
information will be readily available in the event of an 
emergency. Investigators may perform emergency 
unblinding using the IWRS system immediately, without 
prior contact to the study’s Medical Monitor, if they feel it 
is medically necessary and that knowledge of the treatment 
assignment is essential for the patient’s care. If such an 
emergency unblinding is necessary, investigators should 
promptly document and explain to the Medical Monitor or 
Sponsor any premature unblinding of the investigational 
product. 
Neither the investigator nor the site staff will know the 
contents of the tablets administered; however, this 
information will be readily available in the event of an 
emergency. 
Text added to 
provide 
unblinding 
information  
8.2.1.4 Drug 
Dispensing 
Open-Label Extension 
If a subject enters the open-label extension, he/she will 
enter a blinded dose-conversion period. At Visit 9, during 
the conversion period, the subject will receive 2 blinded 
blister cards as directed by the IWRS system and an open-
label bottle of YKP3089 containing one hundred 100 mg 
tablets. The subject will be instructed to take medication 
from each blister card on dates specified on the card. In 
addition, for the first week, the subject will take one 100-
mg tablet from the bottle. For the second week, the subject 
will be instructed to take two 100-mg tablets from the 
bottle. 
Open-Label Extension  
If a subject enters the open-label extension, he/she will enter 
a blinded dose-conversion period. At Visit 9, during the 
conversion period, the subject will receive 2 blinded blister 
cards as directed by the IWRS system and an open-label 
bottle of YKP3089 containing one hundred 50 mg tablets. 
The subject will be instructed to take medication from each 
blister card on dates specified on the card. In addition, for the 
first week, the subject will take two 50-mg tablet from the 
bottle. For the second week, the subject will be instructed to 
take four 50-mg tablets from the bottle. 
Text updated 
for use of 
50mg tablets 
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Section 
Old Text 
Amended Text 
Rationale 
9.1.3 Visit 3, 
Day 1 
(Randomization) 
• 
Instruct the subject to take the first dose of the study 
medication the next morning.  
 
• 
Instruct the subject to take the first dose of the study 
medication 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 on the day of 
randomization after all other Visit 3 procedures have 
been completed. For these subjects, seizures which occur 
after the first dose must be counted and entered in to the 
CRF. 
Language 
added to allow 
subjects to 
have their first 
dose of the 
study 
medication 
administered at 
the study site 
9.3.2  Visit 11, 
Day 141 
The initial target dose for the open-label extension will be 
300 mg once daily. The dose of YKP3089 may be reduced 
to a minimum of 100 mg once daily or increased to a 
maximum of 400 mg once daily by 100-mg or 50-mg 
increments. 
The initial target dose for the open-label extension will be 
300 mg once daily. The dose of YKP3089 may be reduced to 
a minimum of 50 mg once daily or increased to a maximum 
of 400 mg once daily by 100-mg or 50-mg increments. 
 
Text updated 
for the use of  
50mg tablets 
13.7.2 
Data 
Monitoring 
Committee 
The DMC will have access to all unblinded safety data. 
The DMC will perform the following reviews:  
 
1. Review of the safety of the first 60 subjects completing 
titration. 
2. Review of the safety of the first 120 subjects completing 
titration. 
3. Review of the safety of the first 150 subjects completing 
double-blind phase. 
4. Review of the safety of the first 300 subjects completing 
double-blind phase. 
The DMC will have access to all unblinded safety data. The 
DMC will perform the following reviews:  
 
1. Review of the safety of the first 40 subjects completing 
titration. 
2. Review of the safety of the first 80 subjects completing 
titration. 
3. Review of the safety of the first 120 subjects completing 
double-blind phase. 
4. Review of the safety of the first 240 subjects completing 
double-blind phase. 
Due to the 
changes to the 
titration rate, 
all DMC 
meetings will 
occur earlier in 
the course of 
the study. 
The amendment must be reviewed and approved or have a favorable opinion from the Institutional Review Board/ Ethics Committee, prior to 
being implemented. 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................50 
1 
PROTOCOL SYNOPSIS ..........................................................................................55 
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 
Antiepileptic Activity of YKP3089 .........................................................................68 
4.4.2 
Absorption, Distribution, Metabolism, and Excretion ...........................................68 
4.4.3 
Safety Pharmacology and Toxicity Studies ............................................................69 
4.4.4 
Clinical Safety ........................................................................................................70 
4.5 
Dose Justification .........................................................................................................72 
4.5.1 
Double-Blind Dose Selection .................................................................................72 
4.6 
Potential Risks and Benefits ........................................................................................73 
5 
STUDY OBJECTIVES ..............................................................................................74 
6 
STUDY DESIGN ........................................................................................................75 
6.1 
Overview ......................................................................................................................75 
6.1.1 
Screening and Pre-Randomization (Baseline Period) ...........................................76 
6.1.2 
Double-Blind Treatment Period ............................................................................77 
6.1.2.1 
Titration Phase ............................................................................................................ 77 
6.1.2.2 
Double-Blind Maintenance Phase ............................................................................... 78 
6.1.2.3 
Blinded Study Drug Taper: Termination at End of Double-Blind Phase ................... 78 
6.1.3 
Double-Blind Phase Follow-Up Visit: Subjects Not Entering Open-Label 
Extension ................................................................................................................79 
6.1.4 
Open-Label Extension Phase .................................................................................79 
6.1.4.1 
Blinded Study Drug Conversion Period: Subjects Entering the Open-Label Phase ... 79 
6.1.4.2 
Open-Label Extension Treatment Phase ..................................................................... 81 
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6.1.4.3 
Study Drug Taper: Subjects Leaving the Open-Label Extension ............................... 81 
6.1.5 
Dose Adjustments of Study Drug and Concomitant AEDs ....................................82 
6.2 
Study Endpoints ...........................................................................................................83 
6.2.1 
Primary Efficacy Endpoint in the United States and the Rest of the World ..........83 
6.2.2 
Primary Efficacy Endpoint in the countries of Europe, Australia, New 
Zealand, and South Africa .....................................................................................83 
6.2.3 
Secondary Efficacy Endpoint in the countries of Europe, Australia, New 
Zealand, and South Africa .....................................................................................84 
6.2.4 
Secondary Efficacy Endpoint in the United States and the Rest of the World .......84 
6.2.5 
Additional Secondary Efficacy Endpoints .............................................................84 
6.2.6 
Outcome Measurements .........................................................................................85 
6.2.6.1 
Clinical Global Impression of Change (CGIC)........................................................... 85 
6.2.6.2 
Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) .......................................... 85 
6.2.7 
Pharmacokinetic Endpoints ...................................................................................86 
6.3 
Safety Assessments ......................................................................................................86 
6.4 
Interim Analysis ...........................................................................................................87 
7 
SELECTION OF STUDY POPULATION .............................................................88 
7.1 
Study Population and Sites ..........................................................................................88 
7.2 
Subject Recruitment .....................................................................................................88 
7.3 
Inclusion Criteria .........................................................................................................88 
7.4 
Exclusion Criteria ........................................................................................................90 
7.5 
Birth Control Methods Allowable for Enrollment of Subjects ....................................92 
8 
TREATMENTS..........................................................................................................93 
8.1 
Study Medication Information .....................................................................................93 
8.1.1 
Description of Study Medication ...........................................................................93 
8.1.1.1 
Physical Description of the Drug ................................................................................ 93 
8.1.1.2 
Testing ........................................................................................................................ 93 
8.1.1.3 
Packaging and Labeling .............................................................................................. 94 
8.1.2 
Blinding of Study Medication.................................................................................95 
8.1.3 
Supply, Storage, Accountability, and Disposition of Study Medication ................95 
8.2 
Randomization and Study Drug Distribution ..............................................................96 
8.2.1.1 
Screening Number ...................................................................................................... 96 
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8.2.1.2 
Randomization Number .............................................................................................. 97 
8.2.1.3 
Randomization Procedure ........................................................................................... 97 
8.2.1.4 
Drug Dispensing ......................................................................................................... 97 
8.3 
Prior and Concomitant Treatments ..............................................................................99 
8.4 
Prohibited Medications or Devices ..............................................................................99 
8.5 
Dosing Instructions ....................................................................................................100 
9 
STUDY PROCEDURES .........................................................................................100 
9.1 
Screening / Baseline / Randomization (Visits 1, 2 and 3) .........................................100 
9.1.1 
Visit 1, Day -56 ....................................................................................................100 
9.1.1.1 
Seizure Classification Review and Seizure Diary..................................................... 101 
9.1.2 
Visit 2, Day −28 ...................................................................................................102 
9.1.3 
Visit 3, Day 1 (Randomization) ............................................................................102 
9.2 
Double-Blind Treatment Period .................................................................................103 
9.2.1 
Visit 4, Day 15......................................................................................................103 
9.2.2 
Visit 5, Day 29......................................................................................................104 
9.2.3 
Visit 6, Day 43......................................................................................................104 
9.2.4 
Visit 7, Day 71......................................................................................................105 
9.2.5 
Visit 8, Day 99......................................................................................................105 
9.2.6 
Visit 9, Day 127, End of Double-Blind Treatment Period (or Early 
Termination) ........................................................................................................106 
9.2.7 
Visit 10, Day 162 or 14 Days after Last Dose of Study Drug ..............................107 
9.3 
Open-Label Extension Phase .....................................................................................108 
9.3.1 
Visit 9, Day 127: Open-Label Phase ...................................................................108 
9.3.2 
Visit 11, Day 141..................................................................................................109 
9.3.3 
Visit 12: Day 155 .................................................................................................110 
9.3.4 
Visit 13, Day 239..................................................................................................110 
9.3.5 
Visit 14, Day 323..................................................................................................111 
9.3.6 
Visit 15, Day 407..................................................................................................111 
9.3.7 
Visit 16, Day 491, or Termination from Open-Label Phase—Taper Visit ..........112 
9.3.8 
Visit 17, End of Study Follow-up (14 days from the last dose) ...........................113 
9.3.9 
Open-Label Extension Beyond Year One ............................................................114 
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9.4 
Unscheduled Visit/Telephone Contact ......................................................................115 
9.5 
Clinical Laboratory & Pharmacokinetic Evaluations ................................................115 
10 
SAFETY AND ADVERSE EVENTS .....................................................................116 
10.1 
Definitions..................................................................................................................116 
10.1.1 
Adverse Events .....................................................................................................116 
10.1.2 
Serious Adverse Event..........................................................................................116 
10.1.3 
Suspected Adverse Reaction ................................................................................117 
10.1.4 
Adverse Event Reporting Period ..........................................................................117 
10.1.5 
Preexisting Condition ..........................................................................................117 
10.2 
General Physical Examination Findings ....................................................................118 
10.3 
Adverse Event Recording and Assessing ..................................................................119 
10.4 
Reporting of Adverse Events .....................................................................................120 
10.4.1 
Study Sponsor Notification by Investigator .........................................................121 
10.4.2 
Ethics Committee/Institutional Review Board Notification by Investigator ........122 
10.4.3 
Regulatory Authority Notification of IND Safety Reports by Sponsor ................123 
10.5 
Withdrawal of Subject from Study ............................................................................123 
11 
DATA HANDLING PROCEDURES .....................................................................124 
11.1 
Data Handling and Record Keeping ..........................................................................124 
11.1.1 
Confidentiality......................................................................................................124 
11.1.2 
Source Documents ...............................................................................................124 
11.1.3 
Electronic Case Report Forms.............................................................................125 
11.1.4 
Records Retention ................................................................................................125 
12 
STATISTICAL METHODS AND PLANNED ANALYSES ...............................126 
12.1 
Sample size estimation ...............................................................................................126 
12.2 
Statistical Methods .....................................................................................................126 
12.3 
Analysis Data Sets .....................................................................................................127 
12.4 
Baseline Comparability ..............................................................................................128 
12.5 
Primary Efficacy Analyses ........................................................................................128 
12.5.1 
Primary Efficacy Analysis in the United States and the Rest of the World: ........128 
12.5.2 
Primary Efficacy Analyses in the countries of Europe, Australia, New 
Zealand, and South Africa ...................................................................................129 
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12.6 
Secondary Efficacy Analyses ....................................................................................130 
12.6.1 
Secondary Efficacy Analysis in the countries of Europe, Australia, New 
Zealand, and South Africa ...................................................................................130 
12.6.2 
Secondary Efficacy Analysis in the United States and the Rest of the World ......131 
12.7 
Additional Secondary Efficacy Analyses ..................................................................131 
12.8 
Safety Variable Analyses ...........................................................................................132 
12.9 
Pharmacokinetic Analysis ..........................................................................................132 
12.10 Open-Label Extension Analyses ................................................................................132 
12.11 Interim Analysis .........................................................................................................133 
13 
LEGAL ASPECTS, ETHICAL AND ADMINISTRATIVE ISSUES .................133 
13.1 
Good Clinical Practice ...............................................................................................133 
13.2 
Documentation of Consent ........................................................................................133 
13.3 
Delegation of Investigator Responsibilities ...............................................................133 
13.4 
Conflict of Interest .....................................................................................................134 
13.5 
Publication Plan .........................................................................................................134 
13.6 
Protocol Amendments ................................................................................................134 
13.7 
Study Monitoring, Auditing, and Inspecting .............................................................134 
13.7.1 
Study Monitoring Plan .........................................................................................134 
13.7.2 
Data Monitoring Committee ................................................................................135 
13.7.3 
Auditing and Inspecting .......................................................................................136 
APPENDIX A: FULL PHYSICAL EXAMINATION......................................................137 
APPENDIX B: FULL NEUROLOGIC EXAMINATION ...............................................138 
APPENDIX C: BRIEF NEUROLOGIC EXAMINATION .............................................139 
APPENDIX D: DIAGNOSTIC REVIEW FORM ............................................................140 
APPENDIX E: COLUMBIA SUICIDE SEVERITY RATING SCALE 
(BASELINE/SCREENING) ................................................................................................146 
APPENDIX F: COLUMBIA SUICIDE SEVERITY RATING SCALE (SINCE LAST 
VISIT) ...................................................................................................................................149 
APPENDIX G: CLINICAL GLOBAL IMPRESSION OF CHANGE (CGIC) .............152 
APPENDIX H: QUALITY OF LIFE IN EPILEPSY (QOLIE-31-P) .............................153 
14 
REFERENCES .........................................................................................................163 
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1 PROTOCOL SYNOPSIS 
Name of 
company 
SK Life Science Inc 
Title of study 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose-
Response Trial of YKP3089 as Adjunctive Therapy in Subjects with 
Partial-Onset Seizures, with Optional Open-Label Extension 
Protocol number  
YKP3089C017 
Phase of 
development 
Phase 2b 
Study duration 
Baseline phase: 8 weeks 
Double-blind up-titration: 6 weeks 
Double-blind maintenance phase: 12 weeks 
Double-blind crossover to open-label extension: 2 weeks 
Blinded study drug taper: 3 weeks 
Open-label extension phase: Until development is stopped by SK Life 
Science Inc, or the product is approved for marketing, or any time at the 
discretion of SK Life Science Inc. 
Indication 
Partial-onset epilepsy 
Study center(s) 
Approximately 100 sites (multiple countries) 
Number of 
subjects 
400 randomized  
Objectives 
The primary objective of this study is to determine the effective dose 
range of YKP3089 as adjunctive therapy for the treatment of partial 
seizures.  
The trial will also evaluate the safety and tolerability of YKP3089 in the 
partial epilepsy population. 
Inclusion and 
exclusion criteria 
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. 
Men and women 18 to 70 years of age, inclusive, will be permitted to 
enroll in this study. 
During the baseline, subjects must have at least 8 partial seizures, 
including only simple partial seizures with motor component, complex 
partial seizures, or secondarily generalized seizures without a seizure-free 
interval of greater than 25 days any time during the 8-week baseline 
despite appropriate doses of at least 1 and no more than 3 concomitant 
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AEDs. Subjects must have at least 3 of these partial seizures during each 
of the two consecutive 4-week periods in the baseline. 
Patients who meet the above seizure criteria and continue to meet other 
inclusion/exclusion criteria will be randomly assigned to the treatment.  
Design and 
methodology 
This is a multicenter, double-blind, randomized, placebo-controlled 
dose-response study, with an 8-week prospective baseline and an 18-week 
double-blind treatment period (including a 6-week titration phase and 
12-week maintenance phase), followed by a 3-week blinded study drug 
taper period (for subjects leaving the study) or a 2-week blinded 
conversion period (for subjects who will participate in the open-label 
extension). 
Subjects who meet inclusion/exclusion criteria will first undergo an 
8-week baseline period to assess seizure frequency. During the baseline, 
subjects must have at least 8 partial seizures including only simple partial 
seizures with motor component, complex partial seizures, or secondarily 
generalized seizures without a seizure-free interval of greater than 25 days 
any time during the 8-week period. Subjects must have at least 3 of these 
partial seizures during each of the two consecutive 4-week periods in the 
baseline. Subjects with a high enough seizure frequency will be randomly 
assigned in a 1:1:1:1 ratio to receive placebo or to receive YKP3089 100, 
200, or 400 mg given once per day in the morning.  
Subjects will first enter a 6-week titration phase, during which the initial 
dose will be 50mg/day. The planned increase in the daily dose will be 
50mg/day/week increments until 200mg is reached and after which the 
dose will be increased by 100mg/day/week in subjects randomized to 
400mg/day. Subjects having tolerability issues for the first time during 
Weeks 2 to 6 will have their dose reduced by 50 or100 mg depending on 
their attained dose at the time (Reduce by 50mg if taking 100mg, 150mg 
or 200mg; reduce by 100mg if on 300mg or 400mg).Subsequent to this 
reduction, subjects may at the discretion of the investigator, recommence 
the upward titration by 50 mg weekly increments towards their target dose 
until Week 6. If the subject cannot tolerate the new upward titration, the 
daily dose can be reduced one time by 50 mg through the end of week 8.  
Subjects will then enter a 12-week double-blind maintenance phase. Only 
subjects who complete the double-blind maintenance phase will be given 
the option to continue treatment in an open-label extension. Those who 
choose not to enter the open-label extension or who withdraw prematurely 
will taper off the study drug. For those subjects not entering the 
open-label extension, the taper phase will last 3 weeks, followed by a final 
visit 14 days after the last dose of study drug.  
The open-label extension will start with a 2-week blinded crossover 
period, during which all subjects will be converted to open-label 
YKP3089 at a target dose of 300 mg once daily.  
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Test product and 
dose 
YKP3089 50 and 100 mg tablets 
Target doses: 100, 200 or 400-mg per day 
Reference 
therapy & dose 
Placebo 
Statistics and 
analyses 
The primary efficacy endpoint to be evaluated for registration in the 
United States and the Rest of the World is the percent change from the 
pretreatment baseline phase in seizure frequency (average monthly seizure 
rate per 28 days) of all simple partial motor, complex partial, or 
secondarily generalized seizures compared with the double-blind 
treatment phase. The primary efficacy endpoint to be evaluated for 
registration in the countries of Europe, Australia, New Zealand, and South 
Africa is the responder rate defined as a 50% or greater reduction during 
the maintenance phase of the double blind period in the seizure frequency 
from baseline. 
The Primary Efficacy Analysis for United States, and the Rest of the 
World:  
The primary efficacy analysis of the primary endpoint will be based on the 
MITT population. 
The testing strategy for the primary efficacy endpoint is to compare each 
of the YKP3089 dosage groups with the placebo group.  Due to multiple 
treatment comparisons, a step-down procedure will be used to ensure the 
overall type I error rate is controlled at the 5% level. Each of the 
YKP3089 dosage groups will be compared with the placebo group 
according to the following hierarchy: 
1. 
200-mg dosage group versus placebo group 
2. 
400-mg dosage group versus placebo group 
3. 
100-mg dosage group versus placebo group 
 
