Conditions: Partial Onset Seizures
Keywords: Partial Onset Seizures Epilepsy Safety Efficacy Tolerability Pregabalin Lyrica Adjunctive treatment Placebo controlled blinded Eligibility Criteria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 175
Healthy volunteers: no

Brief summary:
This study is designed to evaluate the effectiveness of 2 doses of pregabalin to reduce seizure frequency as an add on therapy in pediatric subjects 1 month to \<4 years of age with refractory partial onset seizures. It is hypothesized that both doses of pregabalin will demonstrate superior efficacy when compared to placebo by reducing the partial onset seizure frequency and that pregabalin will be safe and well tolerated.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Pregabalin Dose Level 1 intervention 2: Pregabalin Dose Level 2 intervention 3: Placebo
Intervention descriptions: intervention 1: Pregabalin liquid dosed daily three times a day in equally divided doses escalated to 7.0 mg/kg/day beginning at Randomization through Taper Phase then tapered to 3.5 mg/kg/day during 1 week Taper Phase intervention 2: Pregabalin liquid dosed daily three times a day in equally divided doses escalated to 14.0 mg/kg/day beginning at Randomization through Taper Phase then tapered to 3.5 mg/kg/day during 1 week Taper Phase intervention 3: Placebo Liquid dosed three times daily beginning at Randomization through Taper Phase

Protocol document:
Prot_001.pdf: 
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Final Protocol Amendment 1, 15 December 2017
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CLINICAL PROTOCOL
A DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, 
MULTICENTER STUDY OF THE EFFICACY AND SAFETY OF PREGABALIN AS
ADJUNCTIVE THERAPY IN CHILDREN 1 MONTH THROUGH <4 YEARS OF 
AGE WITH PARTIAL ONSET SEIZURES 
Compound:
PD-144723
Compound Name:
Pregabalin
US IND Number:
49393
European Clinical Trial Database 
(EudraCT) Number (if applicable):
2013-003420-37
Protocol Number:
A0081042
Phase:
3
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Document History
Document
Version Date
Summary of Changes
Final Protocol
30 December
2013
Not applicable
Amendment 1
(Region specific –
Asia, Europe, 
Middle East, South 
America)
15 December
2017
This is a non-substantial protocol amendment. 
This protocol amendment clarifies the study 
protocol with regards to the change in the 
constant term in the transformation of seizure rate 
and the sample size decision rules. The changes 
outlined below are made to the Protocol 
Summary and Sections 2.2, 3, 7.2.1, 9.1, and 
9.2.1. in all relevant parts of this document except 
where noted for historical accuracy. 
1. The transformation for the primary endpoint 
analysis is superseded in the protocol by the 
following: loge (24-hour seizure rate +1 where 
the revision is to the constant term, to address 
any circumstances of zero seizure rates, which 
is changed from “+1/28” to “+1”. The revised 
term provided better approximation of normal 
distribution of the seizure data based on 
blinded data distribution. The constant “1/28” 
added variability to the data and decreased its 
normality. Therefore, in agreement with the 
FDA, the constant has been revised from 
“1/28” loge (24-hour seizure rate +1/28) to 
“1” (loge (24-hour seizure rate +1). 
2. The decision rules for the blinded sample size 
re-estimation were clarified as follows: 
a.
If the recalculated sample size is less than 
or equal to the original sample size of 
123 subjects total, then the sample size 
will not be adjusted.
b. If the recalculated sample size is greater 
than the original sample size (123 subjects 
total) then the following information will 
be considered:
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
If the re-estimated sample size is 
between 123 and 150, then the sample 
size will be adjusted to the 
re-estimated sample size.

If the re-estimated sample size 
exceeds 150 then it will be increased 
to a sample size of 150 (as agreed with 
the US FDA). 
The blinded sample size re-estimation was 
conducted, and the sample size will be increased 
to approximately 150 subjects.
The US FDA agreed with these two clarifications 
and that a protocol amendment would not be 
required. For other regions, these changes are 
made consistent with the European Medicines 
Agency’s Committee for Medicinal Products for 
Human Use (CHMP) guidance.
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PROTOCOL SUMMARY
Indication:
Adjunctive therapy for children 1 month (44 weeks gestational age) through <4 years of age 
inclusive with partial onset seizures with or without secondary generalization.
Background and Rationale:
Epilepsy is a common disorder in childhood affecting 4 to 5 of every 1000 children.  
Although epilepsy is often well controlled with existing antiepileptic drug (AED) therapy, 
more than 25% of pediatric patients have seizures that are uncontrolled by currently available 
agents, or have adverse effects related to AEDs that complicate management of their 
seizures.  In addition, children with epilepsy often suffer from impaired academic 
performance, with 55% functioning below their grade level and an additional 
16% significantly behind in educational training.1  Children with epilepsy also have a higher 
likelihood of developing behavioral difficulties, which may persist into adulthood.2 Early 
age of onset and a higher number of total lifetime seizures are the strongest correlates of 
academic underachievement.  Therefore, the availability of a new AED that has been shown 
to improve seizure control, and that is well tolerated, is needed.
Pregabalin is approved in more than 100 countries, with indications summarized below for 
the United States (US), European Union (EU), and Japan (JP).  In the US, pregabalin is 
indicated for the adjunctive therapy for adult patients with partial onset seizures.  In addition, 
pregabalin is indicated for the management of neuropathic pain associated with diabetic 
peripheral neuropathy, post herpetic neuralgia, and fibromyalgia and neuropathic pain 
associated with spinal cord injury.  In the EU, pregabalin is indicated as adjunctive therapy in 
adults with partial seizures with or without secondary generalization. In addition, pregabalin 
is indicated for the treatment of peripheral and central neuropathic pain in adults and for 
generalized anxiety disorder in adults. In Japan, pregabalin is indicated for the treatment of 
peripheral neuropathic pain and fibromyalgia. The approved dose range for the adjunctive 
treatment of partial onset seizures in adults is 150 to 600 mg/day, administered twice daily 
(BID) or 3 times daily (TID).  The most common adverse effects reported with pregabalin in 
placebo controlled adjunctive trials in adults with partial onset seizures were dizziness 
(32%) and somnolence (22%). Since initial market approval of Lyricain 2004 through the 
first quarter of 2012, it is estimated that more than 15,900,000 patient years of exposure have
accumulated worldwide.
This study is one of several studies that will be conducted to assess the safety and efficacy of 
pregabalin in pediatric subjects with epilepsy and to address post approval commitments to 
US and EU regulatory authorities.
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Objectives:
Primary Efficacy Objective

The primary objective of this study is to evaluate the efficacy of two dose levels of 
pregabalin compared to placebo as an adjunctive treatment in reducing the frequency 
of partial onset seizures in pediatric subjects 1 month through <4 years of age.
Secondary Efficacy Objective

To evaluate the efficacy of pregabalin compared with placebo on the frequency of 
partial onset seizures as determined by responder rate in pediatric subjects 1 month 
through <4 years of age.

To assess the safety and tolerability of pregabalin in pediatric subjects 1 month 
through <4 years of age with partial onset seizures. 
Study Design:
Study A0081042 is a double-blind, placebo controlled, randomized, parallel group, 
multicenter study to evaluate the efficacy of two dose levels of pregabalin compared to 
placebo administered TID as adjunctive therapy in pediatric subjects 1 month (44 weeks 
gestational age) to <4 years of age with partial onset seizures with or without secondary 
generalization.
Randomization will be stratified by subject age (Stratum 1: <1 year of age; 
Stratum 2: 1-2 years of age; Stratum 3: >2 years of age). Subjects in each age stratum within 
site will be randomized to either placebo or 1 of 2 fixed doses of pregabalin divided TID, 
Dose Level 1: pregabalin 7 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age] or 
Dose Level 2: pregabalin 14 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age] in a 
2:2:1 ratio. Every reasonable effort will be made to enroll a minimum of 10 subjects in each 
of the 3 age strata.
The study is composed of 4 phases: 

Video-Electroencephalographic (EEG) baseline phase with a target minimum of 
48 hours. To ensure that the target minimum of 48 hours of Video-EEG is obtained, 
the total duration of the Video-EEG baseline phase will be up to 72 hours.

5 day double-blind dose escalation phase.

9 day double-blind fixed dose treatment phase, which includes a Video-EEG 
evaluation over the final 3 days at the end of this 9-day phase with a target minimum 
of 48 hours and a total recording duration of up to 72 hours. For subjects who 
successfully complete the target 48 hour Video-EEG or must terminate the 
Video-EEG recording before the end of this 9-day phase, fixed dosing will continue 
until beginning the taper phase.
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
7 day double-blind taper phase.
The total double-blind treatment phase is 21 days.
Every reasonable attempt should be made to obtain the minimum target Video-EEG 
recording of 48 hours, which may require up to 72-hours to obtain. Recognizing the inherent 
challenges in Video-EEG monitoring of pediatric subjects with epilepsy it is expected that 
the target minimum 48 hour Video-EEG recording may not be achievable in all cases. In the 
clinical investigator’s opinion, should circumstances (eg, clinical care, child behavior, 
consent, etc.) mandate a Video-EEG monitoring period less than 48-hours for a given 
subject, please contact the study clinician to review the subject’s clinical circumstances and 
document reasons for not achieving the target minimum duration. 
Subjects who complete the treatment phases of this study through Visit 7 and enter the 
double-blind taper phase will be eligible for screening into Protocol A0081106, a 1-year open 
label safety study (Please refer to 1.5 Study A0081106: 1-Year Open Label Safety Study of 
Pregabalin for more details). Subjects who participated in study A0081042 through Visit 7
will be considered to have completed the study.
In certain instances subjects who require withdrawal from this study may still be eligible for 
screening and entry into the long term safety study A0081106.  Subjects who do not meet the 
inclusion criteria of at least 2 partial seizure during the 48 hour baseline Video-EEG may still 
be eligible for screening for A0081106.  Subjects who have completed the dose escalation 
phase and received at least one dose during the fixed-dose phase may also be eligible for 
screening for Protocol A0081106. For example, subjects who withdrew due to poor 
tolerability or lack of efficacy may be considered.  Such cases should be reviewed with the 
Pfizer study clinician to determine further eligibility.
Endpoints:
Primary Efficacy Endpoint

The primary endpoint will be the log transformed double blind 24 hr seizure rate for 
all partial onset seizures collected at Visit 6 (48 hour Video-EEG assessment phase) 
during the double blind phase as determined by the central reader.  This 24-hour
seizure rate will be calculated as follows for the double-blind phase:
24
monitoring
EEG
-
Video
of
hours
of
#
phase
assessment
hr
-
48
blind
double
in
seizures
of
#
rate
seizure
EEG
hr
-
24
Blind
Double


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
When the log-transformation is used, the quantity 1 is added to the double-blind 24-hr 
EEG seizure rate for all subjects to account for any possible "0" seizure incidence.  
This will result in the following primary efficacy measure: loge (double blind 24-hr 
EEG seizure rate + 1).  Results will be reported as “percent change in seizures” 
relative to placebo. For example, a difference between one of the pregabalin doses 
and placebo of -0.400 on the log transformed scale for the double blind 24-hr seizure 
rate, corresponding to a 33% reduction in the double-blind 24-hour EEG seizure rate 
of the pregabalin group from the placebo group (ie, 100%*[exp-0.400-1]=-33%]).