The 200-mg dosage group will be compared with the placebo group at a 
2-sided 0.05 level as the first step. If no statistically significant difference 
is detected between the 200-mg dosage group and the placebo group, the 
procedure will stop and it will be concluded that none of the YKP3089 
dosages are efficacious. If a statistically significant difference is detected 
between the 200-mg dosage group and the placebo group in favor of the 
200-mg dosage group, the procedure will proceed to the next step to 
compare the 400-mg dosage group with the placebo group at a 2-sided 
0.05 level. If a statistically significant difference is detected between the 
400-mg dosage group and the placebo group in favor of the 400-mg 
dosage group, the procedure will proceed to the next step to compare the 
100-mg dosage group with the placebo group at a 2-sided 0.05 level.  
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An analysis of covariance (ANCOVA) model will be fit to the ranked 
values of the primary efficacy endpoint. The ANCOVA will have terms 
for ranked baseline seizure rate and randomized treatment group. 
 
The primary Efficacy Analysis for Europe, Australia, New Zealand, 
and South Africa:  
The primary efficacy analysis of the primary endpoint will be based on the 
MITT-M population.   
The testing strategy for the primary efficacy endpoint (responder rate) is 
to compare each of the YKP3089 dosage groups with the placebo group. 
A step-down procedure will be used to ensure the type I error rate due to 
multiple treatment comparisons is controlled at the 5% level. Each of the 
YKP3089 dosage groups will be compared with the placebo group 
according to the following hierarchy: 
1. 
200-mg dosage group versus placebo group 
2. 
400-mg dosage group versus placebo group 
3. 
100-mg dosage group versus placebo group 
The 200-mg dosage group will be compared with the placebo group at a 
2-sided 0.05 level as the first step. If no statistically significant difference 
is detected between the 200-mg dosage group and the placebo group, the 
procedure will stop and it will be concluded that none of the YKP3089 
dosages are efficacious. If a statistically significant difference is detected 
between the 200-mg dosage group and the placebo group in favor of the 
200-mg dosage group, the procedure will proceed to the next step to 
compare the 400-mg dosage group with the placebo group at a 2-sided 
0.05 level. If a statistically significant difference is detected between the 
400-mg dosage group and the placebo group in favor of the 400-mg 
dosage group, the procedure will proceed to the next step to compare the 
100-mg dosage group with the placebo group at a 2-sided 0.05 level.  
The data will be summarized using frequencies and percents of subjects 
achieving at least a 50% response to treatment, the responder rate. The 
responder data will be analyzed using a chi-square test.   
Other Efficacy and Safety Analyses:  
The percentage of subjects who have a 75%, 90% and 100% seizure 
reduction during the double blind period and the maintenance phase. 
Responder rates for partial seizure subtypes (including simple partial with 
motor component, complex partial, and secondarily generalized tonic-
clonic seizures) will be summarized. Outcome measurements such as 
quality of life and clinical global impression change will be analyzed. 
Safety will be assessed by the frequency, severity, and timing of adverse 
events, as well as by clinical laboratory test values, 12-lead ECG 
recordings, 
vital 
sign 
measurements, 
physical 
and 
neurologic 
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examinations, and the Columbia-Suicide Severity rating Scale (C-SSRS). 
Open-Label Extension:  
The results of the open-label extension will be reported at a later date 
using summary tables, figures, and data listings. Summaries will be 
presented for demographic information and safety information only. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 LIST OF ABBREVIATIONS 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine aminotransferase  
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase  
AUC0-24 
Area under the plasma concentration versus time curve from 0 to 24 
hours after dosing 
β-hCG 
β-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CBZ  
Carbamazepine 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CRO 
Clinical Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
Computed tomography 
CYP 
Cytochrome P450 
DDD 
Defined daily dose 
DMC 
Data Monitoring Committee 
DRESS syndrome 
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 
HIPAA 
Health Insurance Portability and Accountability Act 
HPDE 
High-density polyethylene 
ICH 
International Conference on Harmonisation 
IND 
Investigational new drug 
IRB 
Institutional review board 
ITT 
Intention to treat 
IWRS 
Interactive Web response system 
kg 
Kilogram 
LEV 
Levetiracetam 
LOCF 
Last observation carried forward 
LTG  
Lamotrigine 
mg/kg 
Milligrams per kilogram 
mg/kg/day 
Milligrams per kilogram per day 
MRI 
Magnetic resonance imaging 
OXC  
Oxcarbazepine 
PBR  
Phenobarbital (phenobarbitone) 
PHI 
Protected health information 
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PHT  
Phenytoin 
PI  
Principal Investigator 
PTZ 
Pentylenetetrazol 
SAE 
Serious adverse event 
SKLSI 
SK Life Science, Inc. 
SUDEP 
Sudden unexpected death in epilepsy 
SUSAR 
Suspected unexpected serious adverse reaction 
TPM  
Topiramate  
VNS 
Vagal nerve stimulator 
VPA 
Valproic acid (divalproex sodium) 
 
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3 STUDY ASSESSMENTS 
Table 1. Study Assessment Flowchart for Double-Blind Study 
Visit windows of ± 2 days are  
allowed for visits 1 through 6  
 
Visit windows of ± 3 days are  
allowed for visits 7 through 10 
 
Screening / Baseline Period 
Double-Blind Treatment Period (18 weeks) 
Follow-up 
Periodb  
(5 weeks)  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9  
or Early 
Termi- 
nationa 
Visit 10  
Baseline Seizure Count 
Safety 
baseline 
Titration Phase (Day 2-43) 
Maintenance Phase (Day 44-127) 
 
Assessment 
Day-56 
Day-28 
Day 1l 
Day 15m 
Day 29m 
Day 43 
Day 71 
Day 99 
Day 127  
Day 162 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
 
 
Medical and seizure history 
X 
 
 
 
 
 
 
 
 
 
Seizure Identification Form  
X 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Heightd and weight  
X 
 
X 
 
X 
 
X 
 
X 
X 
Full physical examination 
X 
 
 
 
 
 
 
 
 
X 
Full neurologic examination 
X 
 
 
 
 
 
 
 
X 
 
Brief neurologic exam 
 
 
X 
X 
X 
X 
X 
X 
  
X  
C-SSRSe 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
Xf 
 
X 
 
 
X 
 
 
X 
  
Serum pregnancy testg 
X 
 
 
 
 
 
 
 
 
X 
Urine pregnancy testg 
 
 
X 
 
 
 
 
 
X 
 
Laboratory safety assessmenth 
X 
 
X 
 
 
X 
 
 
X 
X 
Urinalysis 
X 
 
X 
 
 
 
 
 
X 
X  
YKP3089 levelsi 
 
 
 
 
 
 
X 
X 
 
  
Concomitant AED levelsj 
 
 
X 
 
 
 
X 
X 
 
  
EEG and MRI or CT scank 
X  
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Dispense/review/ 
collect seizure diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Drug accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
 
X 
X 
X 
X 
X 
X 
Xa 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGICn 
 
 
 
 
 
 
 
 
X 
 
QOLIE-31-Po 
 
 
X 
 
 
 
 
 
X 
 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; AED = antiepileptic drug; MRI = magnetic resonance imaging ; CT = computed 
tomography EEG = Electroencephalogram. CGIC = Clinical Global Impression of Change, QOLIE-31-P = Quality of Life in Epilepsy-31-Problems 
a. Subjects who do not plan to enter the optional open-label phase will have a blinded study drug taper. Subjects who plan to enter the open-label phase will 
have a blinded crossover at the beginning of the open-label phase.  
b. Subjects who do not plan to enter the open-label phase will participate in Visit 10 Follow-up on Day 162. All subjects who plan to enter the open-label phase 
will enter the open-label phase at Visit 9 and not participate in Visit 10 Follow-up. 
c. Vital signs include blood pressure and heart rate (supine for 5 minutes followed by standing for 3 minutes); respiration rate and oral temperature in the supine 
position. 
d. Height measured only at Visit 1. 
e. Administer the Baseline/Screening version of the C-SSRS at Screening. Administer the Since Last Visit version at all subsequent visits. 
f. 12-lead ECG will be performed 3 times with a minimum of 2 minutes between recordings. 
g. For female subjects of childbearing potential: If pregnancy is suspected at any time during the study, an interim test may be performed. 
h. Laboratory Assessment: Safety assessment includes blood chemistry and hematology. If the subject meets an exclusion criterion at Visit 1, an unscheduled 
laboratory sampling can be repeated for confirmation. Local laboratories may be used if necessary. 
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. 
j. Trough levels of concomitant AEDs should be obtained whenever possible. If this is not feasible due to the time of the clinic visit, appointments should be 
made so that the time of the blood draws are consistent with the last dose of concomitant AEDs throughout the study. 
k. If a CT or MRI has not been performed within the last 10 years, one must be performed prior to randomization. If an EEG report cannot be obtained, and the 
subject is otherwise eligible, an EEG may be performed 
l. Seizures occurring on Day 1 will not be counted in the study. Day 1 values will be used as safety baseline. Dosing will commence on Day 2. 
m.   Subjects will be contacted by phone on Days 8, 22 and 36 to assess tolerability and the occurrence of any early treatment-emergent adverse events and to 
reinforce compliance 
n. The investigator will complete the questionnaire at Visit 9 (end of maintenance or early termination if applicable) 
o.   The subject will complete the questionnaire at Visit 3 and Visit 9 (end of maintenance or early termination if applicable). This questionnaire is only to be 
implemented in the countries where it is available and validated for the spoken language(s). 
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Table 2. Study Assessment Flow Chart for Open-Label Extension Phase 
Visit windows of ± 3 days allowed 
for Visits 9 and Visit 17 (end of study 
follow-up visit) 
Visit windows of ± 2 days allowed 
for Visits 11 and 12. 
Visit windows of ± 7 days 
allowed for all other open-label visits 
Treatment  
 
End of 
Study 
Follow-up 
Visit 9  
First Day 
of Open- 
Label 
Phase 
Visit 11 
Visit 12 
Visit 13 
Visit 14 
Visit 15 
Visit 16 or 
Termination 
Visit 
Post 1 year 
Visit 17 
Assessment 
Day 127a  
Day 141  
Day 155 
Day 239 
Day 323 
Day 407 
Day 491 
Every 3 
monthsb 
14 days after 
the last dose  
Inclusion/exclusionc 
X 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
X 
 
X 
X 
Xe 
X 
Full physical examination 
X 
 
 
 
 
 
X 
Xf 
 
Full neurologic examination 
X 
 
 
 
 
 
X 
 
X 
Brief neurologic exam 
X 
 
X 
 
X 
 
Xe 
 
C-SSRSg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGh 
X 
 
X 
 
 
 
X 
Xf 
 
Serum pregnancy testi 
 
 
 
 
 
 
 
 
X 
Urine pregnancy testi 
X 
 
X 
 
X 
 
X 
Xe 
 
Laboratory safety assessmentj 
X 
 
X 
 
X 
 
X 
Xe 
X 
Urinalysis 
X 
 
 
 
X 
 
X 
Xf 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/review/ collect 
seizure diary 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug  
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; AED = antiepileptic drug. 
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a. Visit 9 is the same as Visit 9 at the end of double-blind maintenance phase, except that study drug for 2-week blinded crossover period to open-label 
extension will be dispensed to subjects who will participate in the open-label extension. 
b. After 12 months of participation in the open-label extension phase, 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. 
c. Subject should continue to meet the inclusion and exclusion criteria except for seizure frequency.  
d. Vital signs include blood pressure and heart rate (supine for 5 minutes followed by standing for 3 minutes). Respiration rate and oral temperature in the 
supine position. 
e. Every 6 months after Visit 16. 
f. Every 12 months after Visit 16. 
g. Administer the Since Last Visit version of the C-SSRS.  
h.  12-lead ECG. Additional ECGs should be performed at any other time if clinically indicated. 
i. If pregnancy is suspected at any time during the study, an interim test may be performed. 
j.  Laboratory assessment: Safety assessment includes blood chemistry and hematology.  
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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. Therefore, the efficacy of YKP3089 in this population is 
worthy of investigation.  
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. 
Optimization of inclusion criteria. There is no formal definition of intractability in epilepsy, but 
subjects whose seizures persist despite therapy with 2 or more AEDs have been shown to have a 
poor response to subsequent AED regimens.5 Failure may be characterized as a persistence of 
any seizure pattern during treatment with a given AED that, in the judgment of the investigator, 
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has been administered at appropriate doses and for sufficient periods of time. To ensure that 
enrolled subjects meet a rigorous criterion of medical intractability, treatments with at least 3 
different AEDs must have failed (note that these may include AEDs that subjects are currently 
receiving). Establishing an 8-week prospective baseline and specifying a minimum of 8 seizures 
during that time (with at least 3 partial seizures during each of the two consecutive 4-week 
periods) and with no more than 25 consecutive days of freedom from seizures reduces the 
variability in the pretreatment seizure count and thereby increases the power of detection of 
significant changes in seizure frequency during the treatment period with the study drug. 
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. It is a novel small molecule of molecular weight 267.68. Its structure is 
shown in Figure 1. 
 
Figure 1. Structure of YKP3089 
4.4 
Pharmacology 
YKP3089 is a novel small molecule that is currently in Phase 2 of development as an 
antiepileptic agent (IND 76,809). Nonclinical testing of YKP3089 suggested a broad spectrum of 
antiepileptic effects, as well as therapeutic potential for treatment of neuropathic pain and 
possible future investigations of treatment of anxiety. The mechanism of action of YKP3089 is 
currently unknown. Additional details can be found in the current YKP3089 Investigator’s 
Brochure.  
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4.4.1 
Antiepileptic Activity of YKP3089 
YKP3089 has shown evidence of antiepileptic effects in standard preclinical models, as 
described in the current version of the Investigator’s Brochure: 
• The maximal electroshock test, which is used to identify compounds that prevent seizure 
spread 
• The 6 Hz corneal stimulation model, which is a model of psychomotor seizures and therapy-
resistant epilepsy 
o The pentylenetetrazol (PTZ, Metrazol®) test, which is used to identify compounds that 
raise seizure threshold 
• Test for inhibition of seizures provoked by picrotoxin or bicuculline, which antagonize 
GABAA receptors. Bicuculline can also block Ca2+-activated potassium channels. 
• Test for inhibition of seizures induced by pilocarpine, potentiated by lithium carbonate. 
Pilocarpine is administered to rats to induce sustained convulsions that resemble status 
epilepticus and are followed by widespread damage to the forebrain. 
No specific receptor has been identified as being involved in the mechanism of action of 
YKP3089. In vitro studies of panels of receptors showed no significant activation or inactivation. 
Nor did YKP3089 show significant potential to interact with voltage- or receptor-gated channels, 
although some effects on currents mediated by -aminobutyric acid (GABA) were noted. In vitro 
electrophysiology assays showed YKP3089 to be an inhibitor of the inactivated state of sodium 
channels. Thus, the mechanism of antiepileptic activity for YKP3089 is unknown and may be 
novel. Details of these studies can be found in the current version of the Investigator’s Brochure.  
4.4.2 
Absorption, Distribution, Metabolism, and Excretion 
Preclinical and clinical studies have shown that YKP3089 is well absorbed after oral 
administration under fasting and fed conditions. A single ascending dose study showed that the 
half-life of YKP3089 in human subjects was 50.2 ± 15.0 hours (mean ± SD) for a 100-mg oral 
dose, 54.7 ± 16.1 hours for a 200-mg oral dose, and 60.4 ± 11.2 hours for a 300-mg oral dose. 
These values suggest that YKP3089 is suitable for once-daily oral dosage. Details of these 
preclinical and clinical studies can be found in the current version of the Investigator’s Brochure. 
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Protein binding in human plasma was concentration-independent at the range of 0.114 to 
1.4 µg/mL. The protein-bound fraction in human plasma was 61%, with 39% free fraction. 
[14C] YKP3089 was preferentially bound to human albumin protein (~66.7%) and not to 1-acid 
glycoprotein. 
A bioavailability study showed that YKP3089 undergoes minimal first-pass metabolism in 
humans. Preclinical studies showed that YKP3089 did not produce any strong inhibitions or 
inductions of cytochrome P450 (CYP) isozymes, UDP-dependent glucuronosyltransferase, or 
phenol sulfate transferase. Studies of the metabolism of YKP3089 showed several possible 
metabolic pathways. However, only the parent compound and the metabolite produced by 
glucuronidation of the carbamate nitrogen were recovered in human plasma. This suggests 
limited potential for metabolite toxicity. 
A mass balance study in human subjects indicated limited penetration of YKP3089 and its 
metabolites into cellular elements of blood. More than 50% of the radioactivity from a 
radiolabeled dose of YKP3089 was excreted in urine and feces within 24 hours; 93% was 
excreted within 312 hours. For more information, see the Investigator’s Brochure. 
Clinical studies of drug-drug interactions showed that YKP3089 had no pharmacokinetic 
interaction with divalproex. Co-administration of YKP3089 did produce a 19% decrease in 
exposure to carbamazepine (CBZ) plus CBZ epoxide; however, this decrease was not considered 
clinically relevant. Co-administration of YKP3089 with an oral contraceptive (1 mg 
norethindrone and 0.035 mg ethinyl estradiol) showed that the contraceptive had no effect on the 
pharmacokinetics of YKP3089; however, the YKP3089 apparently increased the area under the 
concentration-time curve from 0 to 24 hours postdose (AUC0-24) for norethindrone by 37%. 
Details of the drug-drug interaction studies can be found in the current version of the 
Investigator’s Brochure.  
4.4.3 
Safety Pharmacology and Toxicity Studies 
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). The incidence and severity of these signs increased with 
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increasing dose, and the signs resolved during the recovery periods. In mice and rats, the median 
neurotoxic dose of YKP3089 was calculated to be between 50 and 350 mg/kg, a dose greater 
than that required to elicit antiepileptic effects (ie, 3 to 30 mg/kg). 
In a special neurotoxicity safety pharmacology study in cynomolgus monkeys, no evidence of 
drug-induced epileptic convulsions was observed at 30, 40, or 60 mg/kg/day administered for 
4 days. Severe toxicity was noted at 40 and 60 mg/kg/day requiring euthanasia of 1 animal and 
halting of dosing for 3 others before the end of the scheduled 4 days of administration. At 
60 mg/kg/day, myoclonus and/or intention tremors were noted in 2 of 6 animals. 
YKP3089 had no effect on cardiac (ECG) or circulatory function in monkeys, as measured by 
telemetry. Nor was there evidence of cardiotoxicity in studies of rats or monkeys. YKP3089 at 
doses up to 30 mg/kg had no effect on pulmonary function or cause bronchoconstriction.  
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. No tests of 
carcinogenicity have been conducted.  
4.4.4 
Clinical Safety 
Approximately 400 human subjects have been exposed to YKP3089 in 15 completed (13 Phase 
1, 1 proof-of-concept) and 1 Phase 2a).  
In a multiple ascending dose study in healthy volunteers, when doses of 250 to 300 mg once 
daily were given from Day 1, somnolence, dizziness, and decreases in mean systolic blood 
pressure have been seen, but no serious AEs have been reported. Horizontal nystagmus, ataxia, 
and gait disturbance have also been observed in normal volunteers receiving 250 and 300 mg 
once daily. These reactions resolved after YKP3089 was discontinued at the end of the study. At 
300 mg once daily, a mean shortening of the QTcF interval of 10 to 15 msec was observed.  
In another, now completed Phase 1 multiple ascending dose study in healthy volunteers, 
YKP3089C018, subjects were titrated from a starting dose of 200 mg once daily to a target dose 
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of 400, 500, or 600 mg once daily by 100-mg increments every 5 to 7 days. Adverse events in 
the first and second cohorts are generally mild, with no discernible pattern other than drowsiness. 
All subjects following daily administration of 600 mg YKP3089 experienced multiple 
neurological adverse events including somnolence, ataxia, and nystagmus. Many of these AEs 
were probably related to the study drug and at least 2 subjects had exceeded their maximum 
tolerated dose. Based on the overall condition of the remaining subjects, the study was stopped. 
Two subjects taking YKP3089 discontinued from the cohort targeting 500 mg once daily 
because of an adverse event that was probably related to YKP3089. One subject discontinued for 
facial swelling and rash. The other subject discontinued because of an antiepileptic 
hypersensitivity syndrome with symptoms consistent with DRESS syndrome. In addition, a 41-
year-old male subject receiving 600 once daily of YKP3089 was hospitalized for one day 
because of head trauma subsequent to a fall and an altered state of consciousness. 
A recently completed Phase 2a, randomized, double-blind, placebo-controlled study, 
YKP3089C013, evaluated the efficacy and safety of 200mg of YKP3089 as adjunctive therapy 
for the treatment of partial seizures. YKP3089 treatment began with a 50-mg daily dose, which 
was increased by 50 mg every 2 weeks to a target dose of 200 mg once daily. There was a 6-
week titration and 6-week maintenance period, followed by a 1-week taper period. Subjects who 
completed the double-blind period were eligible to enter an open-label extension.  
In the Phase 2a study , 113 subjects received YKP3089 and 109 received placebo.  Comparison 
of the primary efficacy endpoint, median percent reduction in partial seizure frequency, 
demonstrated a highly statistically significant effect in favor of the YKP3089 group, 55% vs 
21%, p<0.0001. Initial efficacy was observed at doses of 50-100mg/day and maintained 
throughout the 12 week study.  Review of the safety data indicated that 4% of subjects in the 
active and 4% of subjects in the placebo-group dropped out because of adverse events.  Two-
thirds of subjects completed the study at the target dose of 200mg/day.  The most common 
central nervous system adverse events in the YKP3089 group were somnolence, dizziness, 
fatigue, and gait disorder 
Two suspected unexpected serious adverse reaction (SUSAR) occurred in YKP3089 treated 
subjects:  an early manifestation of a drug hypersensitivity reaction characterized by flushed 
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erythema of palms and soles with mild itching of ears and a status epilepticus during tapering. 
During the open-label extension, 2 notable serious adverse events occurred in YKP3089 treated 
subjects: one case of sudden unexpected death in epilepsy (SUDEP) and one case of suicide. 
They were considered remotely related or unrelated to study drug. 
4.5 
Dose Justification 
4.5.1 
Double-Blind Dose Selection 
The primary objective of this study is to determine the effective dose range of YKP3089 as 
adjunctive therapy for the treatment of partial seizures. During the initial design of this protocol,  
a blinded review of the ongoing Phase 2a randomized, double-blind, placebo-controlled study 
YKP3089C013, revealed that few subjects dropped out and that only the two previously 
described serious adverse events were related to YKP3089. Some subjects did not reach the 
maximum target dose of 200 mg. In the multiple ascending dose study, YKP3089C018, a daily 
dose of up to 500 mg was generally well tolerated by healthy volunteers.  
In the open-label extension portion of the Phase 2a study, some subjects reportedly began to have 
clinically significant improvement in their seizure frequency only when they started taking a 
daily dose of 100 to 200 mg. It was concluded that a dose range of 200 to 400 mg/day should 
therefore be broad enough to identify efficacious doses. A 100-mg daily dose was chosen to 
determine the minimum effective dose. Although a dose of 500 mg once daily has generally been 
well tolerated by healthy volunteers, the maximum dose chosen for the study was  400 mg once 
daily, to account for potential adverse pharmacodynamic interaction with the concomitant 
antiepileptic drugs.  
Although the Phase 2a study titrated the daily dose upward by 50 mg every 2 weeks the healthy 
volunteers in the recently completed multiple ascending dose study initiated therapy with a daily 
dose of 200 mg, titrated upward by 100 mg every 5 to 7 days to 400 and 500mg/day, and 
generally well tolerated the faster titration rate. Therefore, it was initially decided that in the 
current study subjects would begin with a daily dose of 100 mg, followed by weekly increments 
of 100 mg in the daily dose, to the target dose. 
 