A minimum of 24 hours of evaluable Video-EEG will be required to utilize the EEG.  
In cases where there is less than 24 hours of evaluable Video-EEG, the seizure rate 
will be set to missing.

The baseline 24 hour EEG seizure rate will be calculated in the same way.
Secondary Efficacy Endpoint

Responder Rate, defined as subjects who have a 50% reduction from baseline in 
partial seizure rate during the double-blind 48 hour EEG period.  Subjects meeting 
this criterion will be considered responders.
Safety Endpoints

The evaluation of safety will include adverse event (AE) data (occurrence, nature, 
intensity, and relationship to study drug), assessment of clinical laboratory data and 
the results of physical examinations, vital signs, neurological examinations and 
electrocardiograms (ECGs).
Study Treatments:
Subjects who complete the baseline phase and meet the eligibility criteria will be randomized 
in a double-blind manner at Visit 3 to a fixed dose of either of the following.  Study drug will 
be administered TID in equally divided doses: 

Placebo;

Level 1: pregabalin 7.0 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age];

Level 2: pregabalin 14.0 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age].
Note that the dose levels will be adjusted by age to account for potential differences in renal 
drug clearance (see Table 2).  For a given level of pregabalin dosing (eg, Level 1), the 
resultant total daily exposures are anticipated to be comparable throughout the age range of 
1 month through <4 years.
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Table 2 below summarizes dosing for the 3 double-blind treatments for the Escalation, 
Fixed-Dosing, and Taper Phases of the study.  All active treatments will start at 
3.5 mg/kg/day [3 mg/kg/day for subjects 1 to 3 months of age] and escalate to the final level 
as shown in Table 2, then taper back to 3.5 mg/kg/day [3 mg/kg/day for subjects 1 to 
3 months of age] after the fixed dose phase.
Table 1.
Double-Blind Dosing By Study Treatment, Study Phase
DOUBLE-BLIND PHASES
Dose Escalation Phase
Fixed-Dose Phase
Taper Phase*
Age >3 months
Age 3 months
Age >3 months
Age 3 months
Age >3 months
Age 3 months
Treatmenta
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Level 1:-
3.5 mg/kg/day
x 5 days
3.0 mg/kg/day
x 5 days
7.0 mg/kg/day
x 9 days
6.0 mg/kg/day
x 9 days
3.5 mg/kg/day 
x 7 days
3.0 mg/kg/day 
x 7 days
Level 2:
Step 1:
3.5 mg/kg/day 
x 2 days
Step 2:
7.0 mg/kg/day 
x 3 days
Step 1:
3.0 mg/kg/day 
x 2 days
Step 2:
6.0 mg/kg/day 
x 3 days
14 mg/kg/day
X 9 days
12 mg/kg/day
X 9 days
Step 1:
7.0 mg/kg/day 
x 4 days
Step 2:
3.5 mg/kg/day 
x 3 days
Step 1:
6.0 mg/kg/day 
x 4 days
Step 2:
3.0 mg/kg/day 
x 3 days
*
Subjects who will not participate in Study A0081106 will discontinue study medication following the 
completion of the taper phase.  For subjects who will enter Study A0081106, all subjects will initiate that 
study at a dose of 3.5 mg/kg/day [3 mg/kg/day for subjects 1 to 3 months of age] and may then escalate 
according to protocol requirements. 
a
Study drug will be administered TID in equally divided doses.
Statistical Methods:
The efficacy analyses will be performed on the modified intent to treat (mITT) population 
which consists of randomized subjects who took at least one dose of study drug during the 
double-blind treatment phase, have a baseline with at least one partial onset seizure identified 
by Video-EEG and a follow-up VideoEEG.  Video-EEG assessments must include at least 
24 hours of evaluable monitoring to be elegible for the mITT population.
Primary Efficacy Analysis 
The primary analysis will be performed on the loge (double-blind 24-hour EEG seizure 
rate + 1) using a linear model with treatment, age stratum, and geographical region (ie, US, 
Europe, Asia, Rest of the World as data allows) as fixed factor effects, and loge (baseline 
24-hour EEG seizure rate + 1) as a continuous covariate. This linear model will include both 
dose groups of pregabalin. The primary analysis will assess each dose of pregabalin versus 
placebo using ordinary estimation, in a step-wise fashion.  Results will be summarized by 
treatment group as an approximation of a percent change from placebo in 24 hr seizure rate.
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Secondary Efficacy Analysis
Secondary efficacy analysis will include the Responder Rate, defined as subjects who have a 
50% reduction from baseline in partial seizure rate during the double-blind 48 hour EEG 
phase. Subjects meeting this criterion will be considered responders.
Sample Size Justification
A total of approximately 123 subjects was originally planned to be randomized in this study 
in a 2:2:1 ratio of placebo, Level 1 and Level 2. This randomization scheme was considered 
to allow a sufficient number of patients to be studied at each dose level for safety, while 
providing adequate power to detect a significant effect for dose Levels 1 and 2.  
Randomization of 123 subjects accounted for a potential 10% discontinuation rate, with a 
resulting sample size of the necessary 110 subjects (44 placebo, 44 Level 1, and 22 Level 2).
The sample size rationale was based on the observed difference in loge (double-blind 24-hour
seizure rate + 28
1 ) between pregabalin and placebo (Table 4).  A difference in the least 
squares means between pregabalin and placebo was estimated to be -0.668 and -0.448 for 
600- and 300 mg doses respectively, with a pooled standard deviation (SD) of 0.73.  This 
difference and pooled SD was obtained from a meta analysis of the -34, -11, -09 study data in 
adult subjects with partial onset seizures.
In order to address the primary analysis comparison between placebo and the Level 2 dose 
group, a sample size of 44 subjects in the placebo group and 22 subjects in the Level 2 dose 
group were anticipated to provide at least 90% power to detect a true difference of -0.668 
using a two-sided test at the 0.05 level of significance with a standard deviation of 0.73.
In order to address the primary analysis comparison between placebo and the Level 1 dose 
group, a sample size of 44 in each of these two groups was anticipated to provide at least 
80% power to detect a true difference of -0.448 using a two-sided test at the 0.05 level of 
significance with a standard deviation of 0.73. 
The constant utilized in the log transformation of the 24-hour seizure rate for the primary 
analysis was changed while the study was ongoing from “1/28” to “1” due to differences in 
the seizure rate distribution assumed during design of the study and the observed, blinded 
data distribution. Changing the constant to 1 provides a better approximation of a normal 
distribution of the seizure data. The constant “1/28” added variability to the data and 
decreased its normality. 
The blinded sample size re-estimation procedure utilized for this study was revised per the 
Statistical Analysis Plan and did not allow for a reduction in the planned sample size of 
123 subjects total or require an increase in sample size greater than 150 subjects. The 
following decision rules were utilized for the blinded sample size re-estimation:
a.
If the recalculated sample size is less than or equal to the original sample size of 
123 subjects total, then the sample size will not be adjusted.
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b. If the recalculated sample size is greater than the original sample size (123 subjects 
total) then the following information will be considered:

If the re-estimated sample size is between 123 and 150, then the sample size will 
be adjusted to the re-estimated sample size;

If the re-estimated sample size exceeds 150 then the sample size will be increased 
to 150.
The blinded sample size re-estimation was conducted, and the sample size will be increased 
to approximately 150 subjects.
Blinded Sample Size Re-estimation
A blinded sample size re-estimation procedure will be applied when approximately two 
thirds of the subjects that make up initial sample size have the opportunity to complete the 
study.
Safety Analysis
Safety will be assessed by summarizing and reviewing the nature, frequency, relationship to 
study drug, and severity of AEs, the results of physical and neurological examinations, 
weight, vital signs, ECG’s and the results of clinical laboratory tests including hematology, 
blood chemistry, and urinalysis. Subject listings of all laboratory data will be provided using 
a standard computer program for laboratory data display.  The listings will highlight values 
outside normal limits and those considered to be possible clinically important deviations.  
Medical history, physical exams, assessment of vital signs, and ECG will be displayed in 
standard listings and summary tables.
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the subject.
Study Periods
Screening 48 Hour 
Video-EEG 
Baseline
Recording
Double Blind 
Dose Escalation 
Phase
Double-Blind Fixed
Dose Treatment 
Phase
48 Hour
Video-EEG 
Treatment 
Recording
Taper/Termination Phase
Completion of
Double Blind
Fixed Dose Phase and 
Begin Taper Phaseb
End of Study or 
Early 
Termination
Clinic Visit Number
Visit 1
Visit 2
Visit 3
*PV
Visit 4
*PV
Visit 5l
Visit 6
Visit 7
Study Day
-14 3
-3 to -1
1 1
4 1
6 1
9 1
12 to 14 
1
15 2
22 3
Informed consent
X
Record demographic information
X
Record medical history 
X
Record seizure history
X
Perform physical and neurological 
examination
Xa
Xe
Xa
Review inclusion/exclusion criteria
X
X
Record antiepileptic medication 
history
X
Record all prior and/or concomitant
medications and non-drug treatments 
and procedures
X
X
X
X
X
X
X
X
X
Dispense seizure event log
Xi
X
Collect and review seizure event log
X
X
Initiate Video electroencephalogram 
(EEG)
X
X
Download Video-EEG data and send 
to reader
X
X
Perform head CT or MRIc
X
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Study Periods
Screening 48 Hour 
Video-EEG 
Baseline
Recording
Double Blind 
Dose Escalation 
Phase
Double-Blind Fixed
Dose Treatment 
Phase
48 Hour
Video-EEG 
Treatment 
Recording
Taper/Termination Phase
Completion of
Double Blind
Fixed Dose Phase and 
Begin Taper Phaseb
End of Study or 
Early 
Termination
Clinic Visit Number
Visit 1
Visit 2
Visit 3
*PV
Visit 4
*PV
Visit 5l
Visit 6
Visit 7
Study Day
-14 ± 3
-3 to -1
1 ± 1
4 ± 1
6 ± 1
9 ± 1
12 to 14 
± 1
15 ± 2
22 ± 3
Perform 12-lead electrocardiogram 
(ECG)
X
X
Collect and record vital signs
X
X
X
X
X
X
Record height/length
X
X
Record weight
X
X
Collect blood and urine samples for 
clinical laboratory assessmentsm
X
X
X
X
Randomizationd
Xj
 