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Recently, a blinded review of the tolerability profile in the first 9 subjects randomized in this 
study, YKP3089C017, was performed. Three subjects had study drug dose reduction and 
subsequently discontinued because of adverse events within four weeks of randomization. One 
of these subjects, a 47 year old male with a history of partial epilepsy, head trauma and a right 
hemiparesis, developed significant somnolence and ataxia and was hospitalized for increasing 
right hemiparesis.  Asymptomatic pulmonary emboli were found incidentally during the 
hospitalization. Two other subjects had study drug dose reductions because of adverse events and 
are continuing therapy. The adverse events reported by these subjects are consistent with the 
adverse event profile of YKP3089 reported in previous studies of YKP3089, including 
somnolence, dizziness and ataxia; however the frequency of discontinuation and dose reductions 
is higher than initially expected. 
Although only a small number of subjects have been exposed to the new titration rate, to ensure 
that the results of this study can be interpreted correctly, the titration rate will be modestly 
slowed to provide for better tolerability and potentially fewer adverse event dropouts. The initial 
dose will be reduced to 50mg/day and the titration rate will slow to 50mg/day/week until 200mg 
is reached and then the dose will be increased by 100mg/week in subjects randomized to 
400mg/day. If the subject experiences tolerability issues during the titration that require 
intervention by the investigator, the  study drug dose will be reduced by 50 or 100mg depending 
on the attained dose at that time. (Reduce by 50mg if taking 100mg, 150mg or 200mg; reduce by 
100mg if on 300mg or 400mg). The lower dose will be maintained for 7-13 days and then the 
investigator, at his/her discretion, may recommence an upward titration to the target dose.  
These changes are being made based on a blinded review of the data and will not impact the 
integrity of this double-blind placebo-controlled dose response study.  
4.6 
Potential Risks and Benefits 
Approximately 400 human subjects have been exposed to YKP3089 in 15 completed (13 Phase 
1, 1 proof-of-concept and 1 Phase 2a).  
In the completed Phase 2a randomized double-blind, placebo-controlled study in subjects with 
partial-onset seizures, only 2 SAEs have been related to YKP3089: an early manifestation of a 
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drug hypersensitivity reaction characterized by flushed erythema of palms and soles with mild 
itching of ears and a status epilepticus during tapering of the study medication. In the open-label 
extension, one case of SUDEP and one case of suicide have been observed. No significant 
laboratory or electrocardiographic abnormalities were identified.  
In a completed Phase 1 drug interaction study with YKP3089 and phenytoin, a case of 
antiepileptic-induced hypersensitivity syndrome was observed. Rash and mucosal ulcers 
developed after 14 days of phenytoin treatment and one dose of YKP3089. The investigator 
deemed this SAE not related to YKP3089 and characterized it as phenytoin-induced 
hypersensitivity syndrome. 
As described previously, in a completed Phase 1 multiple ascending dose study, one subject 
developed fever, rash, leukocytosis, eosinophilia, and hepatic enzyme and electrolyte 
abnormalities. The drug was stopped and the signs and symptoms resolved thereafter. This was 
diagnosed as an antiepileptic hypersensitive syndrome with symptoms consistent with DRESS 
syndrome and probably related to YKP3089. 
The incidence of rashes in YKP3089 and placebo treated subjects in completed Phase 1 trials and 
in a Phase 2a studies is approximately 4% in each group. 
At this time, the preclinical antiepileptic profile of YKP3089 and the first Phase 2a randomized, 
double-blind, placebo-controlled study suggest that YKP3089 could provide additional seizure 
control in patients with poorly controlled epilepsy with limited safety risks.  
5 STUDY OBJECTIVES  
The primary objective of this study is to determine the effective dose range of YKP3089 as 
adjunctive therapy for the treatment of partial seizures.  
The trial will also evaluate the safety and tolerability of YKP3089 in the partial epilepsy 
population. 
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6 STUDY DESIGN 
6.1 
Overview 
This is a multicenter, double-blind, randomized, placebo-controlled study with an 8-week 
prospective baseline and an 18-week double-blind treatment period (including a 6-week titration 
phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period 
(for subjects leaving the study) or a blinded 2-week conversion period (for subjects participating 
in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug. 
Subjects who meet all inclusion criteria and none of the exclusion criteria will first undergo an 8-
week baseline to assess seizure frequency. Subjects who have experienced at least 8 seizures 
during the baseline period without a seizure-free interval of greater than 25 days any time during 
those 8 weeks will be randomly assigned in a 1:1:1:1 ratio to receive placebo or YKP3089 100, 
200, or 400 mg given once per day in the morning. Subjects must have at least 3 partial seizures 
during each of the two consecutive 4-week periods of the baseline. 
Subjects will first enter a 6-week titration phase, during which the initial dose will be 50mg/day. 
The planned increase in the daily dose will be 50mg/day/week increments until 200mg is reached 
and after which the dose will be increased by 100mg/day/week in subjects randomized to 
400mg/day . Subjects will then enter a 12-week double-blind maintenance phase. 
Only subjects who complete the double-blind maintenance phase will be given the option to 
continue treatment in an open-label extension. Those who choose not to enter the open-label 
extension or who withdraw prematurely will taper off the study drug. 
For those subjects not entering the open-label extension, the taper period will last 3 weeks and 
will be followed by a final visit 14 days after the last dose of study drug. 
Those subjects entering the open-label extension will enter a 2-week blinded crossover period, 
during which all subjects will be converted to a target dose of 300 mg once daily of open-label 
YKP3089.  
 
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Figure 2 provides an overview of the study design. 
Figure 2. Overview of Study Design 
  
6.1.1 
Screening and Pre-Randomization (Baseline Period) 
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 
Screening
(Visit 1)
Eligibility 
Criteria 
Met
Randomization
(Visit 3)
Placebo
100mg
200mg
400mg
Titration (6 weeks)
Maintenance 
(12 Weeks )
Withdrawn 
Subjects
OLE
Taper
(3 weeks)
Blinded Conversion to OLE (2 Weeks )
Baseline Period
8 weeks
Double-Blind Treatment
Period (DB) 18 weeks 
Open-Label
Extension
Phase (OLE)
Completed DB  but 
opted out of OLE
Taper (3 weeks)
Follow up visit
(2 weeks from last dose)
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indicating willingness to participate in the study. Investigators will be required to fill in a 
Diagnostic Review Form to be assessed by an independent consulting group (eg, Epilepsy Study 
Consortium) to ensure consistency of the diagnosis. 
In the final determination of eligibility for the trial, screened subjects will be assessed for seizure 
frequency at the end of the 8-week prospective baseline period. 
After the 8-week baseline period, subjects who meet all of the inclusion criteria and none of the 
exclusion criteria will be randomly assigned to receive placebo or 100, 200, or 400 mg of 
YKP3089 once daily in the morning. The dosing will start the morning following randomization.  
6.1.2 
Double-Blind Treatment Period 
The double-blind treatment period will consist of a 6-week titration phase followed by a 12-week 
maintenance phase.  
6.1.2.1 
Titration Phase 
During the initial 6-week up-titration phase of the double-blind treatment period, subjects 
assigned to receive YKP3089 will receive blinded study medication according to the dosage 
schedule shown in Table 3.  
Table 3. YKP3089 Initial Double-Blind Up-Titration 
YKP3089  
target dose  
(mg/day) 
 
 
YKP3089 dose (mg/day) 
Week 1  
Week 2 
Week 3  
Week 4 
Week 5 
Week 6 
100 
50 
100 
100 
100 
100 
100 
200 
50 
100 
150 
200 
200 
200 
400 
50 
100 
150 
200 
300 
400 
During Week 1, no dose reduction will be permitted. Subjects who have significant tolerability 
issues should discontinue treatment with study drug. If study drug is not tolerated for the first 
time at any time during Weeks 2 through 6, subjects may have a reduction in their daily dose. 
The size of the reduction will depend on the dose at the time poor tolerability is noted (Reduce 
by 50mg if taking 100mg, 150mg or 200mg; reduce by 100mg if on 300mg or 400mg). Subjects 
will remain at the reduced dose level for a minimum of 7 days and up to 13 days.  
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Thereafter, the subjects may at the discretion of the investigator, recommence the upward 
titration at 50-mg increments in the daily dose once a week towards the target dose until week 6. 
If the subject cannot tolerate the new upward titration, the daily dose can be reduced one time by 
50 mg through the end of week 8. No upward titration will be allowed after Week 6. No two 
consecutive dose reductions will be allowed.  
If a tolerability issue occurs, dosage adjustments need to be made at a scheduled visit or at an 
unscheduled visit at the discretion of the investigator. At the visit, the subject will be issued a 
new set of cards to be determined by the interactive web response system (IWRS). 
To improve tolerability, the investigator may instruct the subject to take the dose of study 
medication in the evening. The investigator may alter the timing or amount of an individual dose 
of a concomitant AED, but the total daily dose and dosing frequency of the concomitant AED 
must remain unchanged during the double-blind phase. 
During titration, the investigator may instruct the subject to hold the daily dose of the study drug 
up to a maximum of 2 days per week.  
6.1.2.2 
Double-Blind Maintenance Phase 
After the 6-week up-titration phase, subjects will enter the double-blind maintenance phase. The 
subjects will be instructed to take their study medication once daily in the morning for 12 weeks. 
Subjects will follow the schedule of study visits and assessments detailed in Table 1. 
The investigator may instruct the subject to take the dose of study medication in the evening if 
clinically indicated and consistent with other aspects of the protocol. The investigator may alter 
the timing or amount of an individual dose of a concomitant AED, but the total daily dose and 
dosing frequency of the concomitant AED must remain unchanged during the double-blind 
phase. No YKP3089 dose adjustments are permitted after week 8. 
6.1.2.3 
Blinded Study Drug Taper: Termination at End of Double-Blind Phase 
Subjects who will not participate in the optional open-label phase will enter a 3-week, double-
blind taper period when they complete the maintenance phase or discontinue prematurely. The 
dosage of YKP3089 will be tapered according to the schedule shown in Table 4. To maintain 
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blinding during the taper period, YKP3089 or placebo, as appropriate, will be dispensed in 
blister cards at Visit 9 to all subjects. The taper period will be followed by a Follow-up Visit 14 
days after the last dose of study drug. Subjects will follow the schedule of study visits and 
assessments detailed in Table 1. 
During the taper period, investigators will be allowed to adjust the AED dosage or add 
concomitant AEDs. 
Table 4. Blinded Study Drug Taper Schedule 
Final Double-Blind Dose of 
YKP3089 (mg/day) 
YKP3089 Dose During Taper (mg/day) 
Week 1 
Week 2 
Week 3 
0 (placebo)/50/100 
0 
0 
0 
150 or 200 
100 
0 
0 
250 or 300 
200 
100 
0 
350 or 400 
300 
200 
100 
6.1.3 
Double-Blind Phase Follow-Up Visit: Subjects Not Entering Open-Label Extension 
Subjects who do not elect to participate in the optional open-label extension will have their 
Follow-up Visit 14 days after completion of the 18-week double-blind treatment phase and the 
3-week blinded study drug taper period. The post-treatment Follow-up Visit (Visit 10) will occur 
14 days after last dose of study medication for all subjects ending study participation. 
6.1.4 
Open-Label Extension Phase  
Subjects who complete the 12-week double-blind maintenance phase and still meet all inclusion 
criteria and none of the exclusion criteria except for seizure frequency are eligible to continue in 
an optional open-label extension phase. For subjects who elect to participate in the optional 
open-label extension, Visit 9 of the double-blind phase will also be the first visit of the open-
label extension.  
6.1.4.1 
Blinded Study Drug Conversion Period: Subjects Entering the Open-Label Phase 
Subjects will have a 2-week double-blind conversion period at the beginning of the open-label 
extension phase of the study. In order to keep the treatment blind, subjects from all four dose 
groups will be converted to a target dose of 300 mg/day after two weeks of blinded conversion 
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period. This conversion period will begin at Visit 9. Subjects will follow the study medication 
schedule shown in Table 5. The daily dose will consist of 4 tablets of YKP3089 or placebo 
(depending on the dose regimen assigned during the double-blind phase) from a blinded blister 
card plus tablets (2 for Week 1 and 4 for Week 2) from an open-label bottle of 50-mg YKP3089 
tablets taken every morning. Starting at Visit 11, the subjects will take three 100-mg tablets from 
the open-label bottle every morning.  
Table 5. Blinded Study Drug Conversion to Open-Label Target of 300 mg/day YKP3089 
YKP3089 dose 
group (mg/day) 
during double-
blind period 
Dose of YKP3089 (mg/day)a 
Dispensed at Visit 9 
Dispensed at Visit 11 
Week 1 
Week 2 
Week 3 
From Card 
From Open-
Label Bottle 
From Card 
From Open-
Label Bottle 
From Card 
From Open-
Label Bottle 
0 (placebo)/50 
0 
2X50 
0 
4X50 
No card 
300 
100 
100 
2X50 
100 
4X50 
No card 
300 
150/200 
100 
2X50 
100 
4X50 
No card 
300 
250/300 
200 
2X50 
100 
4X50 
No card 
300 
350/400 
200 
2X50 
100 
4X50 
No card 
300 
 
aThe total daily dose is the amount taken from the blister card plus the amount taken from the bottle of 50-mg tablets 
(eg, the placebo group from the double-blind phase receives placebo from the blister card and two  50-mg tablets 
from the bottle every day during Week 1 of the conversion period, placebo from the blister card and four 50-mg 
tablets from the bottle every day during Week 2 of the conversion period, and then three 100-mg tablets from the 
bottle per day starting in Visit 11).  
During the first week of the conversion period, the investigator can increase or decrease the 
open-label dosage by 50-100 mg if clinically indicated (ie, recurrence of seizures, adverse 
events). During the second week of the conversion period, the investigator can decrease the 
open-label dosage by 50-200 mg or increase the open label dosage by a maximum of 100 mg if 
clinically indicated (ie, recurrence of seizures, adverse events). All dose adjustments must be 
made with tablets from the open label bottles.  All tablets from the cards must be taken on 
Week 1 and Week 2 during the conversion period.   
Although the target dose for subjects is 300mg at Visit 11, subjects may be taking 50-400 mg at 
Visit 11 depending upon tolerability and efficacy during the conversion period. 
Doses of concomitant AEDs may be adjusted during the conversion phase. 
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6.1.4.2 
Open-Label Extension Treatment Phase  
The initial target dose for the open-label extension will be 300 mg/day. However, if a subject is 
not tolerating the 300 mg/day dose, YKP3089 dose may be reduced to a minimum of 50 mg/day. 
If the investigator feels that a subject requires a dose that is higher than 300 mg/day, the dose can 
be increased to a maximum of 400 mg/day once the target dose of 300 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. No dose reductions are 
permitted if the subject is taking 50 mg/day YKP3089. If 50 mg/day YKP3089 is not tolerated, 
the subject will withdraw from the study. Monotherapy with YKP3089 will not be allowed. The 
investigator may add, remove, or adjust the dosage of concomitant AEDs, as clinically indicated. 
In the event of poor tolerability, the investigator may instruct the subject to take 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 2. After 12 months of participation in 
the open-label extension phase, 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. 
6.1.4.3 
Study Drug Taper: Subjects Leaving the Open-Label Extension  
Subjects who are withdrawn from the open-label extension study will taper YKP3089 according 
to the schedule described in Table 6, unless for safety reasons the investigator judges it necessary 
to discontinue study drug immediately. The investigator is encouraged to discuss the tolerability 
criteria with the Sponsor or its designee. 
Table 6. Study Drug Taper Schedule for Subjects Completing Open-Label Extension  
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 
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The final 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. 
6.1.5 
Dose Adjustments of Study Drug and Concomitant AEDs 
During week 1, no dose reduction will be permitted. Subjects who have significant tolerability 
issues should discontinue treatment with study drug. If study drug is not tolerated at some point 
during weeks 2 through 6, subjects may have a reduction in the daily dose. The size of the 
reduction will depend on the dose at the time poor tolerability is noted (Reduce by 50mg if 
taking 100mg, 150mg or 200mg; reduce by 100mg if on 300mg or 400mg). Subjects will remain 
at the reduced dose level for a minimum of 7 days and up to 13 days. Thereafter, the subjects 
may, at the discretion of the investigator, recommence the upward titration to the target dose at 
50-mg increments in the daily dose once a week until week 6. If the subject cannot tolerate the 
new upward titration, the daily dosage can be reduced once by 50 mg up through the end of 
Week 8. No upward titration will be allowed after Week 6. No two consecutive dose reductions 
will be allowed. 
Dosage adjustments related to tolerability issues need to be made at a scheduled visit or at an 
unscheduled visit at the discretion of the investigator. At the visit, the subject will be issued a 
new card or set of cards to be determined by IWRS. 
For further instruction on dose adjustments, please refer to study manual. 
The initial target dose for the open-label extension will be 300 mg/day. However, if a subject is 
not tolerating the 300 mg/day dose, YKP3089 dose may be reduced to a minimum of 50 mg/day. 
If the investigator feels that a subject requires higher than 300 mg/day, the dose can be increased 
to a maximum of 400 mg/day once the target dose of 300 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. No dose reductions are permitted if 
subject is taking 50 mg/day YKP3089. If 50 mg/day YKP3089 is not tolerated, the subject will 
withdraw from the study. Monotherapy with YKP3089 will not be allowed. The investigator may 
add, remove, or adjust the dosage of concomitant AEDs, as clinically indicated. In the event of 
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poor tolerability, the investigator may instruct the subject to take the dose of study medication in 
the evening or divide the total daily dose into 2 doses. 
6.2 
Study Endpoints 
The primary efficacy endpoints reflect the United States Food and Drug Administration (FDA) 
recommendation of percent reduction in seizure frequency for registration which is adopted by 
many countries in the rest of the world, and the European Agency for the Evaluation of 
Medicinal Products (EMEA) recommendation of the responder rate for registration in Europe, 
which is also adopted by Australia, New Zealand, and South Africa.  
6.2.1 
Primary Efficacy Endpoint in the United States and the Rest of the World 
The primary efficacy endpoint to be evaluated for registration in the United States and the Rest 
of the World is the percent change from the pretreatment baseline phase in seizure frequency 
(average monthly seizure rate per 28 days) of all simple partial motor, complex partial, or 
secondarily generalized seizures compared with the double-blind treatment phase.  
The baseline rate (B) is calculated by counting the number of seizures over the baseline period 
and dividing by the number of days in the interval with non-missing seizure data and then 
multiplying by 28. The double-blind rate (D) is calculated in a similar manner. The percent 
change is equal to 100*(D-B)/B. Simple partial seizures without a motor/visual component will 
not be counted. 
This value will be undefined if B=0. For the primary efficacy analysis, there will not be any 
baseline values with zero seizures. However, for the analysis of seizure sub-types, there is a 
possibility that B may be zero. In this case, B will be set to a value of 1. 
6.2.2 
Primary Efficacy Endpoint in the countries of Europe, Australia, New Zealand, 
and South Africa 
The primary efficacy endpoint to be evaluated for registration in the countries of Europe, 
Australia, New Zealand, and South Africa is the responder rate defined as a 50% or greater 
reduction during the maintenance phase of the double blind period in the seizure frequency from 
baseline. 
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The responder endpoint is a binary indicator endpoint defined as 1 if the primary endpoint is <= -
50%, and 0 otherwise 
6.2.3 
Secondary Efficacy Endpoint in the countries of Europe, Australia, New Zealand, 
and South Africa 
The secondary efficacy endpoint to be evaluated for registration in the countries of Europe, 
Australia, New Zealand and South Africa is the percent change from the pretreatment baseline 
phase in seizure frequency (average monthly seizure rate per 28 days) of all simple partial motor, 
complex partial, or secondarily generalized seizures compared with the maintenance phase of the 
double-blind treatment phase.  
The baseline rate (B) is calculated by counting the number of seizures over the baseline period 
and dividing by the number of days in the interval with non-missing seizure data and then 
multiplying by 28. The double-blind rate (D) is calculated in a similar manner. The percent 
change is equal to 100*(D-B)/B. Simple partial seizures without a motor/visual component will 
not be counted. 
This value will be undefined if B=0. For the primary efficacy analysis, there will not be any 
baseline values with zero seizures. However, for the analysis of seizure sub-types, there is a 
possibility that B may be zero. In this case, B will be set to a value of 1. 
6.2.4 
Secondary Efficacy Endpoint in the United States and the Rest of the World 
The secondary efficacy endpoint to be evaluated for registration in the United States and the Rest 
of the World is the responder rate defined as a 50% or greater reduction during the double blind 
period in the seizure frequency from baseline.   The responder endpoint is a binary indicator 
endpoint defined as 1 if the primary endpoint is <= -50%, and 0 otherwise 
6.2.5 
Additional Secondary Efficacy Endpoints 
• 
Higher response rates of (defined by cutoffs of -75%, -90% and -100%) simple partial 
seizures with motor component plus complex partial seizures plus secondarily generalized tonic 
clonic seizures during the double-blind period and maintenance phase.  
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• 
Percentage change in other seizure types will be calculated in the same way as the 
primary endpoint except for selecting the specific seizure types:  
o 
Complex partial  
o 
Secondarily generalized tonic-clonic  
o 
Simple partial motor 
6.2.6 
Outcome Measurements 
6.2.6.1 
Clinical Global Impression of Change (CGIC) 
The investigator will complete the CGIC questionnaire at Visit 9 (end of maintenance or Early 
Termination if applicable) to assess the subject’s clinical status since starting study drug.  This 
assessment should take into account seizure frequency and severity, the occurrence of AEs, and 
overall functional status of the subject (Appendix G: Clinical Global Impression of Change 
(CGIC)).   
6.2.6.2 
Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) 
Subjects will complete the QOLIE-31-P at Visit 3 (end of baseline) and Visit 9 (end of 
maintenance or Early Termination if applicable) to assess their status since starting study 
drug.  Note, the QOLIE-31-P will only be completed by the subject; the caregiver will not be 
allowed to complete this questionnaire on behalf of the subject (Appendix H: Quality of Life in 
Epilepsy (QOLIE-31-P)) 
QOLIE-31-P must be completed as described in Appendix H: Quality of Life in Epilepsy 
(QOLIE-31-P). Subjects must not have had any simple motor or complex partial seizures within 
4 hours, or generalized seizures within 24 hours before administration of the scale. If subjects 
have these seizure types but have fully recovered from their seizures, the outcome scale may be 
administered to the subjects. If subjects have not fully recovered from their seizures, the outcome 
scale only will be done at an unscheduled visit after recovery from seizures. If subjects 
experience daily seizures and the visit cannot be rescheduled, the outcome scale will be omitted. 
If a subject is cognitively impaired and unable to understand the scale or if a subject is unable to 
read, the subject will be excluded from the completion of the scale.  
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This questionnaire is only to be implemented in the countries where it is available and validated 
for the spoken language(s). 
6.2.7 
Pharmacokinetic Endpoints 
Trough AED levels (oxcarbazepine [OXC], topiramate [TPM], carbamazepine [CBZ], valproate 
[VPA], lamotrigine [LTG], lacosamide (LMD) and levetiracetam (LEV) only) during the 
baseline will be compared to those during the treatment period in subjects randomized to 100, 
200, or 400 mg/day YKP3089 or placebo to determine potential drug interactions.  
6.3 
Safety Assessments 
Safety during the double-blind phase 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) in 
YKP3089-treated subjects compared to placebo-treated subjects.  
Any patient who reports a rash by telephone or is observed to have a rash should be carefully 
evaluated for a drug hypersensitivity syndrome; the evaluation should include hematology and 
chemistry blood tests. If a subject reports a rash by telephone, an unscheduled visit should be 
performed promptly.  
Adverse Events 
Adverse events (AEs) will be reported by the subject (or, when appropriate, by a caregiver, 
surrogate, or the subject’s legally acceptable representative) for the duration of the study. AEs 
will be followed by the investigator for a length of time as determined by the sponsor. Specific 
details on AE reporting are provided in Section 11. 
Clinical Laboratory Tests 
• Hematology: hemoglobin, hematocrit, white blood count with differential, RBC count, 
platelet count, and calculated indices 
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• Serum chemistry: blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, total 
bilirubin, direct bilirubin, alkaline phosphatase, aspartate transaminase (AST), alanine 
aminotransferase (ALT), albumin, 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) at Visits 1 and 10 and urine pregnancy tests 
performed at the clinical site at Visit 3 & 9 which will be confirmed by a serum pregnancy 
test if positive. 
Electrocardiogram 
Triplicate (to be performed 3 times with a minimum of 2 minutes between each recording) and 
routine 12-lead ECGs will be performed periodically during the study. 
Vital Signs 
Blood pressure and heart rate will be measured after the subject has been supine for 5 minutes 
and again after the subject has been standing for 3 minutes. Respiratory rate and oral temperature 
will be measured with the subject supine. 
Physical and Neurologic Examinations 
See Appendix A, Appendix B, and Appendix C: BRIEF Neurologic Examination. 
6.4 
Interim Analysis 
No interim analysis will be performed 
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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. 
Approximately 520 subjects will be screened to achieve a minimum of 400 subjects randomly 
assigned to study drug, 100 subjects for each dose group: placebo or 100 mg, 200 mg, or 400 mg 
YKP3089. 
7.2 
Subject Recruitment 
Subjects will be selected from the principal investigator’s and Sub-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, age 18 to 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. 
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). 
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5. Have uncontrolled partial seizures despite having been treated with at least one AED within 
approximately the last 2 years.  
6. During the 8-week baseline period, subjects must have at least 8 partial seizures including 
only simple partial seizures with motor component, complex partial seizures, or secondarily 
generalized seizures without a seizure-free interval of greater than 25 days any time during 
the 8 weeks baseline. Subjects must have at least 3 of these partial seizures during each of the 
two consecutive 4-week segments of the baseline period. 
7. Currently on stable antiepileptic treatment regimen:  
a) Subject must have been receiving stable doses of 1 to 3 AEDs for at least 4 weeks prior to 
screening (Visit 1) to be continued unchanged throughout the study 
b) Vagal nerve stimulator (VNS) will not be counted as an AED; however, the parameters 
must remain stable for at least 4 weeks prior to baseline. The VNS must have been 
implanted at least 5 months prior to Visit 1. 
c) 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. See Exclusion Criterion No. 12 for intermittent 
benzodiazepine rescue parameters.  
8. 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 randomization.  
9. Ability to reach subject by telephone. 
10. 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.  
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7.4 
Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from participating in the study: 
1. 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 
2. A history of nonepileptic or psychogenic seizures 
3. Presence of only nonmotor simple partial seizures or primary generalized epilepsies 
4. History of seizure clusters (episodes lasting less than 30 minutes in which multiple 
seizures occur with such frequency that the initiation and completion of each individual 
seizure cannot be distinguished) within 3 months prior to Visit 1 
5. Presence or previous history of Lennox-Gastaut syndrome 
6. Scheduled epilepsy surgery within 8 months after Visit 1 
7. Pregnancy or lactation 
8. Any clinically significant laboratory abnormality that in the opinion of the investigator 
would exclude the subject from the study 
9. Evidence of significant active hepatic disease. Liver transaminases (AST or ALT) above 
twice the upper limit of normal or total or direct bilirubin not within normal limits  
10. An active CNS infection, demyelinating disease, degenerative neurologic disease, or any 
CNS disease deemed to be progressive during the course of the study that may confound 
the interpretation of the study results 
11. Any clinically significant psychiatric illness, psychological, or behavioral problems that, 
in the opinion of the investigator, would interfere with the subject’s ability to participate 
in the study  
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12. Presence of psychotic disorders and/or unstable recurrent affective disorders evident by 
use of antipsychotics; presence or recent history (within 6 months) of major depressive 
episode 
13. Use of intermittent rescue benzodiazepines more than once per month (1 to 2 doses in a 
24-hour period is considered 1 rescue) in the 1 month period prior to Visit 1 
14. History of alcoholism, drug abuse, or drug addiction within the past 2 years 
15. Current use of felbamate with less than 18 months of continuous exposure 
16. Current use of diazepam, phenytoin, phenobarbital, or metabolites of these drugs (within 
1 month of Visit 1) 
17. Current or recent (within the past year) use of vigabatrin. Subjects with a prior history of 
treatment with vigabatrin must have documentation showing no evidence of a vigabatrin 
associated clinically significant abnormality in a visual perimetry test. 
18. History of status epilepticus within 3 months of Visit 1 
19. History of 1 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 
20. History of AED-associated rash that involved conjunctiva or mucosae or more than one 
maculopapular rash that required discontinuation 
21. Creatinine clearance less than 50 mL/min, as calculated by the Cockcroft-Gault equation 
22. Absolute neutrophil count less than 1500/µL 
23. Clinical or ECG evidence of serious cardiac disease, including ischemic heart disease, 
uncontrolled heart failure, and major arrhythmias, or relevant replicated changes in QT 
intervals (QTcF less than 340 msec or greater than 450 msec in males and greater than 
470 msec in females) 
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24. Platelet counts lower than 80,000/µL in subjects treated with VPA 
25. A "yes" answer to Question 1 or 2 of the C-SSRS (Baseline/Screening version) Ideation 
Section in the past 6 months or a "yes" answer to any of the Suicidal Behavior Questions 
in the past 2 years. 
26. More than 1 lifetime suicide attempt 
27. Participation in any other trials involving an investigational product or device within 30 
days of screening (or longer, as required by local regulations) 
28. Current use of any of the following medications: clopidogrel, fluvoxamine, amitriptyline, 
clomipramine, bupropion, methadone, ifosfamide, cyclophosphamide, efavirenz, or 
natural progesterone (within 1 month of Visit 1)  
29. History of positive antibody/antigen test for hepatitis B, hepatitis C, or HIV 
30. Presence of congenital short QT syndrome 
31. A history of any previous exposure to YKP3089 
Any potential exception to exclusion criteria allowing de minimis (clinically trivial and 
meaningless) variations must be approved by the medical monitor.  
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:  
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• Hormonal contraception (for at least 3 months prior to Visit 1) in combination with a barrier 
method. Note: Although synthetic progestins are acceptable, natural progesterone is not 
acceptable because of a potential drug-drug interaction with YKP3089. 
• Intrauterine device (placement at least 3 months prior to Screening visit) 
• Diaphragm with spermicide 
• Cervical cap 
• Condoms with contraceptive gel/foam or cream  
• Surgical sterilization (tubal ligation at least 6 months prior to screening or partner who has 
had vasectomy at least 6 months prior to screening) 
• Postmenopausal (as defined by absent menses for at least 12 months) 
• 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 YKP3089C017 to use contraception with partners of 
childbearing potential during their participation in the study. 
8 TREATMENTS 
8.1 
Study Medication Information 
8.1.1 
Description of Study Medication  
8.1.1.1 
Physical Description of the Drug  
Tablets of 50 mg and 100 mg of YKP3089 and placebo tablets are 10 mm in diameter, round, 
biconvex, plain-faced, brown-coated tablets that are scored on one side. All are identical in 
appearance.  
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. 
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8.1.1.3 
Packaging and Labeling 
For the double-blind phase and the blinded conversion to open-label phase, 50 mg and 100 mg 
YKP3089 and matching placebo tablets will be packaged in 2-panel blister cards—one panel for 
the label and the other for the medication. There will be 9 blister card types, one for each of the 
possible daily doses in this study: placebo, 50, 100, 150, 200, 250, 300, 350, and 400 mg. Each 
medication panel of the blister card will contain nine rows and four columns of tablets for 7 days 
of treatment plus 2 extra days for a total of 9 days. Each row will contain the same total dose.  
Picture of the medication panel of the blister card 
 