Xf
Xg
Xh
Evaluate and record study medication 
compliance
X
X
X
X
Dosing compliance training/review 
and demonstration 
X
X
X
*Telephone visit to assess dosing 
compliance and AE’s
X
X
Dispense dosing diary
X
X
X
X
Collect and review dosing diary
X
X
X
X
Dispense study medication
Xk
X
X
Assess and record adverse events
X
X
X
X
X
X
X
X
a.
Full physical and neurological exams at this visit.
b.
Subjects who require early discontinuation should begin the taper period at the time the decision is made to discontinue.  All Visit 6 and 7 procedures should 
be performed as possible.
c.
If not performed previously.  In the event that a CT or MRI scan is needed, it should be performed as soon as possible after Visit 1 if it cannot be performed 
the day of this visit and must be completed and reviewed prior to randomization.
d.
Subjects who meet all inclusion and none of the exclusion criteria will be randomized on Day 1 of Visit 3 and study drug will be dispensed at this visit.
CCI
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e.
Neuro and physical exams at this visit will be brief.
f.
(
). 
g.
h.
 
i.
Dispense seizure event log to track seizure events duringVideo-EEG and train parent(s)/guardian(s)/caregiver(s) on its use and completion.
j.
Verify the criteria for total number of qualifying seizures has been met by review of the Video-EEG by the investigator prior to randomization.
k.
Administer first dose of study medication in clinic.
l.
Subjects who complete or terminate Video-EEG recording before Day 15 will continue fixed dosing until beginning the taper phase at Visit V6 on Day 15.
m. If it is not possible to collect a urine sample, despite appropriate efforts, the urine sample can be omitted for that visit.  The reason for lack of sample must be 
recorded and documented in source documentation.
CCI
CCI
CCI
CCI
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................17
LIST OF FIGURES .................................................................................................................17
APPENDICES .........................................................................................................................18
1. INTRODUCTION ...............................................................................................................19
1.1. Indication.................................................................................................................19
1.2. Background and Rationale ......................................................................................19
1.3. Dose Rationale ........................................................................................................21
1.4. Justification for Placebo Arm..................................................................................22
1.5. Study A0081106: 1-Year Open Label Safety Study of Pregabalin.........................22
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................22
2.1. Objectives................................................................................................................22
2.2. Endpoints.................................................................................................................23
3. STUDY DESIGN.................................................................................................................24
3.1. Screening and Baseline Phase.................................................................................26
3.2. Dose Escalation Phase (5 Days) and Fixed Dose Phase (9 Days) and Taper 
Phase (7 Days)...........................................................................................................26
4. SUBJECT SELECTION......................................................................................................27
4.1. Inclusion Criteria.....................................................................................................27
4.2. Exclusion Criteria....................................................................................................29
4.3. Sponsor Qualified Medical Personnel.....................................................................30
5. STUDY TREATMENTS.....................................................................................................30
5.1. Allocation to Treatment ..........................................................................................30
5.2. Breaking the Blind ..................................................................................................31
5.3. Drug Supplies..........................................................................................................31
5.3.1. Formulation and Packaging........................................................................31
5.3.2. Preparation and Dispensing........................................................................32
5.3.3. Administration............................................................................................32
5.3.4. Compliance.................................................................................................33
5.4. Drug Storage and Drug Accountability...................................................................33
5.5. Concomitant Medication(s).....................................................................................34
5.5.1. Permitted Medications................................................................................35
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5.5.2. Prohibited Medications...............................................................................35
6. STUDY PROCEDURES .....................................................................................................36
6.1. Visit 1 Screening (Day -14 ±3) ...............................................................................36
6.1.1. Visit 2 Baseline Video-EEG (Day -3 to -1)................................................37
6.2. Double-Blind Dose Escalation Phase......................................................................37
6.2.1. Visit 3 (Day 1 ±1) Randomization and Entry into Double-blind Dose 
Escalation Phase...............................................................................................37
6.2.2. Telephone Visit (Day 4 ±1) ........................................................................38
6.3. Double-Blind Fixed-Dose Treatment Phase ...........................................................38
6.3.1. Visit 4 (Day 6 ±1).......................................................................................38
6.3.2. Telephone Visit (Day 9 ±1) ........................................................................40
6.3.3. Visit 5 Video-EEG (Day 12 to 14 ±1)........................................................40
6.3.4. Visit 6 Begin Taper Phase (Day 15 ±2)......................................................41
6.4. Completion of Taper (End of Study/Early Termination)........................................41
6.4.1. Visit 7 (Day 22 ±3).....................................................................................42
6.5. Subject Withdrawal.................................................................................................42
7. ASSESSMENTS..................................................................................................................44
7.1. Efficacy Assessments..............................................................................................44
7.2. Acquisition of Seizure Counts: Video-Electroencephalogram (EEG)....................44
7.2.1. Primary Efficacy Parameter........................................................................44
7.2.2. Secondary Efficacy Parameter....................................................................45
7.3. Safety Assessments .................................................................................................45
7.4. Clinical Laboratory Assessments............................................................................45
7.4.1. Estimated Creatinine Clearance (mL/min/1.73m2).....................................45
7.4.2. Hematology.................................................................................................46
7.4.3. Clinical Chemistry......................................................................................46
7.4.4. Urinalysis....................................................................................................46
7.5. Vital Signs, Height/Length and Weight ..................................................................47
7.6. Physical and Neurological Examination .................................................................47
7.7. Electrocardiogram (ECG)........................................................................................47
7.8. Imaging....................................................................................................................47
CCI
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8. ADVERSE EVENT REPORTING......................................................................................49
8.1. Adverse Events........................................................................................................49
8.2. Reporting Period .....................................................................................................50
8.3. Definition of an Adverse Event...............................................................................50
8.4. Abnormal Test Findings..........................................................................................51
8.5. Serious Adverse Events...........................................................................................51
8.5.1. Protocol-Specified Serious Adverse Events...............................................52
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................52
8.6. Hospitalization ........................................................................................................53
8.7. Severity Assessment................................................................................................54
8.8. Causality Assessment..............................................................................................55
8.9. Withdrawal Due to Adverse Events (See also section on Subject 
Withdrawal)...............................................................................................................55
8.10. Eliciting Adverse Event Information ....................................................................55
8.11. Reporting Requirements........................................................................................55
8.11.1. Serious Adverse Event Reporting Requirements .....................................56
8.11.2. Non-Serious Adverse Event Reporting Requirements .............................56
8.11.3. Sponsor Reporting Requirements to Regulatory Authorities ...................56
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................57
9.1. Sample Size Determination.....................................................................................57
9.2. Efficacy Analysis ....................................................................................................59
9.2.1. Analysis of Primary Endpoint ....................................................................60
9.2.2. Analysis of Secondary Endpoints...............................................................60
9.2.3. Multiple Testing Procedures.......................................................................60
9.3. Sensitivity Analysis to Assess the Impact of Missing Data....................................61
9.4. Safety Analysis........................................................................................................62
9.5. Interim Analysis ......................................................................................................62
9.6. Data Monitoring Committee ...................................................................................62
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................62
11. DATA HANDLING AND RECORD KEEPING .............................................................63
CCI
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11.1. Case Report Forms/Electronic Data Record .........................................................63
11.2. Record Retention...................................................................................................63
12. ETHICS..............................................................................................................................64
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............64
12.2. Ethical Conduct of the Study ................................................................................64
12.3. Subject Information and Consent..........................................................................64
12.4. Subject Recruitment ..............................................................................................65
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................65
13. DEFINITION OF END OF TRIAL...................................................................................65
13.1. End of Trial in a Member State.............................................................................65
13.2. End of Trial in all Other Participating Countries ..................................................65
14. SPONSOR DISCONTINUATION CRITERIA ................................................................65
15. PUBLICATION OF STUDY RESULTS..........................................................................66
15.1. Communication of Results by Pfizer ....................................................................66
15.2. Publications by Investigators ................................................................................67
16. REFERENCES ..................................................................................................................68
LIST OF TABLES
Table 1.
Double-Blind Dosing By Study Treatment, Study Phase.......................................8
Table 2.
Double-Blind Dosing By Study Treatment, Study Phase.....................................27
Table 3.
Double-Blind Dosing By Study Treatment, Study Phase.....................................31
Table 4.
Power Calculations and Sample Size Assumptions for the Primary 
Endpoint (loge (24-hour seizure rate + 28
1 ) ..........................................................58
LIST OF FIGURES
Figure 1.
Liquid Oral Dosing Syringes (1, 3, and 10 mL left to right)................................74
Figure 2.
Liquid Oral Dosing Example................................................................................75
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APPENDICES
Appendix 1. International League Against Epilepsy 2010 and Revised 1981 
Classification ........................................................................................................69
Appendix 2. Clinical Dosing Instructions for Liquid Oral Solution:.......................................73
Appendix 3. List of Abbreviations...........................................................................................76
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1. INTRODUCTION
Epilepsy is a common disorder in childhood affecting 4 to 5 of every 1000 children.  
Although epilepsy is often well controlled with existing antiepileptic drug (AED) therapy, 
more than 25% of pediatric patients have seizures that are uncontrolled by currently available 
agents, or have adverse effects related to AEDs that complicate their seizure control.  In 
addition, children with epilepsy often suffer from impaired academic performance, with 
55% functioning below their grade level and an additional 16% significantly behind in 
educational training.1 Children with epilepsy also have a higher likelihood of developing 
behavioral difficulties, which may persist into adulthood.2 Early age of onset and a higher 
number of total lifetime seizures are the strongest correlates of academic underachievement.  
Therefore, the availability of a new AED that has been shown to improve seizure control and 
that is generally well tolerated is needed.
1.1. Indication
Adjunctive therapy for pediatric subjects 1 month (44 weeks gestational age) through
<4 years of age with partial onset seizures with or without secondary generalization.
1.2. Background and Rationale
Pregabalin [CI-1008, (S)-3-(amino methyl)-5-methylhexanoic acid] binds with high affinity 
to the 2site (an auxiliary subunit of voltage gated calcium channels) in central nervous 
system tissues.  Results with genetically modified mice and with compounds structurally 
related to pregabalin indicate that binding to the 2subunit may be involved in pregabalin’s 
anti-seizure effects in animal models.  In vitro, pregabalin reduces the calcium-dependent 
release of several neurotransmitters, possibly by modulation of calcium channel function.
Gabapentin (Neurontin) and pregabalin (Lyrica) are the only 2 2agents that are 
approved for use as medications for the treatment of partial onset seizures.  Both are believed 
to exert their pharmacologic action by binding to the 2site of voltage gated calcium 
channels.  Gabapentin is approved as adjunctive therapy in the treatment of partial seizures in 
adults and children (US children aged 3 years of age and older: EU-children aged 6 years of 
age and older).  Gabapentin is well tolerated in both adult and pediatric patients.  The most 
common treatment-emergent adverse events reported in a controlled trial of gabapentin for 
the adjunctive treatment of epilepsy in subjects 3 to 12 years of age were viral infection, 
fever, nausea and/or vomiting, and somnolence. 
Pregabalin is approved in more than 100 countries, with indications summarized below for 
the United States (US), European Union (EU), and Japan (JP).  In the US, pregabalin is 
indicated for the adjunctive therapy for adult patients with partial onset seizures.  In addition, 
pregabalin is indicated for the management of neuropathic pain associated with diabetic 
peripheral neuropathy, post herpetic neuralgia, and fibromyalgia and neuropathic pain 
associated with spinal cord injury.  In the EU, pregabalin is indicated as adjunctive therapy in 
adults with partial seizures with or without secondary generalization. In addition, pregabalin 
is indicated for the treatment of peripheral and central neuropathic pain in adults and for 
generalized anxiety disorder in adults. In Japan, pregabalin is indicated for the treatment of 
peripheral neuropathic pain and fibromyalgia. The approved dose range for the adjunctive 
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treatment of partial onset seizures in adults is 150 to 600 mg/day, administered twice daily 
(BID) or 3 times daily (TID).  The most common adverse effects reported with pregabalin in 
placebo controlled adjunctive trials in adults with partial onset seizures were dizziness 
(32%) and somnolence (22%).  Since initial market approval of Lyricain 2004 through the 
first quarter of 2012, it is estimated that more than 15,900,000 patient years of exposure have 
accumulated worldwide. 
Pregabalin pharmacokinetic (PK) data from adult clinical pharmacology studies and one 
clinical pharmacology study in pediatric subjects with epilepsy (Study A0081074) show that 
pregabalin pharmacokinetics are linear and predictable.  Multiple dose pharmacokinetics are 
predictable from single dose data. Pregabalin is rapidly absorbed when administered in the 
fasted state.  The rate of pregabalin absorption is decreased when given with food.  However, 
administration of pregabalin with food has no clinically relevant effect on the total amount of
pregabalin absorbed. Therefore, pregabalin can be taken with or without food.  Pregabalin is 
eliminated from the systemic circulation primarily by renal excretion as unchanged drug with 
a mean plasma pregabalin half-life of 6.3 hours in adults.  Pregabalin clearance is 
proportional to creatinine clearance, and the major influence on its clearance is reduced or 
impaired renal function. Since pregabalin is predominantly excreted unchanged in the urine 
(<2% of a dose recovered in urine as metabolites), undergoes negligible metabolism, and 
does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other 
agents through metabolic interactions or protein binding displacement. In vitro and in vivo 
studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug 
interactions.  In adult subjects, no pharmacokinetic interactions were seen between 
pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, 
phenytoin, phenobarbital, and topiramate.  Important pharmacokinetic interactions would 
also not be expected to occur between pregabalin and other commonly used antiepileptic 
drugs.
The pharmacokinetics (PK), safety, and tolerability of pregabalin were evaluated in pediatric 
subjects 1 month to 16 years of age with partial onset seizures in the double-blind, 
placebo-controlled Phase 1 Study A0081074.  Dose levels 2.5, 5.0, 10.0, and 15.0 mg/kg/day 
(given in equally divided doses twice daily) were administered for 8 days. Single and 
multiple dose PK were evaluated.  Pregabalin peak concentration (Cmax) and total exposure 
(area under the curve AUC) increased linearly with increasing dose (2.5, 5.0, 10.0 and 
15.0 mg/kg/day) for each age group (1 month to 23 months, 2 to 6 years, 7 to 11 years, and 
12 to 16 years).  Pregabalin terminal t½ averaged about 3 to 4 hours in pediatric subjects 
from 1 month to 6 years of age, and 4 to 6 hours in those 7 years of age and older.  
Pregabalin oral clearance normalized per body weight was 43% higher in the children with 
body weight less than 30 kg than in children whose body weight was 30 kg and higher. 
Apparent oral clearance of pregabalin was directly related to creatinine clearance. When 
dosed on a mg/kg/day basis, pregabalin daily exposure was approximately 30% lower in 
these subjects weighing less than 30 kg. The data from Study A0081074 has been used to 
define the dose range and frequency to be investigated in this study (Study A0081042) and 
additional Phase 3 efficacy and safety studies in the pediatric epilepsy population. 
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Pregabalin has been shown to be effective in the treatment of epilepsy in adults and is 
currently approved for the adjunctive treatment of POS in adults over a dose range of 150 to 
600 mg/day (when taken 2 or 3 times a day). Thus, pregabalin’s mechanism of action, being 
different from other anti-epileptic drugs, has the potential to expand treatment choices for 
children with epilepsy. This study is considered to have a positive risk benefit ratio for 
enrolling patients based on extensive previous experience with pregabalin in adults with POS 
and with the comprehensive safety screening and monitoring plans included in the present 
study design.
This study is one of several studies that will be conducted to assess the safety and efficacy of 
pregabalin in pediatric subjects with epilepsy and to address post approval commitments to 
US Food Drug Administration (FDA) and EU European Medicines Agency (EMA)
regulatory authorities.
Complete information for pregabalin may be found in the Single Reference Safety Document 
which for this study is the Investigator Brochure.
1.3. Dose Rationale
The recommended dosing regimen in both the US and EU for adjunctive therapy with 
Lyricain adults with partial onset seizures ranges from 150 to 600 mg/day given BID or 
TID.  This dosing regimen approximates that for the range of 2.5 mg to 10.0 mg/kg/day 
assuming a 60 kg adult individual.  The two dose levels for this study will, therefore, provide 
exposures comparable to those achieved in adults with 300 mg/day or 600 mg/day dosing.  
Pregabalin will be administered TID in equally divided doses.