The blister card label contains information that meets applicable regulatory requirements. Every 
blister card will be randomly assigned a unique medication ID #.  
For the open-label phase, medication will be packaged in high density polyethylene (HDPE) 
bottles each containing 100 tablets of either 50 mg or 100 mg of YKP3089. 
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8.1.2 
Blinding of Study Medication 
Study medication will be both double-blind and open-label. During the double-blind phase, the 
packaging and labeling of the clinical trial medication will maintain the double-blind design of 
the trial. The treatment administered will not be known to the subjects or the study personnel at 
the clinical site. Selected individuals from the Sponsor and/or designee and at the clinical 
research organization (CRO) may be unblinded to the study treatments on a need-to-know basis 
as described in the CRO’s standard operating procedures (SOP) on blinding and unblinding. The 
study will be unblinded following database lock according to the CRO’s SOP.  
Neither the investigator nor the site staff will know the contents of the tablets administered; 
however, this information will be readily available in the event of an emergency. Investigators 
may perform emergency unblinding using the IWRS system immediately, without prior contact 
to the study’s Medical Monitor, if they feel it is medically necessary and that knowledge of the 
treatment assignment is essential for the patient’s care. If such an emergency unblinding is 
necessary, investigators should promptly document and explain to the Medical Monitor or 
Sponsor any premature unblinding of the investigational product. 
The administration of each dose of study drug or placebo will be identical. 
For the interim analysis and the data monitoring committee (DMC) reviews, only the statistician 
and statistical programmer responsible for providing the interim analysis results, key clinical 
members of the interim analysis committee, and the DMC will be unblinded to the individual 
treatment assignments. 
8.1.3 
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 (active drug or comparator) will be documented in the 
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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 
Randomization and Study Drug Distribution 
8.2.1.1 
Screening Number 
The subject will be assigned a screening number 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 number 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 
01002003. Re-screened subjects will retain their screening number and the 2 screenings will be 
differentiated by their screening dates. Only 1 re-screening will be allowed. 
In the open-label extension, the subject will retain the same screening number.  
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8.2.1.2 
Randomization Number 
The randomization number will be assigned by the IWRS using the next available randomization 
number in the randomization code list for the subject’s country. 
8.2.1.3 
Randomization Procedure 
Subjects will be assigned with equal chance to 1 of the 4 treatment groups based on a 
randomization schedule prepared by the designated statistician. The randomization will be 
balanced using permuted blocks across the 4 treatment groups. The code is computer generated 
using the plan procedure in the SAS computer program. Validation of the randomization code is 
performed by quality assurance review. After finalization, the randomization code is placed in a 
directory with no access by the clinical study team. Once database closure has been completed, a 
request for unblinding is sent to the project biostatistician, at which time the code is broken and 
disseminated to the clinical study team for statistical analysis and clinical review.  
8.2.1.4 
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 initials and subject’s date of birth). The IWRS will 
identify blinded blister cards and/or open label bottles of tablets to be dispensed appropriate to 
the phase of study. 
Prior to dispensing, the investigator will record on each blister card label the subject number, 
study week number, date dispensed, site number, visit number, phone contact, and investigator 
name. The investigator will record adjacent to Day numbers on the card itself the date on which 
each dose is to be taken. On each dispensed open label bottle, the investigator will record 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 card and bottle dispensed are populated in the system 
correctly. 
Double blind Phase  
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At Visit 3, if the subject meets the criteria for randomization, the IWRS will provide a subject 
randomization number. The system will then identify the unique medication number on each of 2 
blister cards to be dispensed to the subject. Each blister card provides a 1-week supply of 
medication plus 2 extra days supply to serve as a reserve as needed. At subsequent visits, after 
the subject information has been entered, the system will identify medication numbers for 2 
blister cards during the titration phase or four blister cards during the maintenance phase to be 
dispensed to the subject. During a double blind taper, 3 blister cards will be dispensed. 
Prior to dispensing, the investigator will record on each blister card label the subject number, 
study week number, date dispensed, site number, visit number, phone contact, and investigator 
name. The investigator will record adjacent to Day numbers on the card itself the date on which 
each dose is to be taken. In addition, the investigator will record in the electronic case report 
form (eCRF) the medication number printed on each card dispensed. 
Open-Label Extension 
If a subject enters the open-label extension, he/she will enter a blinded dose-conversion period. 
At Visit 9, during the conversion period, the subject will receive 2 blinded blister cards as 
directed by the IWRS system and an open-label bottle of YKP3089 containing one hundred 
50-mg tablets. The subject will be instructed to take medication from each blister card on dates 
specified on the card. In addition, for the first week, the subject will take two 50-mg tablet from 
the bottle. For the second week, the subject will be instructed to take four 50-mg tablets from the 
bottle. 
After the conversion period, the subject will enter the open-label treatment period and will 
receive open-label bottles containing YKP3089 (50- or 100-mg) tablets at each visit. At each 
visit, the IWRS system will be accessed to obtain bottle numbers. The returned bottles may be 
re-dispensed to the same subject after drug accountability is performed. 
Dose Adjustments 
If a tolerability issue occurs, all dosage reductions need to be made at a scheduled visit or at an 
unscheduled visit at the discretion of the investigator. At the visit, the subject must return all the 
remaining medication cards. The subject will be issued one or more replacement cards to be 
determined by interactive web response system (IWRS).    
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8.3 
Prior and Concomitant Treatments 
Subjects must be taking 1 to 3 concomitant AEDs at a stable dosage for at least 12 weeks before 
Randomization. They should continue these prescribed AED regimens unchanged throughout the 
double-blind phase of the study. To improve tolerability issues, the investigator may alter the 
timing or amount of an individual dose of a concomitant AED, but the total daily dose and 
dosing frequency of the concomitant AED must remain unchanged during the double-blind 
phase. During the open-label extension phase of the study, the investigator will be allowed to 
change the dosage of concomitant AEDs. Concomitant AEDs can be changed, but the subject 
should not be treated with YKP3089 monotherapy. Intermittent benzodiazepines (other than 
diazepam) may be taken as rescue medication once during the baseline period and twice during 
the treatment phase (2 doses in a 24-hour period is considered 1 rescue). Intermittent rescue 
medication can be used during the open-label extension. 
8.4 
Prohibited Medications or Devices 
Medication 
Not allowed 
Allowed 
• Clopidogrel, fluvoxamine, 
amitriptyline, clomipramine, 
bupropion, methadone, ifosfamide, 
cyclophosphamide, efavirenz, and 
natural progesterone 
• Diazepam, phenytoin, phenobarbital, 
or metabolites of these drugs  
During the study 
and within 30 
days prior to 
Visit 1 
If taken anytime 30 days 
before Visit 1 
• Vigabatrin  
 
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) 
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• 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 
 