Level 1: 7.0 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age].

Level 2: 14 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age].
Throughout the protocol, Level 1 will be used to indicate pregabalin 7.0 mg/kg/day 
[6 mg/kg/day for subjects 1 to 3 months of age] dosing and Level 2 will be used to indicate 
pregabalin 14.0 mg/kg/day dosing [3 mg/kg/day for subjects 1 to 3 months of age].
Since pregabalin clearance normalized for body weight is approxinmately 40% higher in 
pediatric subjects weighing less than 30 kg relative to adults and pediatric subjects weighing 
>30 kg, a daily dose 40% higher relative to that for adults is needed to achieve exposure 
similar to that of adults. In addition, since pregabalin terminal t½ is expected to be 
approximately 3 to 4 hours in pediatric subjects from 1 month to <4 years of age, shorter than 
the t½ in older pediatric and adult subjects, a TID dosing regimen will be utilized for this 
study. In addition, in consideration of potential differences in renal drug clearance in 
subjects 1 month to 3 months of age relative to subjects >3 months of age, a downward dose 
adjustment is needed to achieve similar exposures.  Throughout the protocol, 7 mg/kg/day 
will be used to indicate Level 1 dosing and 14.0 mg/kg/day will be used to indicate Level 2 
dosing.  The adjusted dose for pediatric subjects 1 to 3 months of age will be shown in 
brackets/parentheses in select sections, but for brevity will not be shown in all sections.
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The rate of pregabalin taper in this pediatric study in patients with epilepsy is consistent with 
the taper rate used in the adult epilepsy trials and reflected in approved labeling. Study 
medication will, therefore, be gradually discontinued over 1 week to minimize the potential 
of increased seizure frequency. 
1.4. Justification for Placebo Arm 
The placebo arm is critical to include in Study A0081042 to achieve the scientific objectives 
of the study in evaluating the safety and efficacy of pregabalin and to then provide important 
medical information in labeling for the potential use of pregabalin in pediatric epilepsy 
patients.  Given the variability and episodic nature that can influence the number, type, and 
frequency of seizures in epilepsy patients, use of a placebo control is an inherent and critical 
component of the study design to test the hypothesis of seizure reductions in the 
2 pregabalin-treated groups necessarily compared with placebo treated subjects.  Use of 
placebo is also critical to characterize the safety and tolerability of pregabalin in pediatric 
subjects.  In addition, Study A0081042 is designed to meet regulatory requirements for 
demonstrating safety and efficacy in pediatric epilepsy subjects with data compared typically 
to a placebo control for that purpose.  However, it should be noted that adjunctive therapy is 
used in this study and therefore all placebo and actively treated subjects will be required to 
continue their current AED therapy concomitant to study medication. 
1.5. Study A0081106: 1-Year Open Label Safety Study of Pregabalin
Subjects who complete the treatment phases of this study through Visit 7 and enter the 
double-blind taper phase will be eligible for screening into Protocol A0081106: A 12-Month 
Open Label Study to Evaluate the Safety and Tolerability of Pregabalin as Adjunctive 
Therapy in Pediatric Subjects 1 Month to 16 Years of Age with Partial Onset Seizures and 
Pediatric and Adult  Subjects 5 to 65 Years of Age with Primary Generalized Tonic-Clonic 
Seizures.  Subjects will be considered to have completed Study A0081042 at Visit 7.
In certain instances subjects who require withdrawal from this study may still be eligible for 
screening and entry into the long term safety study A0081106.  Subjects who do not meet the 
inclusion criteria of at least 1 partial seizure during the 48 hour baseline Video-EEG may still 
be eligible for screening for A0081106.  Subjects who have completed the dose escalation 
phase and received at least one dose during the fixed-dose phase, but withdraw due to poor 
tolerability or lack of efficacy, may also be eligible for screening for Protocol A0081106.  
Such cases should be reviewed with the Pfizer study clinician to determine further eligibility.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Efficacy Objective:

The primary objective of this study is to evaluate the efficacy of two dose levels of 
pregabalin compared to placebo as an adjunctive treatment in reducing the frequency 
of partial onset seizures in pediatric subjects 1 month through <4 years of age. 
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Secondary Efficacy Objective:

To evaluate the efficacy of pregabalin compared to placebo on the frequency of 
partial onset seizures as determined by responder rate in pediatric subjects 1 month 
through <4 years of age.

To assess the safety and tolerability of pregabalin in pediatric subjects 1 month
(44 weeks gestational age) through <4 years of age with partial onset seizures. 
2.2. Endpoints
Primary Efficacy Endpoint: 

The primary endpoint will be the log transformed double blind 24 hr seizure rate for 
all partial onset seizures collected at Visit 6 (48 hour Video-EEG assessment phase)
during the double blind phase as determined by the central reader.  This 24-hour 
seizure rate will be calculated as follows for the double-blind period:
24
monitoring
EEG
-
Video
of
hours
of
#
phase
assessment
hr
-
48
blind
double
in
seizures
of
#
rate
seizure
EEG
hr
-
24
Blind
Double



When the log-transformation is used, the quantity 1 is added to the double blind 24-hr 
EEG seizure rate for all subjects to account for any possible "0" seizure incidence.  
This will result in the following primary efficacy measure: loge (double blind 24-hr 
EEG seizure rate + 1). Results will be reported as “percent change in seizures” 
relative to placebo. For example, a difference between one of the pregabalin doses 
and placebo of -0.400 on the log transformed scale for the double blind 24-hr seizure 
rate, translates into a 33% reduction in the double blind 24-hour EEG seizure rate of 
the pregabalin group from the placebo group (ie, 100%*[exp-0.400-1]=-33%]). 

A minimum of 24 hours of evaluable Video-EEG will be required to utilize the EEG.  
In cases where there is less than 24 hours of evaluable Video-EEG, the seizure rate 
will be set to missing.

The baseline 24-hr EEG seizure rate will be calculated in the same respective manner. 
Secondary Efficacy Endpoint: 

Responder Rate, defined as subjects who have a 50% reduction from baseline in 
partial seizure rate during the double-blind 48 hour Video-EEG phase.  Subjects 
meeting this criterion will be considered responders. 
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Safety Endpoints: 

The evaluation of safety will include adverse event (AE) data (occurrence, nature, 
intensity, and relationship to study drug), assessment of clinical laboratory data and 
the results of physical examinations, vital signs, weight, neurological examinations, 
and electrocardiograms (ECGs).
3. STUDY DESIGN
Study A0081042 is a double-blind, placebo-controlled, randomized, parallel group, 
multicenter study to evaluate efficacy and safety of two dose levels of pregabalin compared 
to placebo administered TID as adjunctive therapy in pediatric subjects 1 month (44 weeks 
gestational age) through <4 years of age with partial onset seizures with or without secondary 
generalization.
Approximately 150 subjects will be enrolled in this study as determined from the blinded 
sample size re-estimation (refer to Section 9.1). 
Randomization will be stratified by subject age (Stratum 1: <1 year of age; 
Stratum 2: 1-2 years of age; Stratum 3: >2 years of age). Subjects in each age stratum within 
the site will be randomized to either placebo or 1 of 2 fixed doses of pregabalin divided TID, 
Dose Level 1: pregabalin 7 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age] or 
Dose Level 2: pregabalin 14 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age] in a 
2:2:1 ratio. Every reasonable effort will be made to enroll a minimum of 10 subjects in each 
of the 3 age strata.
The study is composed of 4 phases: 

Video-Electroencephalographic (EEG) baseline phase with a target minimum of 
48 hours. To ensure that the target minimum of 48 hours of Video-EEG is obtained, 
the total duration of the Video-EEG baseline phase will be up to 72 hours.

5 day double-blind dose escalation phase.

9 day double-blind fixed dose treatment phase, which includes a Video-EEG 
evaluation over the final 3 days at the end of this 9-day phase with a target minimum 
of 48 hours and a total recording duration of up to 72 hours. For subjects who 
successfully complete the target 48 hour Video-EEG or must terminate the 
Video-EEG recording before the end of this 9-day phase, fixed dosing will continue 
until beginning the taper phase.

7 day double-blind taper phase.
The total double-blind treatment phase is 21 days.
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Every reasonable attempt should be made to obtain the minimum target Video-EEG 
recording of 48 hours, which may require up to 72-hours of recording. Recognizing the 
inherent challenges in Video-EEG monitoring of pediatric subjects with epilepsy it is 
expected that the target minimum 48 hour Video-EEG recording may even then not be 
achievable in all cases. In the clinical investigator’s opinion, should circumstances 
(eg, clinical care, child behavior, consent, etc.) mandate a Video-EEG monitoring period less 
than 48-hours for a given subject, please contact the study clinician to review the subject’s 
clinical circumstances and document reasons for not achieving the target minimum duration. 
Subjects who complete the treatment phases of this study through Visit 7 and enter the 
double-blind taper phase will be eligible for screening into Protocol A0081106, a 1-year open 
label safety study (Please refer to Section 1.5 Study A0081106: 1-Year Open-Label Safety 
Study of Pregabalin for more details).  Subjects who participated in study A0081042 through 
Visit 7 will be considered to have completed the study. 
Study Design Diagram:
14.0 mg/kg/day pregabalinc
  Screen
Randomization
Dose 
Escalation 
Fixed dose 
Taper
End of study/
Screen for A0081106
Visit V1           V2        V3                      V4                                             V5     V6                V7*
Day -14            -3           1                         6
              12      15                 22
7.0 mg/kg/dayc pregabalinb
Placebo
7.0 b
mg/kg/day
pregabalin
3.5 a
mg/kg/day 
pregabalin
Baseline
Video 
EEG
48
Hours
* Eligible subjects may be assessed for screening into study A0081106 and complete end of 
study activities for A0081042 at Visit 7 (V7)
a [3 mg/kg/day for subjects 1 to 3 months of age]; 
b [6 mg/kg/day for subjects 1 to 3 months of age]; 
c [12 mg/kg/day for subjects 1 to 3 months of age]
Video 
EEG
48
Hours
Study treatment + current AEDs
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3.1. Screening and Baseline Phase
Prior to screening, informed consent will be obtained from the parents/guardians. Subjects 
must have had at least 3 partial onset seizures in the month prior to screening.  Subjects must 
be receiving a stable dose of 1-3 AEDs for 7 days before screening.  Subjects meeting the 
inclusion/exclusion criteria on the first Screening Visit (Visit 1) are enrolled in the study.
After verification of the diagnosis, at Visit 2, the subject is fitted with a continuous EEG 
recording device for a 48 hour Video-EEG baseline partial onset seizure frequency 
evaluation. During the 48 hr baseline phase subjects will be maintained on their current AED 
regimen.  The investigator will evaluate the baseline Video-EEG for the purpose of 
determining if the subject meets the inclusion criteria.  Subjects who experience at least 
2 partial-onset seizures, with or without secondary generalization, during the 48 hour 
Video-EEG observation period will be randomized to treatment at Visit 3.  A central reader 
will evaluate the Video-EEG data to determine the number of baseline seizures for the 
analysis of efficacy.  Subjects that are randomized, but are subsequently determined by the 
central reader to have less than 2 partial-onset seizures will be allowed to continue in the 
study.  Sublects who are determined by the central reader to have potentially exclusionary 
seizures types will be discussed with the study clinician and investigator to determine if the 
subject must be withdrawn from the study.
Subjects who fail screening and cannot enter the study, may, under certain circumstances, be 
re-screened for study inclusion at a later date.  For example, re-screening may occur if a 
subject fails due to exclusionary lab values, use of disallowed concomitant medications or 
intercurrent illness should this change at a later date. Any subjects being considered for 
re-screening should be discussed by the Investigator with the Pfizer Study Clinician or 
Medical Monitor.
3.2. Dose Escalation Phase (5 Days) and Fixed Dose Phase (9 Days) and Taper Phase 
(7 Days)
Subjects who complete the baseline phase and meet the eligibility criteria will be randomized 
in a double-blind manner at Visit 3 to one of the following study treatments in a 2:2:1 ratio
(placebo: Level 1: Level 2).  Level 1 and Level 2 pregabalin doses will be based on weight 
recorded at Visit 3.  Study drug will be administered TID in equally divided doses. 
Study Treatments:

Placebo;

Level 1: 7.0 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age;

Level 2: 14 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age].
Subjects randomized to receive either Level 1 or Level 2 pregabalin will have a 5 day 
escalation phase, a 9 day fixed dose phase, and a 7 day taper phase.  The taper phase should 
begin following the completion of the Double-Blind Fixed Dose Treatment Phase at Visit 6.  
Note: subjects who require early discontinuation should begin the taper period after the 
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decision is made to discontinue. Subject’s daily dosing will be recorded by their 
parent(s)/guardian(s)/caregiver(s) as appropriate, in a daily dosing diary.  Table 2 below 
summarizes dosing for the 3 double-blind treatments for the Escalation, Fixed-Dosing, and 
Taper Phases of the study.  All active treatments will start at 3.5 mg/kg/day [3 mg/kg/day for
subjects 1 to 3 months of age] and escalate to the final level as shown in Table 2, then taper 
back to 3.5 mg/kg/day [3 mg/kg/day for subjects 1 to 3 months of age] after the fixed dose 
phase.
Table 2.
Double-Blind Dosing By Study Treatment, Study Phase
DOUBLE-BLIND PHASES
Dose Escalation Phase
Fixed-Dose Phase
Taper Phase*
Age >3 months
Age 3 months
Age >3 months
Age 3 months
Age >3 months
Age 3 months
Treatmenta
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Level 1:-
3.5 mg/kg/day
x 5 days
3.0 mg/kg/day
x 5 days
7.0 mg/kg/day
x 9 days
6.0 mg/kg/day
x 9 days
3.5 mg/kg/day 
x 7 days
3.0 mg/kg/day 
x 7 days
Level 2:
Step 1:
3.5 mg/kg/day 
x 2 days
Step 2:
7.0 mg/kg/day 
x 3 days
Step 1:
3.0 mg/kg/day 
x 2 days
Step 2:
6.0 mg/kg/day 
x 3 days
14 mg/kg/day
X 9 days
12 mg/kg/day
X 9 days
Step 1:
7.0 mg/kg/day 
x 4 days
Step 2:
3.5 mg/kg/day 
x 3 days
Step 1:
6.0 mg/kg/day 
x 4 days
Step 2:
3.0 mg/kg/day 
x 3 days
*
Subjects who will not participate in Study A0081106 will discontinue study medication following the 
completion of the taper phase.  For subjects who will enter Study A0081106, all subjects will initiate that 
study at a dose of 3.5 mg/kg/day [3 mg/kg/day for subjects 1 to 3 months of age] and may then escalate 
according to protocol requirements. 
a
Study drug will be administered TID in equally divided doses.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
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1. Evidence of a personally signed and dated informed consent document indicating that 
the parent(s)/guardian(s) have been informed of all pertinent aspects of the study.  
When there are 2 parents, or 2 guardians, consent should be obtained from both of the 
child’s parents/guardians if present at the meeting where the informed consent 
document is signed.
2. Subjects and Parent(s)/guardian(s)/caregiver(s) who are willing and able to comply 
with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and female subjects, 1 month (44 weeks gestational age) through <4 years of 
age inclusive on the date of the Screening Visit with a diagnosis of epilepsy with 
seizures classified as simple partial, complex partial or partial becoming secondarily 
generalized, according to the International League Against Epilepsy (ILAE 20103
see Appendix 1) Diagnosis must be established by:

Subject’s seizure history (eg, description of seizures excluding confounding 
disorders such as pseudoseizures etc), family history and neurological exam.

Subjects must have previously had a contrast enhanced computed tomography 
(CT) or magnetic resonance imaging (MRI) scan of the brain and EEG testing.  
Results must be consistent with the diagnosis of focal onset epilepsy and must 
demonstrate that no abnormality is likely to be progressive.