• It is recommended that the study medication is taken once daily in the morning.   
• In the event of poor tolerability during double blind phase, the investigator may instruct the 
subject to take the dose of study medication in the evening 
• In the event of poor tolerability during open label phase, the investigator may instruct the 
subject to take the dose of study medication in the evening or divide the total daily dose 
into 2 doses 
• Study medication can be taken with or without food 
• Study medication must be swallowed 
9 STUDY PROCEDURES 
Visit windows of ± 2 days are allowed for Visits 1 through 6 and visit windows of ± 3 days are 
allowed for Visits 7 through 10. 
9.1 
Screening / Baseline / Randomization (Visits 1, 2 and 3) 
9.1.1 
Visit 1, Day -56 
As shown in Table 1, the following will be performed during Visit 1:  
• Obtain informed consent (obtained from the subject prior to any study-related procedures) 
• Review and record inclusion and exclusion criteria  
• Record medical and seizure history and demographics 
• Complete Diagnostic Review Form (see Section 9.1.1.1 and Appendix D) 
• Record vital signs 
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• Conduct full physical examination (see Appendix A), including height and weight 
• Conduct full neurologic examination (see Appendix B) 
• Administer C-SSRS (Baseline/Screening version) (Appendix E: COLUMBIA SUICIDE 
SEVERITY RATING SCALE (Baseline/Screening)) 
• Perform triplicate 12-lead ECG  
• Perform serum pregnancy test (female subjects of childbearing potential; if positive, subject 
will not be enrolled) 
• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• An MRI or CT scan will be performed during the baseline period if the subject has not had a 
neuroimaging study within 10 years of Visit 1. This will be used to document the absence of 
a brain lesion, and a copy of the report will be made available to the Sponsor.  
• 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. 
• Record concomitant medications 
• Dispense seizure diary 
• Schedule Visit 2 to occur in 4 weeks 
Subjects will be given a diary at each visit to record all of their seizures including the type and 
number. (see Section 9.1.1.1, Seizure Classification Review and Seizure Diary). The subject’s 
seizure diary will be collected and reviewed at each visit and a new diary will be dispensed.  
9.1.1.1 
Seizure Classification Review and Seizure Diary 
Immediately following Visit 1, the principal investigator, sub-investigator or his or her designee 
will complete the Diagnostic Review Form (see Appendix D), which will include information 
about the subject and their seizure types. After being signed by the investigator, the Diagnostic 
Review Form will then be faxed or e-mailed to the independent consulting physician group (eg, 
Epilepsy Study Consortium) and reviewed to confirm that the reported phenomena are indeed 
seizures. If corrections, clarifications, or additional information is required, the site will be asked 
to respond to the query and revise the Diagnostic Review Form. The revised Diagnostic Review 
Form will be returned to the consortium for a second review. The review process must be 
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completed and an agreement reached between the principal investigator and the independent 
consulting physician group (eg, Epilepsy Consortium) regarding seizure classification prior to 
the subject being randomized.  
Once the Diagnostic Review Form is approved, it will be signed by the consortium and returned 
to the site. The approved Diagnostic Review Form will remain in the subject’s medical chart. 
9.1.2 
Visit 2, Day −28 
As shown in Table 1, the following will be performed at Visit 2:  
• Measure vital signs 
• Review of seizure diary with the subject for completion and accuracy 
• Record Adverse Events  and use of concomitant medication 
• Dispense new seizure diary 
• Schedule a return to occur in 4 weeks for Visit 3  
9.1.3 
Visit 3, Day 1 (Randomization) 
All subjects who have not discontinued will be scheduled to appear at the clinic for Visit 3, 
which is 1 day before the start of the treatment period of the study. At Visit 3, subjects who 
continue to meet all of the inclusion criteria and none of the exclusion criteria will be randomly 
assigned to receive study drug (see Section 8.2.1.3). 
As shown in Table 1, the following will be performed at Visit 3:  
• Review seizure diary and confirm the subject meets seizure frequency criterion. 
• Record vital signs  
• Measure weight 
• Conduct brief neurologic examination  
• Administer C-SSRS (Since Last Visit version) 
• Administer Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)  
• Perform 12-lead ECG (standard) 
• Perform urine pregnancy test (for female subjects of childbearing potential) 
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• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Draw blood for concomitant AED levels (before first dose of study medication.) 
• Record concomitant medications 
• Record AEs 
• Review and record inclusion and exclusion criteria (including documentation of approved 
Diagnostic Review Form from the Epilepsy Study Consortium) 
• Randomly assign the subject to receive study drug if all of the inclusion criteria and none of 
the exclusion criteria are met 
• Dispense seizure diary 
• Dispense study drug as instructed by IWRS 
• Instruct the subject to take the first dose of the study medication 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 on the day of randomization after all other Visit 3 procedures have 
been completed. For these subjects, seizures which occur after the first dose must be counted 
and entered in to the CRF. 
• Schedule a return to occur in 2 weeks for Visit 4 
9.2 
 Double-Blind Treatment Period  
9.2.1 
Visit 4, Day 15 
As shown in Table 1, the following will be performed at Visit 4: 
• Record vital signs  
• Conduct brief neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Record concomitant medications 
• Review seizure diary 
• Perform drug accountability 
• Record AEs 
• Dispense seizure diary 
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• Dispense study drug as instructed by IWRS  
• Schedule a return to occur in 2 weeks for Visit 5  
9.2.2 
Visit 5, Day 29 
As shown in Table 1, the following will be performed at Visit 5:  
• Record vital signs  
• Measure weight 
• Conduct brief neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Record concomitant medications 
• Review of seizure diary 
• Perform drug accountability 
• Record AEs 
• Dispense seizure diary 
• Dispense study drug as instructed by IWRS 
• Schedule a return to occur in 2 weeks for Visit 6  
9.2.3 
Visit 6, Day 43  
As shown in Table 1, the following will be performed at Visit 6: 
• Record vital signs  
• Conduct brief neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Perform 12-lead ECG (standard) 
• Draw blood for laboratory safety assessment 
• Record concomitant medications 
• Review seizure diary 
• Perform drug accountability 
• Record AEs 
• Dispense seizure diary 
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• Dispense study drug as instructed by IWRS 
• Schedule a return to occur in 4 weeks for Visit 7 
9.2.4 
Visit 7, Day 71 
As shown in Table 1, the following will be assessed at Visit 7: 
• Record vital signs  
• Measure weight 
• Conduct brief neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Draw blood for YKP3089 levels. 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. 
• Draw blood for concomitant AED levels 
• Record concomitant medications 
• Review of seizure diary 
• Perform drug accountability 
• Record AEs 
• Dispense seizure diary 
• Dispense study drug as instructed by IWRS. 
• Schedule a return to occur in 4 weeks for Visit 8 
9.2.5 
Visit 8, Day 99 
As shown in Table 1, the following will be performed at Visit 8: 
• Record vital signs  
• Conduct brief neurologic exam 
• Administer C-SSRS (Since Last Visit version) 
• Draw blood for YKP3089 levels. 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. 
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• Draw blood for concomitant AED levels 
• Record concomitant medications 
• Review seizure diary 
• Perform drug accountability 
• Record AEs 
• Dispense seizure diary 
• Dispense study drug as instructed by IWRS. 
• Schedule a return to occur in 4 weeks for Visit 9 
9.2.6 
Visit 9, Day 127, End of Double-Blind Treatment Period (or Early Termination) 
For subjects who will be entering open-label extension phase, see Section 9.3 for required 
assessments and procedures.  
For subjects who will not be entering the open-label extension phase of the study (after 
completing the double-blind maintenance or terminating prematurely), the procedures to be 
followed at Visit 9 are shown in Table 1. 
At Visit 9, subjects who discontinue treatment at the end of the double-blind phase of the study 
will receive study drug for the double-blind study taper (see Section 6.1.2.3) and a new seizure 
diary. They will be scheduled to return to the clinic for the Follow-up Visit (Visit 10), 14 days 
after the last dose of study drug, which corresponds to Day 162 after the start of treatment with 
YKP3089 or placebo. 
If participation in the study is being terminated before Visit 9, the subject will undergo at the 
time of termination all of the evaluations scheduled for Visit 9. If the clinical situation warrants a 
taper period, subjects will be dispensed study drug for the double-blind study taper (see Section 
6.1.2.3). They will be scheduled to return to the clinic for the Follow-up Visit (Visit 10), 14 days 
after the last dose of study drug (see Table 1 and Section 9.2.7).  
As shown in Table 1, the following will be performed at Visit 9:  
• Record vital signs  
• Measure weight 
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• Perform full neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Administer Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)  
• Administer Clinical Global Impression of Change (CGIC) 
• Perform 12-lead ECG (standard) 
• Perform urine pregnancy test (for female subjects of child-bearing potential) 
• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Record concomitant medications 
• Review seizure diary 
• Perform drug accountability 
• Record AEs 
• Dispense seizure diary 
• Dispense study drug (taper) as instructed by IWRS 
• Schedule a return to occur in 5 weeks for Visit 10 
9.2.7 
Visit 10, Day 162 or 14 Days after Last Dose of Study Drug 
Visit 10 represents the Follow-up Visit scheduled for 14 days after the last dose of study drug for 
subjects who are discontinuing at the end of the double-blind phase of the study and for subjects 
who discontinue early. There is no Visit 10 for subjects who are entering the open-label phase of 
the study. 
At Visit 10 (or at the Follow-up Visit scheduled for 14 days after the last dose of study drug for 
subjects who discontinue early), the following will be assessed, as shown in Table 1: 
• Record vital signs 
• Measure weight 
• Perform full physical examination 
• Conduct brief neurologic examination  
• Administer C-SSRS (Since Last Visit version) 
• Serum pregnancy test (for female subjects of child-bearing potential) 
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• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Record concomitant medications 
• Review seizure diary 
• Perform drug accountability 
• Record AEs 
Visit 10 represents the end of study participation for subjects who are discontinuing after the 
double-blind phase. No study drug will be dispensed at Visit 10. For information about Visits 9 
and 11 for subjects who will continue in the open-label extension phase, see Section 9.3.  
9.3 
Open-Label Extension Phase 
The open-label extension phase begins at Visit 9, when the subjects who are to continue in the 
open-label phase start a blinded study drug conversion period (See Section 9.3.1) instead of the 
blinded study drug taper that is intended for subjects who are discontinuing after the 
double-blind treatment period (see 9.2.6).  
Visit windows of ± 3 days are allowed for visits 9 and end of study Follow-up Visit, visit 
windows of ± 2 days are allowed for visits 11 and 12, and visit windows of ± 7 days are allowed 
for all other open-label visits. 
9.3.1 
Visit 9, Day 127: Open-Label Phase 
All subjects who have not discontinued and plan to enter the open-label phase of the study will 
undergo Visit 9 assessments as shown in Table 2: 
• Review and record inclusion/exclusion criteria (the same as for the double-blind phase except 
for seizure frequency) 
• Record vital signs 
• Measure weight 
• Conduct full physical examination 
• Conduct full neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
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• Perform 12-lead ECG 
• Perform urine pregnancy test (for female subjects of childbearing potential) 
• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Record concomitant medication 
• Review seizure diary 
• Perform drug accountability 
• Review AEs 
• Dispense seizure diary 
• Dispense study drug (double-blind blister card and open-label bottle) as instructed by IWRS. 
• Schedule a return to occur in 2 weeks for Visit 11. Note: There is no Visit 10 for subjects 
who have not discontinued and who enter the open-label phase of the study. 
9.3.2 
Visit 11, Day 141 
The initial target dose for the open-label extension will be 300 mg once daily. The dose of 
YKP3089 may be reduced to a minimum of 50 mg once daily or increased to a maximum of 400 
mg once daily by 100-mg or 50-mg increments. 
As shown in Table 2, the following will be assessed at Visit 11: 
• Record vital signs 
• Conduct brief neurologic examination  
• Administer C-SSRS (Since Last Visit version) 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary 
• Dispense seizure diary 
• Dispense open-label study drug bottles as instructed by IWRS 
• Schedule a return to occur in 2 weeks for Visit 12 
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At this point, the subjects will have finished the blinded conversion from the double-blind 
regimen and will be using an open-label regimen. Starting at this visit, changes to the subject’s 
concomitant AED regimen are permitted. 
9.3.3 
Visit 12: Day 155  
As shown in Table 2, the following will be assessed at Visit 12: 
• Record vital signs 
• Administer C-SSRS (Since Last Visit version) 
• Perform 12-lead ECG  
• Perform urine pregnancy test (for female subjects of childbearing potential) 
• Draw blood for laboratory safety assessment 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary 
• Dispense seizure diary 
• Dispense open-label study drug bottles as instructed by IWRS 
• Schedule a return to occur in 12 weeks for Visit 13 
9.3.4 
Visit 13, Day 239 
As shown in Table 2, the following assessments will be performed at Visit 13: 
• Record vital signs 
• Measure weight 
• Conduct brief neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary 
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• Dispense seizure diary 
• Dispense open-label study drug bottles as instructed by IWRS 
• Schedule a return to occur in 12 weeks for Visit 14 
9.3.5 
Visit 14, Day 323 
As shown in Table 2, the following assessments will be performed at Visit 14: 
• Record vital signs 
• Administer C-SSRS (Since Last Visit version) 
• Perform urine pregnancy test (for female subjects of childbearing potential) 
• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary 
• Dispense seizure diary 
• Dispense open-label study drug bottles as instructed by IWRS 
• Schedule a return to occur in 12 weeks for Visit 15 
9.3.6 
Visit 15, Day 407 
As shown in Table 2, the following assessments will be made at Visit 15: 
• Record vital signs 
• Measure weight 
• Conduct brief neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary 
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• Dispense seizure diary 
• Dispense open-label study drug bottles as instructed by IWRS 
• Schedule a return to occur in 12 weeks for Visit 16 
9.3.7 
Visit 16, Day 491, or Termination from Open-Label Phase—Taper Visit 
As shown in Table 2, the following will be performed at Visit 16 or at the time of early 
termination from the open-label phase. 
At Visit 16, if clinically indicated, the subjects will begin the study drug taper described in 
Section 6.1.4.3. At the end of this drug taper, the subject will have discontinued YKP3089. The 
following assessments will be made at Visit 16: 
• Record vital signs 
• Measure weight 
• Conduct full physical examination 
• Conduct full neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Perform 12-lead ECG 
• Perform urine pregnancy test (for female subjects of childbearing potential) 
• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary  
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: 
• Dispense open-label medication  
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• Dispense seizure diary 
• Schedule a return to occur in 3 months for next visit 
• See section 9.3.9 for further instructions 
For subjects leaving the open-label treatment due to any reasons at any time before 1 year or 
leaving at Visit 16 due to no benefit or any reasons: 
• Dispense taper open-label study drug bottles as instructed by IWRS if needed 
• Schedule a return to occur in 2 weeks of the last dose for Visit 17 if tapered 
• Schedule a return to occur in 2 weeks for Visit 17 if not tapered 
9.3.8 
Visit 17, End of Study Follow-up (14 days from the last dose) 
Visit 17 represents the Follow-up Visit after discontinuation of study drug in the open-label 
extension phase. 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 2, the following assessments will be performed at Visit 17: 
• Record vital signs  
• Measure weight 
• Conduct full neurologic examination 
• Administer C-SSRS (Since Last Visit version) 
• Serum pregnancy test (for female subjects of child-bearing potential) 
• Draw blood for laboratory safety assessment 
• Obtain urine for urinalysis 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
No study drug will be dispensed. 
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9.3.9 
Open-Label Extension Beyond Year One 
Subjects who complete Visit 16 and will continue in the open-label extension 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 16 
• Record vital signs  
• Administer C-SSRS (Since Last Visit version) 
• Record concomitant medications 
• Perform drug accountability 
• Record AEs 
• Review seizure diary  
• Dispense open-label study drug bottles as instructed by IWRS 
Perform the following every 6 months from Visit 16 
• Measure weight  
• Conduct brief neurologic examination  
• Perform urine pregnancy test (for female subjects of childbearing potential) 
• Draw blood for laboratory safety assessment 
Perform the following every 12 months from Visit 16 
• Perform full physical exam 
• Perform 12-lead ECG  
• 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.  
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After the first year of open-label treatment, the visits will be numbered sequentially beginning 
with Visit 18.  
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 16. This visit will be assigned the next sequential number. After 
this visit, the subject will be scheduled to return for Visit 17 (end-of-study follow-up, 14 days 
after the last dose of study medication).  
9.4 
Unscheduled Visit/Telephone Contact 
Subjects will be contacted by phone on Days 8, 22 and 36 to assess tolerability and the 
occurrence of any early treatment-emergent adverse events and to reinforce compliance.  
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. 
9.5 
Clinical Laboratory & Pharmacokinetic Evaluations  
Clinical laboratory evaluations will be performed at Visits 1, 3, 6, 9, 10, 12, 14, 16, and 17 and 
every 6 months afterwards or at any time during the study as deemed necessary by the 
investigator to assess potential health issues or AEs. Samples will be collected at Visits 1, 3, 9, 
10, 14, 16 and 17 and every 12 months afterwards for urinalysis. Female subjects (of 
childbearing potential) will undergo a serum ß-hCG pregnancy test at Visits 1 and 10 and a urine 
ß-hCG pregnancy test at Visits 3 and 9 or at any time pregnancy is suspected.  Additionally, 
blood samples will be drawn to determine plasma levels of concomitant AED (OXC, TPM, CBZ, 
VPA, LTG, LMD and LEV only) prior to study drug administration (Visit 3) and during steady-
state concomitant treatment with YKP3089 (Visits 7 and 8). At Visits 7 and 8, additional blood 
samples (~8 mL each) 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. Additional blood samples may be drawn 
for levels of concomitant AEDs during the double-blind treatment phase if the investigator 
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believes that symptoms of toxicity may be related to concomitant AEDs, rather than the study 
drug, and during the open-label extension phase for any reason; these samples will be analyzed 
by the local laboratory. 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 CRF. 
All safety laboratory samples will be analyzed by a central laboratory. 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. 
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: 
• Results in study withdrawal 
• Is associated with an SAE 
• Is associated with clinical signs or symptoms 
• Leads to additional treatment or to further diagnostic tests 
• 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: 
• Fatal 
• Life-threatening 
• Requires or prolongs hospital stay 
• Results in persistent or significant disability or incapacity 
• A congenital anomaly or birth defect 
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• 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 to the end of the study treatment follow-up, which for this 
study is 21 days. For this study, the AE reporting period is defined as 30 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. 
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10.2 
General Physical Examination Findings 
At Screening and prior to Visit 3, 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: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality. 
• The abnormality suggests a disease and/or organ toxicity. 
• 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). 
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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: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition. Surgery should not be reported as an outcome of an AE if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• 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. 
• An Emergency Room visit is not considered hospitalization. 
10.3 
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 
• Distinct temporal relationship with drug treatment 
• Known reaction to agent or chemical group, or predicted by known 
pharmacology 
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• Event cannot be explained by subject’s clinical state or other factors 
Probable 
• Reasonable temporal relationship with drug treatment 
• Likely to be known reaction to agent or chemical group, or predicted by 
known pharmacology 
• Event cannot easily be explained by subject’s clinical state or other factors 
Possible 
• Reasonable temporal relationship with drug treatment 
• Event could be explained by subject’s clinical state or other factors 
Remote 
• Poor temporal relationship with drug treatment 
• Event easily explained by subject’s clinical state or other factors 
Unrelated 
• Event occurring before dosing 
• Event or intercurrent illness due wholly to factors other than drug treatment 
The following definitions for rating severity will be used: 
• Mild: The AE is easily tolerated and does not interfere with daily activity. 
• Moderate:  The AE interferes with daily activity, but the subject is still able to function. 
• Severe: The AE is incapacitating and requires medical intervention. 
10.4 
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 CRF. All 
clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded in 
the source document, though they should be grouped under one diagnosis. 
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 
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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. 
10.4.1 
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 PPD 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 fax 
to SKLSI’s designee PPD within one business day 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 faxed to SKLSI’s designee PPD within 
one business day 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 PPD within one 
business day of receipt of new/updated information.  The SAE Reporting Requirements and 
contact information are outlined in Table 7. 
Seizures in this refractory subject population are anticipated with the weekly seizure frequency 
used as a primary study endpoint.  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 7. Serious Adverse Event Reporting Requirements 
 