In the event that a CT or MRI scan is needed, it should be performed as soon 
as possible after Visit 1 if it cannot be performed the day of this visit and must 
be completed and reviewed prior to randomization.
4. Currently receiving a stable dose of 1 to 3 antiepileptic drugs (stable within 7 days 
prior to screening).  Benzodiazepine medication used on a regular basis at a stable 
dosage will be considered 1 of the concurrent antiepileptic treatments, Vagus Nerve 
Stimulator when present will also be considered 1 of the concurrent antiepileptic 
treatments. 
5. A 12-lead ECG at screening without clinically significant abnormal findings as 
determined by the investigator. Potentially clinically significant abnormal findings 
will be reviewed by a pediatric cardiologist at the central ECG laboratory.
6. Subjects must have had at least 3 observed seizures in the month prior to screening.
7. Subjects must have at least 2 partial onset seizures as determined by the investigator
or designee during the 48 hour baseline Video-EEG phase.
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4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Primary generalized seizures (including in the setting of co-existing partial onset 
seizures) which may include, for example:

Clonic, tonic, and clonic-tonic seizures (note that partial onset seizures that 
become secondarily generalized are not exclusionary);

Absence seizures;

Infantile spasms;

Myoclonic, myoclonic atonic, myoclonic tonic seizures.
2. Lennox-Gastaut syndrome, Benign Epilepsy with Centrotemporal Spikes (BECTS) 
and Dravet syndrome.
3. A current diagnosis of febrile seizures or seizures related to an ongoing acute medical 
illness.
4. Exacerbation of partial onset seizures due to fever occurring within 60 days of 
screening.
5. Status epilepticus within 1 year prior to screening.
6. Seizures related to acute medical illness. 
7. Any change in AED regimen (type of medication or dose) within 7 days of the 
Screening Visit or during the Baseline Phase. 
8. Progressive structural central nervous sytem (CNS) lesion or a progressive 
encephalopathy.
9. Progressive errors of metabolism. 
10. Known or suspected chronic hematologic, hepatic or renal disease (AST and ALT)
above 3 times the upper limit of normal (ULN); or bilirubin, BUN, or creatinine 
above 2 times the ULN within the previous 6 months prior to screening). Subjects 
who experienced neonatal hyperbilirubinemia may be included after consulting with 
the study clinician.
11. Estimated creatinine clearance (ClCR) <80 mL/min/1.73 m2 (see Section 7.4.1).
12. Subjects whose parents/caregivers are investigational site staff members directly 
involved in the conduct of the trial or otherwise supervised by the Investigator.
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13. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
30 days before the current study begins and/or during study participation.
14. Other severe acute or chronic medical, psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of the 
study results or in the judgment of the investigator, would make the subject 
inappropriate for entry into this study. Patients with complex medical histories, 
including genetic or chromosomal syndromes, should be discussed with the study 
clinician prior to screening.
15. The concomitant use of gabapentin, felbamate, and vigabatrin is prohibited. 
16. Previous treatment of epilepsy with pregabalin.
17. Weight >30.0 kg.
4.3. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list. To facilitate access to appropriately qualified 
medical personnel on study related medical questions or problems, subject’s
parents/caregivers are provided with a contact card.  The contact card contains, at a 
minimum, protocol and investigational compound identifiers, patient study number, contact 
information for the investigational site and contact details for a help desk in the event that the 
investigational site staff cannot be reached to provide advice on a medical question or 
problem originating from another healthcare professional not involved in the subjects 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the subjects parents/caregivers directly and if a subjects 
parents/caregiver calls that number they will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
Subjects who complete the 48 hr Baseline Phase and meet the eligibility criteria will be 
randomized in a double-blind manner at Visit 3. Subjects will be randomized to placebo or 
one of 2 fixed doses divided TID, either Level 1: pregabalin 7.0 mg/kg/day [6 mg/kg/day for
subjects 1 to 3 months of age], or Level 2: pregabalin 14.0 mg/kg/day divided TID
[12 mg/kg/day for subjects 1 to 3 months of age], in a 2:2:1 ratio (Section Dose Escalation 
Phase (5 Days) and Fixed Dose Phase (9 Days) and Taper Phase (7 Days). Randomization 
will be stratified by site and subject age (Stratum 1: <1 year of age; Stratum 2: 1-2 years of 
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age; Stratum 3: >2 years of age).  Every reasonable effort will be made to enroll a minimum 
of 10 subjects in each of the 3 age strata.
Table 2 below summarizes dosing for the 3 double-blind treatments for the Escalation, 
Fixed-Dosing, and Taper Phases of the study.
Table 3.
Double-Blind Dosing By Study Treatment, Study Phase
DOUBLE-BLIND PHASES
Dose Escalation Phase
Fixed-Dose Phase
Taper Phase*
Age >3 months
Age 3 months
Age >3 months
Age 3 months
Age >3 months
Age 3 months
Treatmenta
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Level 1:-
3.5 mg/kg/day
x 5 days
3.0 mg/kg/day
x 5 days
7.0 mg/kg/day
x 9 days
6.0 mg/kg/day
x 9 days
3.5 mg/kg/day 
x 7 days
3.0 mg/kg/day 
x 7 days
Level 2:
Step 1:
3.5 mg/kg/day 
x 2 days
Step 2:
7.0 mg/kg/day 
x 3 days
Step 1:
3.0 mg/kg/day
x 2 days
Step 2:
6.0 mg/kg/day 
x 3 days
14 mg/kg/day
X 9 days
12 mg/kg/day
X 9 days
Step 1:
7.0 mg/kg/day 
x 4 days
Step 2:
3.5 mg/kg/day 
x 3 days
Step 1:
6.0 mg/kg/day 
x 4 days
Step 2:
3.0 mg/kg/day 
x 3 days
*
Subjects who will not participate in Study A0081106 will discontinue study medication following the 
completion of the taper phase.  For subjects who will enter Study A0081106, all subjects will initiate that 
study at a dose of 3.5 mg/kg/day [3 mg/kg/day for subjects 1 to 3 months of age] and may then escalate 
according to protocol requirements. 
a
Study drug will be administered TID in equally divided doses.
5.2. Breaking the Blind
This will be a double-blind study, ie, the subject/parent(s)/caregiver(s) and investigator will 
not know what study medication the subject will receive. The study drug and placebo will be 
identical in appearance in order to achieve the study blinding. 
Blinding codes should only be used for an individual subject and the blind broken only in an 
emergency situation or when it is critical to guide treatment and care of a given subject for 
reasons of subject safety. At the initiation of the study, the study site will be instructed on 
the method for breaking the blind for an individual subject.  The method will be either a
manual or electronic process. When breaking the blind is required the investigator should 
contact Pfizer before breaking the blind if possible. When the blinding code is broken for a 
subject, the reason must be fully documented and entered on the subject's case report form.
5.3. Drug Supplies
5.3.1. Formulation and Packaging
Study medication will be supplied by Pfizer as 20 mg/mL solution and matching placebo 
solution (see Appendix 2 for more detail).  All study medication is to be packaged in bottles 
that are child resistant.
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Pregabalin oral solution and the matching placebo contain a sweetening agent (sucralose) and 
a flavor (artificial strawberry).
5.3.2. Preparation and Dispensing
The Investigator will receive shipments of clinical drug supplies, must verify and 
acknowledge their receipt, and retain related documentation.
The Sponsor will provide study medication that will be dispensed through the 
telerandomization system (Interactive Voice Response System or IVRS) according to a 
randomization code provided by the Clinical Statistics Department.  The supplies will be 
identified by the IVRS using a container number.  The IVRS will monitor the study 
medication inventory and re-supply as necessary. 
The double-blind medication will be dispensed at Visit 3 and Visit 4.  The 1-week taper 
medication will be dispensed at Visit 6 or, for those subjects who discontinue before 
completing 2 weeks of treatment, at an unscheduled early termination visit.
5.3.3. Administration
Pregabalin or matching placebo will be administered orally TID. The dose (volume of 
solution) to be drawn from the bottle will be based on the weight of the subject at Visit 3 as 
well as the randomized treatment arm. 
Medication errors may result in this study from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the adverse event 
(AE) page of the case report form (CRF) and on the serious adverse event (SAE) form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) CRF page (refer to ADVERSE EVENT REPORTING
section for further details).
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5.3.4. Compliance
Subjects will be administered the study medication according to the instructions provided, 
and should adhere to the dosing schedule as closely as possible, with study medication 
administered TID.  Parent(s)/guardian(s)/caregiver(s) will complete a dosing diary and will
bring the diary and the medication bottle(s) back to the clinic at each visit.  Medication 
bottles will be weighed by the site staff when dispensed.  The bottles will again be weighed 
when returned at each visit, in order to determine the approximate volume of study 
medication used.  The caregiver will be queried about any volume discrepancies.  All 
dispensed study medication bottles should be locally kept available for checks by the study 
monitor.
Compliance will be defined as the percentage of required doses that were ingested.  Subjects 
who are consistently not compliant with the dosing regimen should be evaluated by the 
Investigator and discussed with the Pfizer Clinician for possible discontinuation from the 
study.
The following guidelines are provided in the event a pediatric subject does not retain the oral 
dose administered. If the subject regurgitates or spits out the study drug within 15 minutes 
after administration, the study drug should be re-administered at the same dose/volume.  If 
the subject regurgitates after more than 15 minutes have elapsed post administration, no 
additional study drug should be administered until the next scheduled dose.  Regurgitation 
and any additional dosing should be noted in the Dosing Diaries and captured in the dosing 
log CRFs.  Subjects with repeated regurgitation/redosing should be discussed with the Pfizer
clinician.
Administration of the liquid oral dose through a nasogastric (NG) feeding tube will be 
permitted and should be documented accordingly. If a subject has an NG tube that was 
inserted prior to entry into the study, it should be documented in the subjects’ “Medical 
History”.  If a subject has an NG tube inserted during the course of the study, it should be 
documented in the subjects’ “Concomitant Treatments” as a non-drug treatment.  Specifying 
whether the NG tube was inserted or removed during the study is to be documented.
5.4. Drug Storage and Drug Accountability
It is the site’s responsibility to handle and store the clinical study supplies under secure and 
locked conditions.  Note that pregabalin is a controlled substance in the US, and therefore 
must be stored according to US/Federal Drug Enforcement Agency (DEA) regulations in the 
US.  The US sites will provide a copy of the DEA license, and proper state/local license if 
applicable, to the Sponsor.  For those countries where pregabalin is not a controlled 
substance, the sites are to comply with their local regulations.
Study medication should be stored at 15-25C.  Access to the stored study medication should 
be limited to the Investigator, Subinvestigators, the Study Coordinator, and the Pharmacist 
(when applicable).  The Investigator, or an approved representative, eg, Pharmacist, will 
ensure that all study medications are stored in a secured area, under recommended storage 
conditions and in accordance with applicable regulatory requirements.  Investigators and site 
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staff are reminded to check temperatures daily (ie, manually or by using alarm systems to 
alert of any excursions) and ensure that thermometers are working correctly as required for 
proper storage of investigational products. Any temperature excursions should be reported to 
the sponsor.  If the study medication is determined to have been stored or delivered outside 
the outlined temperature range, the study team should be informed to evaluate the 
circumstances and provide appropriate guidance.
Storage conditions stated in the Single Reference Safety Document (SRSD) (ie, Investigator 
Brochure (IB)) will be superseded by the label storage.
The investigational product(s) must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor.  
Once a deviation is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.
Study medication will be dispensed under the supervision of investigator site personnel.
The Investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study medication(s).  All medication bottles dispensed to study subjects 
must be returned to the Investigator.  A Pfizer approved drug accountability form must be 
used.  The form must identify the study medication, including batch or code numbers, and 
account for its disposition on a subject-by-subject basis, including specific dates and 
quantities.  The forms must be signed by the individual who dispensed the drug, and copies 
must be provided to Pfizer.
Unused study drug and unused or used study drug materials must be kept in a secure location 
for final accountability and reconciliation.  At the end of the clinical trial all drug supplies 
unallocated or unused should be returned to a Pfizer vendor for destruction by completing the 
Destruction of Investigational Product Form.  The Investigator must provide an explanation 
for any destroyed or missing study drug and/or study drug materials.  Pfizer may authorize 
destruction at the trial site, and the Investigator must ensure that the materials are destroyed 
in compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Pfizer.  Destruction must be adequately documented.
5.5. Concomitant Medication(s)
Subjects are required to maintain their current AED therapy of 1-3 AE treatments at stable
dosages throughout the baseline, double-blind and taper phases of the study.  Subjects who 
require AED dose or regimen change during this period must exit the study.
Prior and concomitant medication information will be collected for all subjects for the period 
of 30 days prior to screening and during the study.  Once enrolled, any medication a subject 
takes other than the study medication specified by the protocol is considered a concomitant 
medication.  This includes all antiepileptic medications.  All concomitant medication must be 
recorded in the subject’s medical record and on the appropriate Case Report Form (CRF) 
page.  Information collected must include medication, start date and stop date.  Additionally, 
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for stable (nonPRN) antiepileptic medications, information collected must include 
medication, dosage, start date, and stop date.
5.5.1. Permitted Medications
The Investigator must be aware of all medications the subject is receiving prior to 
participation in the study.  The following listing of medications/classes of medications is 
meant to provide guidance regarding permitted medications but should not be considered a 
comprehensive list.  A member of the Pfizer study team should be consulted for assistance in 
determining whether or not specific medications not contained on this list should be 
permitted or prohibited.
Non-prescription medications, including herbal and home remedies, are also considered 
concomitant medications and should be recorded, along with other medications on the 
Concomitant Medication Log of the Case Report Form (CRF).
Examples of medications or classes of medications for which Episodic Use is permitted:

Acetaminophen/paracetamol;

Aspirin (chronic use also permitted);

Bronchodilators (chronic use also permitted);

Inhaled steroids (chronic use also permitted);

Nonsteroidal anti-inflammatory drugs (NSAIDs).
Examples of medications or classes of medications for which Chronic Use is permitted:

Antiepileptic drugs;

Aspirin;

Bronchodilators;

Inhaled steroids;

Multivitamins.
5.5.2. Prohibited Medications
Concurrent treatment with other investigational agents or devices is not allowed during the 
study.  The washout period of all centrally- acting compounds (CNS-active) that have to be 
discontinued per protocol has to be at least 2 weeks prior to screening Visit 1.
The use of gabapentin, Felbamate, or Vigabatrin is prohibited during the study.
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Administration of CNS – active compounds, regardless of indication, is prohibited during the 
trial, with the following exceptions:

Prescribed medications consistent with inclusion/exclusion criteria;

During study participation subjects must remain on stable AED regimens (same 
dosage as at screening and throughout the baseline observation period) of 1 to 
3 anti-epileptic treatments (eg, drugs or vagus nerve stimulator (VNS)) concomitantly 
throughout the trial. 
6. STUDY PROCEDURES 
The trial schedule of events and the specific procedures performed at each visit are shown in 
the Schedule of Activities.  A subject may be seen at any time for reasons of safety.
6.1. Visit 1 Screening (Day -14 3)
Prior to study entry the following screening procedures will be performed at Visit 1: 

Obtain written informed consent from one or both parents (if available), or the child’s 
legal guardian(s);

Review eligibility per inclusion/exclusion criteria;

Record demographic data (eg, date of birth, sex race, etc);

Record primary diagnosis; classify seizure types. Record complete medical history 
including seizure related history and antiepileptic medication history;

Perform full physical exam which includes vital signs, including blood pressure (BP)
and pulse;

Record height/length and weight;

Perform full neurological examination;

Record all prior/concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s, currently and within 30 days of Visit 1;

Perform computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
the brain if it has not been performed previously;
Note: in the event that a CT or MRI scan is needed, it should be performed as soon as 
possible after Visit 1 if it cannot be performed the day of this visit and must be 
completed and reviewed prior to randomization.

Perform 12-lead electrocardiogram (ECG).
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
Collect blood and urine specimens for clinical laboratory assessments.  If it is not 
feasible to obtain a urine sample, then no urine sample will be required.
Note: In the event that the subject has an abnormal laboratory value and the subject 
meets all other entry criteria, the laboratory test may be repeated within 7 days of the 
receipt of the screening visit results at the discretion of the investigator. If repeat test 
is within normal limits the subject may be considered eligible after consultation with 
the medical monitor or study clinician.
6.1.1. Visit 2 Baseline Video-EEG (Day -3 to -1)
The following activities will be performed at Visit 2, which is scheduled to assess partial 
onset seizure frequency by Video-EEG monitoring as an inpatient.

Placement of EEG electrodes and recording device and instruction of 
parent(s)/guardian(s)/caregiver(s) of its usage.

Dispense seizure event log to track observed seizure events during Video-EEG and 
train parent(s)/guardian(s)/caregiver(s) on its use and completion.

Record all concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s.

Assess and record adverse events.
6.2. Double-Blind Dose Escalation Phase
6.2.1. Visit 3 (Day 1 1) Randomization and Entry into Double-blind Dose Escalation 
Phase
Randomization: Subjects who satisfy all of the eligibility criteria at this study visit may be 
randomized and will receive the initial dose of study medication at the clinic during this visit. 
The following activities will be performed at Visit 3:

Verify conformance with entry criteria by reviewing inclusion/exclusion criteria.

Verify the criteria for total number of qualifying seizures has been met by review of 
the Video-EEG by the investigator/or designee.

Record all concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s.

Record weight and height/length.

Assess and record adverse events.

Perform brief physical examination which includes recording vital signs including 
blood pressure and pulse.
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•
Perform brief neurological examination.
•
Collect blood and urine specimens for clinical laboratory assessments.  If it is not 
feasible to obtain a urine sample, then no urine sample will be required.
•
Assign randomization number and dispense blinded study medication via 
tele-randomization system.
•
Train parent(s)/guardian(s)/caregiver(s) on study medication dosing and 
administration and demonstrate use of oral syringe/bottles.  Have 
parent(s)/guardian(s)/caregiver(s) practice dosing in office to verify comprehension of 
dosing instructions.
•
Administer first dose of study medication in clinic.
•
Dispense daily dosing diary.
•
Download Video-EEG recording data.
•
Transmit Video-EEG data to central reader for assessment.
•
Collect seizure event log and send to central reader. 
6.2.2. Telephone Visit (Day 4 ±1)
The Investigator (or designee) will contact the parent(s)/guardian(s)/caregiver(s) by 
telephone on Day 4 to ensure study medication compliance and provide guidance for 
accurate dosing as required.
•
Review compliance with dosing regimen.
•
Review completion of daily dosing diary.
•
Review concomitant medications and non-drug treatments and procedures, including 
any ongoing AED’s.
•
Assess and record adverse events.
6.3. Double-Blind Fixed-Dose Treatment Phase
6.3.1. Visit 4 (Day 6 ±1)
. If possible, 
this visit should be scheduled around the usual time of dosing.  
Parent(s)/guardian(s)/caregiver(s) should be instructed to hold the dosing of study medication 
prior to the visit.  If the visit is scheduled to occur more than 12 hours since the last dose, the 
subject should take the scheduled dose of study medication as usual. 
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The following activities will be performed at Visit 4:
•
;
•
For subjects who held their dose of study medication (see Section 
 
).
•
 
 
.
•
. 
•
 
.  Have parent(s)/guardian(s)/caregiver(s) administer this 
dose to verify continued comprehension of dosing instructions.  This dose 
should be taken using previously dispensed study medication and not the 
medication dispensed at Visit 4.  Record if a meal was consumed within 
2 hours prior to and 1 hour following this dose of study medication.
•
 
. 
•
For subjects who did not hold their dose of study medication (see
Section
).
•
Subject should take his/her dose of study medication as usual.  This dose 
should be taken using previously dispensed study medication and not the 
medication dispensed at Visit 4. 
•
 
•
 
 
 
•
Record all concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s.
•
Collect and record vital signs, including sitting or supine BP and pulse.
•
Evaluate and record study medication compliance.
•
Collect and review dosing diary.
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
Assess and record adverse events. 

Dispense study medication.

Dispense daily dosing diary.

Verify accurate dose administration via oral syringe/bottles. Have 
parent(s)/guardian(s)caregiver(s) demonstrate dosing in office to verify continued 
comprehension of dosing instructions.
6.3.2. Telephone Visit (Day 9 1)
The Investigator (or designee) will contact the parent(s)/guardian(s)/caregiver(s) by 
telephone on the third day of the fixed dose period to ensure study medication compliance 
and provide guidance for accurate dosing as required. 

Review compliance with dosing regimen.

Review completion of dosing diary.

Review concomitant medications and non-drug treatments and procedures, including 
any ongoing AED’s.

Assess and record adverse events.
6.3.3. Visit 5 Video-EEG (Day 12 to 14 1)
The following activities will be performed at Visit 5, which is scheduled to assess partial 
onset seizure frequency by inpatient Video-EEG monitoring.

Placement of EEG electrodes and recording device and instruction of 
parent(s)/guardian(s)/caregiver(s) of its usage.

Dispense seizure event log to track observed seizure events during Video-EEG and 
train parent(s)/guardian(s)/caregiver(s) on its use and completion.

Record all concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s.

Evaluate and record study medication compliance.

Collect and record vital signs.

Assess and record adverse events. 

Collect and review dosing diary.

Dispense daily dosing diary.
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•
Dosing compliance training/review and demonstration.
6.3.4. Visit 6 Begin Taper Phase (Day 15 ±2)
The Double-blind Fixed Dose Treatment phase is completed.  Following completion of the 
9-day fixed dose treatment and double-blind Video-EEG assessment subjects will begin the 
1 week Taper Phase.  Subjects who require early termination prior to Visit 6 should also 
begin the taper and follow the procedures for Visits 6 and 7 below. 
•
Collect blood and urine samples for clinical laboratory assessments. If it is not 
feasible to obtain a urine sample, then no urine sample will be required.
•
 
•
 
.
•
Record all concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s.
•
Evaluate and record study medication compliance.
•
Download on treatment Video-EEG recording data.
•
Transmit Video-EEG data to central reader for assessment.
•
Collect seizure event log and send to central reader. 
•
Assess and record adverse events.
•
Collect and record vital signs, including BP and pulse.
•
Collect and review dosing diary.
•
Dispense study medication for taper.
•
Dispense subject daily dosing diary.
6.4. Completion of Taper (End of Study/Early Termination)
The taper phase is completed at Visit 7.  Subjects will complete Study A0081042 at this visit.
Subjects may be screened for Study A0081106.
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6.4.1. Visit 7 (Day 22 ±3)
•
Record all concomitant medications and non-drug treatments and procedures, 
including any ongoing AED’s.
•
Perform 12-lead ECG.
•
Perform full physical examination which includes recording vital signs including BP 
and pulse.
•
Perform full neurological examination.
•
Collect blood and urine specimens for clinical laboratory assessments.  If it is not 
feasible to obtain a urine sample, then no urine sample will be required.
•
Evaluate and record study medication compliance.
•
Collect and review dosing diary.
•
Assess and record adverse events.
If the subject terminates the study early, then samples for clinical laboratory analysis and 
 
 will be collected at this visit.  If greater than 48 hr have elapsed since the last dose of 
study medication, then do not collect 
:
•
  