Type of SAE 
Reporting 
Time 
Frame 
Reporting 
Method 
Telephone Number, 
Fax Number, or e-mail address 
All SAEs 
Within 24 
hours of 
awareness 
Fax or  
E-mail* 
+ 44 1223 374102 (North America and Rest of 
world)  EMEAASIASafetyCentral.SM@europe.ppdi.com 
Fatal or  
Life-
Threatening 
Immediate 
Telephone + 44 1223 374240 (North America and Rest of 
world) 
Within 24 
hours of 
awareness 
Fax or E-
mail* 
+ 44 1223 374102 (North America and Rest of 
world) EMEAASIASafetyCentral.SM@europe.ppdi.com 
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Urgent safety 
concerns 
requiring a 
medical 
monitor 
As Needed 
Telephone + 1-888-483-7729 (North America) 
+ 44 1223 374240 (Rest of world) 
 
* The SAE report form must be used for reporting. 
At the time of the initial report, the investigator should provide as much of the following 
information as possible: 
• Study identifier 
• Study center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status  
• Whether study treatment was discontinued 
• The reason why the event is classified as serious 
• 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. 
10.4.2 
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. 
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10.4.3 
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. 
10.5 
Withdrawal of Subject from Study  
Subjects may be withdrawn from the study prior to completion of the study if: 
• Consent is withdrawn by the subject 
• The subject fails to adhere to the protocol requirements 
• An intolerable AE is experienced 
• The subject becomes pregnant 
• 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. 
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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: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• 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. 
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; 
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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 discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the Sponsor. If it becomes necessary 
for the Sponsor or the appropriate regulatory authority to review any documentation relating to 
this study, the investigator must permit access to such reports. 
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The following records are considered essential documents:  
• Signed informed consent documents for all subjects 
• Subject identification code list, Screening log (if applicable), and enrollment log 
• Record of all communications between the investigator and the IRB/IEC 
• Composition of the IRB/IEC or other applicable statement  
• Record of all communications between the investigator and Sponsor (or CRO) 
• List of sub-investigators and other appropriately qualified persons to whom the investigator 
has delegated significant trial-related duties, together with their roles in the study and their 
signatures 
• Compact Disks (CDs) of eCRFs and related documentation of corrections for all subjects 
• Drug accountability records 
• Record of any body fluids or tissue samples retained 
• All other source documents (subject records, hospital records, laboratory records, etc) 
• All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) and any applicable country 
requirements. 
12 STATISTICAL METHODS AND PLANNED ANALYSES  
12.1 
Sample size estimation 
A sample size of 100 subjects per treatment group will provide 80% power to detect a difference 
of 16% in median percent reduction in seizure frequency between an active dosage group and 
placebo group, at a 2-sided significance level of 0.05, assuming a standard deviation of 40%.  
12.2 
Statistical Methods 
Summary statistics and analyses will be presented by the treatment group category assigned to 
the subject regardless of the dosage of drug administered.  Categorical variables will be 
summarized as frequencies and percentages. Descriptive statistics for continuous variables will 
include sample size, mean, median, standard deviation, and minimum and maximum values. 
SAS® version 9.2 or later will be used for all data summaries, statistical analyses, and data 
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listings. Inferential statistical tests will be 2-sided and will employ a tolerance for type I error 
(alpha, α) of 0.05. Data will be used as collected. Full details of the analysis plan will be 
included in the Statistical Analysis Plan (SAP) and finalized prior to any un-blinding of efficacy 
data. 
Analyses of Missing Data 
The primary efficacy endpoint definition in the United States and Rest of the world states that 
seizure rates will be calculated using days with non-missing seizure data.  The definition does 
not explicitly account for days with missing data, i.e., days during which the presence or absence 
of seizures was not recorded in personal diaries.  However the definition implicitly accounts for 
missing data in that it is identical to a definition in which days with missing data are assumed to 
have the same seizure rate as days with non-missing data.    
Similar to the United States definition of the primary efficacy endpoint, the primary endpoint 
(responder) definition in the countries of Europe, Australia, New Zealand and South Africa 
implicitly accounts for missing data during maintenance phase in that it is identical to a 
definition in which days with missing data are assumed to have the same seizure rate as days 
with non-missing data. An additional analysis will be performed in which subjects who dropped 
out during the titration phase will be included in the analysis by having their maintenance phase 
data imputed using the available titration data. 
The same approach will be used for missing data in the analysis of all secondary efficacy end 
points.  
12.3 
Analysis Data Sets 
For all populations, subjects will be analyzed according to the target (randomized) dosage group 
including subjects who fail to achieve the target dosage during the titration phase. 
Enrolled subjects: All subjects who have given informed consent to participate in this study will 
be considered enrolled subjects. 
Intention-to-treat (ITT): All randomized subjects will be considered intention-to-treat subjects.  
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Modified intention-to-treat (MITT) subjects: All randomized subjects who have taken at least one 
dose of YKP3089 (or placebo) and have any post-baseline seizure data will be considered 
modified intention-to-treat subjects.  
Modified intention-to-treat (MITT-M) subjects in Maintenance phase: All randomized subjects 
who have completed the titration phase and have taken at least one dose of YKP3089 (or 
placebo) in the maintenance phase and have any maintenance phase seizure data will be 
considered modified intention-to-treat subjects in the maintenance phase.  
Per protocol population (PP): All randomized subjects who have no major protocol violations 
and have at least 80% drug compliance will be considered per-protocol subjects. 
Safety evaluable subjects (SE): All ITT subjects. 
12.4 
Baseline Comparability  
All demographic measurements (age, gender, height, and weight) and all safety measurements 
(ECGs, vital signs, and clinical laboratory values) will be summarized by dose level.  
12.5 
Primary Efficacy Analyses  
12.5.1 
Primary Efficacy Analysis in the United States and the Rest of the World: 
The primary efficacy analysis of the primary endpoint will be based on the MITT population. 
The testing strategy for the primary efficacy endpoint (percent change in seizure frequency) is to 
compare each of the YKP3089 dosage groups with the placebo group.  Due to multiple treatment 
comparisons, a step-down procedure will be used to ensure the overall type I error rate is 
controlled at the 5% level. Each of the YKP3089 dosage groups will be compared with the 
placebo group according to the following hierarchy: 
1. 
200-mg dosage group versus placebo group 
2. 
400-mg dosage group versus placebo group 
3. 
100-mg dosage group versus placebo group 
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The 200-mg dosage group will be compared with the placebo group at a 2-sided 0.05 level as the 
first step. If no statistically significant difference is detected between the 200-mg dosage group 
and the placebo group, the procedure will stop and it will be concluded that none of the 
YKP3089 dosages are efficacious. If a statistically significant difference is detected between the 
200-mg dosage group and the placebo group in favor of the 200-mg dosage group, the procedure 
will proceed to the next step to compare the 400-mg dosage group with the placebo group at a 2-
sided 0.05 level. If a statistically significant difference is detected between the 400-mg dosage 
group and the placebo group in favor of the 400-mg dosage group, the procedure will proceed to 
the next step to compare the 100-mg dosage group with the placebo group at a 2-sided 0.05 level.  
An analysis of covariance (ANCOVA) model will be fit to the ranked values of the primary 
efficacy endpoint. The ANCOVA will have terms for ranked baseline seizure rate and 
randomized treatment group. Ties will be handled using the default option in SAS    
It should be noted that the primary efficacy analysis uses a non-parametric approach. Because of 
this, effect sizes are not estimated and tested directly, since testing is made on the rank of the 
primary efficacy value. However, summary tables for the actual (not the ranked) primary 
efficacy endpoint will be presented.   
Descriptive results of the primary efficacy end point will be provided for the subjects who were 
titrated under the original protocol.   
12.5.2 
Primary Efficacy Analyses in the countries of Europe, Australia, New Zealand, and 
South Africa 
The primary efficacy analysis of the primary endpoint will be based on the MITT-M population.   
The testing strategy for the primary efficacy endpoint (responder rate) is to compare each of the 
YKP3089 dosage groups with the placebo group. A step-down procedure will be used to ensure 
the type I error rate due to multiple treatment comparisons is controlled at the 5% level. Each of 
the YKP3089 dosage groups will be compared with the placebo group according to the following 
hierarchy: 
1. 
200-mg dosage group versus placebo group 
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2. 
400-mg dosage group versus placebo group 
3. 
100-mg dosage group versus placebo group 
The 200-mg dosage group will be compared with the placebo group at a 2-sided 0.05 level as the 
first step. If no statistically significant difference is detected between the 200-mg dosage group 
and the placebo group, the procedure will stop and it will be concluded that none of the 
YKP3089 dosages are efficacious. If a statistically significant difference is detected between the 
200-mg dosage group and the placebo group in favor of the 200-mg dosage group, the procedure 
will proceed to the next step to compare the 400-mg dosage group with the placebo group at a 2-
sided 0.05 level. If a statistically significant difference is detected between the 400-mg dosage 
group and the placebo group in favor of the 400-mg dosage group, the procedure will proceed to 
the next step to compare the 100-mg dosage group with the placebo group at a 2-sided 0.05 level.  
The data will be summarized using frequencies and percents of subjects achieving at least a 50% 
response to treatment, the responder rate. The responder data will be analyzed using a chi-square 
test.   
12.6 
Secondary Efficacy Analyses  
12.6.1 
Secondary Efficacy Analysis in the countries of Europe, Australia, New Zealand, 
and South Africa 
The secondary efficacy analysis will be based on the MITT-M population. 
The secondary efficacy analysis is to compare each of the YKP3089 dosage groups with the 
placebo group for the percent reduction in seizure frequency.  
An analysis of covariance (ANCOVA) model will be fit to the ranked values of the change in 
seizure frequency during the maintenance phase. The ANCOVA will have terms for ranked 
baseline seizure rate and randomized treatment group. Ties will be handled using the default 
option in SAS.  
It should be noted that the efficacy analysis uses a non-parametric approach. Because of this, 
effect sizes are not estimated and tested directly, since testing is made on the rank of the change 
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in seizure frequency. However, summary tables for the actual (not the ranked) change in seizure 
frequency will be presented.   
12.6.2 
Secondary Efficacy Analysis in the United States and the Rest of the World 
The secondary efficacy analysis will be based on the MITT population 
The secondary efficacy analysis is to compare each of the YKP3089 dosage groups with the 
placebo group for the responder rate.  
The data will be summarized using frequencies and percents of subjects achieving at least a 50% 
response to treatment, the responder rate. The responder data will be analyzed using a chi-square 
test. 
12.7 
Additional Secondary Efficacy Analyses 
 
These secondary efficacy analyses will be based on the MITT or MITT-M population 
• Higher response rate of (75, 90 and 100%) of simple partial seizures with motor 
component plus complex partial seizures plus secondarily generalized tonic clonic 
seizures during the double-blind period and maintenance phase will be summarized.  
• Median percent change for partial seizure subtypes (including simple partial with motor 
component, complex partial, and secondarily generalized tonic-clonic seizures) will be 
summarized.   
• Seizure rate over time  will be analyzed using following scheme 
o A moving average for each dose group will be computed using 4 week periods with 2 
week overlap beginning from Visit 3 (V3-V5, V4-V6, V5-V6+2 weeks and so on) 
• For the QOLIE-31 analysis, changes from baseline (Visit 3) to the the final value 
(defined as the last observation obtained in the double-blind phase) (Visit 9) for each 
treatment group will be summarized using descriptive statistics. Differences between 
each treatment group and the placebo group in the change from baseline will also be 
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summarized using descriptive statistics. The minimally important change (MIC) was 
defined as a change from baseline ≥11.8 at the End Point for the weighted overall 
QOLIE-31 score. The incidence of subjects meeting the MIC criteria will be summarized 
by treatment group. 
• CGIC will be summarized using descriptive statistics for each treatment group and the 
placebo group. 
 
12.8 
Safety Variable Analyses 
All ITT subjects will be evaluable for safety. The number and percent of subjects reporting AEs 
(including treatment-emergent laboratory abnormalities) will be tabulated by randomized 
treatment group. 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), ECGs, and C-SSRS will be summarized using descriptive statistics. 
12.9 
Pharmacokinetic Analysis 
Individual plasma concentrations of YKP3089 will be tabulated with the corresponding time 
related to study drug administration by dose group.  
Descriptive statistical analyses will be performed on the plasma concentrations of the YKP3089 
obtained during steady-state treatment (Visit 7 and 8) 
Descriptive statistical analyses will be performed on the plasma concentrations of the 
concomitant AEDs obtained during steady-state concomitant treatment (Visit 7 and 8) and those 
at baseline (Visit 3) to assess the effect of YKP3089 on these AEDs. 
12.10 Open-Label Extension Analyses 
The results of the open-label extension will be reported at a later date using summary tables, 
figures, and data listings.  
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12.11 Interim Analysis 
No interim analysis will be performed 
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. 
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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 Institutional Review Board, 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. 
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13.7.2 
Data Monitoring Committee 
The safety of subjects in the study will be monitored by an independent Data Monitoring 
Committee (DMC). The mandate of the DMC is to provide an independent review of the safety 
of YKP3089 in subjects with chronic partial seizures.  
The DMC will be composed of an unblinded biostatistician and 3 physicians. All members of the 
DMC will be experienced in the clinical trials process and in the assessment of safety data from 
clinical trials.  
The DMC will have access to all unblinded safety data. The DMC will perform the following 
reviews:  
1. 
Review of the safety of the first 40 subjects completing titration. 
2. 
Review of the safety of the first 80 subjects completing titration. 
3. 
Review of the safety of the first 120 subjects completing double-blind phase. 
4. 
Review of the safety of the first 240 subjects completing double-blind phase. 
These specified reviews are to occur after dose escalation or study completion. The primary data 
to be reviewed should be adverse events, but all safety data will be made available for review. 
After completing the review the DMC Chair will prepare a brief report. The DMC can perform 
other reviews whenever it believes that a review would be informative regarding patient safety. 
The DMC will not review efficacy data.  
The DMC will have a teleconference with the sponsor after each of the above specified 
milestones. The DMC can schedule a teleconference with the sponsor whenever the DMC 
identifies a safety issue. The DMC will be granted the authority, after discussion with the 
sponsor, of restricting dose escalation, adding safety assessments or halting the study temporarily 
or permanently. 
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13.7.3 
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.  
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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: 
________________ 
 
 
 
 
 
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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 
 
 
 
 
 
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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 
 
 
 
 
 
 
 
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APPENDIX D: DIAGNOSTIC REVIEW FORM 
   
 
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APPENDIX E: COLUMBIA SUICIDE SEVERITY RATING SCALE (BASELINE/SCREENING) 
 
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APPENDIX F: COLUMBIA SUICIDE SEVERITY RATING SCALE (SINCE LAST VISIT) 
  
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APPENDIX G: CLINICAL GLOBAL IMPRESSION OF CHANGE (CGIC) 
 
 
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APPENDIX H: QUALITY OF LIFE IN EPILEPSY (QOLIE-31-P)  
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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.  
5. Kwan P, Brodie MJ. Early identification of intractable epilepsy. N Engl J Med 2000;342:314-
319 
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