 
6.5. Subject Withdrawal
Subjects may be withdrawn from the study at any time at their parent(s)/guardian(s) request,
or they may be withdrawn at any time at the discretion of the investigator or sponsor for 
safety or behavioral reasons, or the inability of the subject/parent(s)/guardian(s) to comply 
with the protocol required schedule of study visits or procedures at a given site. 
Events to consider that may result in withdrawal could include but are not limited to:
•
Adverse events;
•
Intercurrent illness;
•
Loss to follow-up;
•
Lack of efficacy;
•
Exacerbation of seizures relative to screening/baseline;
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
Non-compliance with study medication, protocol requirements, or study related
procedures;

Serious eligibility or violations of the protocol (eg, the subject does not have the 
target disease);

Study termination by Sponsor or regulatory authorities;

Parent’s/guardian decision to withdraw/withdrawal of consent;

Investigator discretion in case of occurrence of any medical condition, requirement 
for prohibited concomitant medication or treatment, or circumstances that would 
expose the subject to substantial risk and/or would not allow the subject to adhere to 
protocol requirements.
Protocol specified withdrawal procedures are the same as those to be performed at Visits 6
and 7 (Section STUDY PROCEDURES).
In certain instances subjects who require withdrawal from this study may still be eligible for 
screening for entry into long term safety Study A0081106. Such cases should be reviewed 
with the Pfizer study clinician to determine further eligibility. Subjects who are withdrawn 
due to reasons of loss to follow up, protocol non-compliance, protocol violations or who have 
withdrawn consent will not be eligible for Study A0081106 under any circumstances.
Under certain circumstances, when subjects leave the study early (early termination ET), 
dosing with the taper medication may be inadvisable.  The decision not to taper the subject is 
upon agreement from the Sponsor's Study Clinician or Designee. If the taper will not be 
utilized then all assessments required at Visit 6 and 7 should be conducted as possible. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject’s parent/caregiver subject and information received during contact attempts must be 
documented in the subject’s medical record). In any circumstance, every effort should be 
made to document subject outcome, if possible.  The investigator should inquire about the 
reason for withdrawal, request that the parent(s)/guardian(s) return all unused investigational 
product, request that the subject/parent(s)/guardian(s) return for a final visit, if applicable, 
and follow-up with the parent(s)/guardian(s) regarding any unresolved adverse events. 
If the subject withdraws from the trial and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
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7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study sponsor will be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
Efficacy assessment will be evaluated based on seizure frequency in the last 48 hours of the 
2 week double-blind treatment phase determined from the central read of the Video-EEG. 
The seizure event log will be utilized by the central reader to assist in evaluation of difficult 
to interpret Video-EEG findings.  Assessment of efficacy is based on the reduction in the 
frequency of partial onset seizures during the same 48 hours of the 2 week double-blind 
treatment phase.
7.2. Acquisition of Seizure Counts: Video-Electroencephalogram (EEG)
Baseline and treatment phase Video-EEG will include a target minimum of 48 hours of 
continuous Video-EEG monitoring after placement of electrodes. Every reasonable attempt 
should be made to obtain the minimum target Video-EEG recording of 48 hours, which may 
require up to 72-hours of recording. Recognizing the inherent challenges in Video-EEG 
monitoring of pediatric subjects with epilepsy it is expected that the target minimum 48 hour 
Video-EEG recording may not be achievable in all cases. In the clinical investigator’s 
opinion, should circumstances (eg, clinical care, child behavior, consent, etc.) mandate a 
Video-EEG monitoring period less than 48-hours for a given subject, please contact the study 
clinician to review the subject’s clinical circumstances and document reasons for not 
achieving the target minimum Video-EEG duration. Results of the baseline monitoring must 
be available and reviewed by the central reader as soon as possible.  EEG tracings will be 
done with a placement of 20 recording electrodes including FP1, FP2, F3, F4, C3, C4, P3, 
P4, 01, 02, F7, F8, T3, T4, T5, T6, Fz, Cz, Pz and reference and ground electrodes. The 
initial recording impedance should be below 5 KOhms. 
7.2.1. Primary Efficacy Parameter
The primary efficacy parameter is the log transformed double blind 24-hour EEG seizure rate 
during Visit 6 (48-hour Video-EEG Assessment Phase) of the Double-Blind Treatment 
Phase.
This 24-hour seizure rate will be calculated for each subject using the following algorithm:
24
monitoring
EEG
-
Video
of
hours
of
#
phase
assessment
hr
-
48
blind
double
in
seizures
of
#
rate
seizure
EEG
hr
-
24
Blind
Double


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A log-transformation will be applied to the 24-hr seizure rate for each subject after adding a 
value of " 1"; ie, loge (double blind 24-hr EEG seizure rate + 1).  When the 
log-transformation is used, the quantity 1 is added to the double blind 24-hr EEG seizure rate 
for all subjects to account for any possible "0" seizure incidence. This will result in the 
following primary efficacy measure: loge (double blind 24-hr EEG seizure rate + 1). Results 
will be reported as “percent change in seizures” relative to placebo.  For example, a 
difference between one of the pregabalin doses and placebo of -0.400 on the log transformed 
scale for the double blind 24-hr seizure rate, translates into a 33% reduction in the double 
blind 24-hour EEG seizure rate of the pregabalin group from the placebo group 
(ie, 100%*[exp-0.400-1]=-33%]). 
A minimum of 24 hours of evaluable Video-EEG will be required to utilize the data for 
analysis of efficacy.  In cases where there is less than 24 hours of evaluable Video-EEG, the 
seizure rate will be set to missing.
The baseline 24-hr Video-EEG seizure rate will be calculated similarly.
7.2.2. Secondary Efficacy Parameter
A key secondary efficacy parameters is Responder Rate, defined as subjects who have a 
50% reduction from baseline in partial seizure rate during the double-blind 48 hour 
Video-EEG period.  Subjects meeting this criterion will be considered responders.
7.3. Safety Assessments
All subjects who have taken 1 dose of study medication (Safety population) will be included 
in the evaluation for safety, using adverse event data (eg, occurrence, nature, intensity, and 
relationship to study drug and dosing level), clinical laboratory data, and the results of 
physical examinations, vital signs, neurological examinations and ECGs.
7.4. Clinical Laboratory Assessments
Blood and urine samples for clinical laboratory measurements will be analyzed by a central 
laboratory.
7.4.1. Estimated Creatinine Clearance (mL/min/1.73m2) 
Creatinine clearance will be calculated by the central laboratory at Screening (Visit 1) only.  
For laboratories using the Jaffe chromogen reaction to quantify serum creatinine levels, the 
following equations should be used to calculate creatinine clearance.  Other equations may be 
considered when serum creatinine levels are measured by other methods. 
For Subjects 1 year of age and <4 years of age:
ClCR = 0.55 × length (cm)/serum creatinine (mg/dL) 
For Subjects 1 month of age and <1 year of age:
ClCR = 0.45×length (cm)/serum creatinine (mg/dL)
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If the unit of the serum creatinine value is in micromoles/L, the serum creatinine 
concentration must first be converted to mg/dL using the following equation.
Converting serum creatinine concentration from μmoles/L to mg/dL:
Serum Creatinine (mg/dL) =
Serum Creatinine (μM/L)
88.4
7.4.2. Hematology 
Blood samples will be collected at Screening (Visit 1), Visit 3, and at the completion of the 
Double-Blind Fixed Dose Phase (Visit 6) or at the Early Termination Visit, if necessary, to 
assess hematology parameters, including: red blood cell count (RBC), hemoglobin (HGB), 
hematocrit (HCT), platelets, and white blood cell count (WBC) (with differential), 
neutrophils, lymphocytes, monocytes and eosinophils.
7.4.3. Clinical Chemistry
Blood samples will be collected at Screening (Visit 1), Visit 3, and at the completion of the 
Double-blind Fixed Dose Phase (Visit 7) or at the Early Termination Visit, if necessary, to 
assess clinical chemistries, including: total bilirubin, direct and indirect bilirubin, alkaline 
phosphatase (ALP), alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), creatine phosphokinase (CPK) blood urea nitrogen (BUN), creatinine, 
glucose, total protein, albumin, total cholesterol, triglycerides, sodium, potassium, chloride 
and calcium.  In addition, Endocrine panel (free T4 and TSH, IGF-1, and IGFBP-3) and 
Hepatitis serology (Anti-HAV IgM; S-HB Ag; S-HCV) will be assessed at Visit 1 only.
Approximate blood volumes to be obtained, per visit, are as follows, for children >5kg in 
weight*:
V1 Screening:
10.5 mL
V3:
4.5 mL
V4: 
<2 mL (for 
)
V6:
4.5 mL plus <1 mL (for 
)
V7 EOS or ET:
4.5 mL plus optional <1 mL (for 
)
Unscheduled visit:
12.3 mL maximum (all testing optional)
: 
<1 mL 
* Blood sampling may be reduced for potential subjects who do not have the weight/blood volume capacity to 
undergo the protocol-specified blood collection requirements [for example <5 kg], as per local regulations and 
institutional guidelines. Prior to implementation of any reduction in blood sampling, the investigator is required 
to contact the Pfizer Study Clinician (via e-mail or phone) to discuss the applicability of a proposed reduced 
blood sampling plan. At a minimum, samples for chemistry and hematology will be collected at indicated 
visits.
7.4.4. Urinalysis
Urine samples will be collected at Screening (Visit 1), Visit 3, and completion of the 
Double-blind Fixed Dose Phase (Visit 6) or at the Early Termination Visit, if necessary, to 
assess the following: pH, specific gravity, colorimetric urine protein, glucose and ketones.  
Microscopic analysis will be performed only if the results of the urinalysis are abnormal and 
will include: red blood cells (RBCs), white blood cells (WBCs), casts, crystals, and bacteria.  
If it is not possible to collect a urine sample, despite appropriate efforts, the urine sample can 
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be omitted for that visit.  The reason for lack of sample must be recorded and documented in 
source documentation.
7.5. Vital Signs, Height/Length and Weight
Blood pressure and pulse in the sitting or supine position are to be recorded at each visit as 
specified in the STUDY PROCEDURES section. Height/length will also be recorded at the 
Visit 1 and Visit 3, Weight will be recorded at Visits 1 and 3.  Weight recorded at Visit 3 will 
be used to calculate the dosing assignment for all subsequent visits. 
7.6. Physical and Neurological Examination
A physical examination will be performed and must be completed by a Medical Doctor 
(MD), Doctor of Osteopathy (DO), Nurse Practitioner (NP) or Physician Assistant (PA) or 
appropriate equivalent based upon normative country specific practices.
Full physical and neurological exams will be performed at Visit 1 and Visit 7 (ie, at the 
completion of the study or early termination). A brief physical exam and neurological exam
documenting significant changes from the baseline exam will be performed at Visit 3.
Physical examinations will evaluate the following body systems/organs: general appearance; 
dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and 
neurological. 
Any clinically significant changes from the entry examination will be recorded as adverse 
events and the specific finding(s) documented with an Investigator Comment. 
Neurological exam will assess: level of consciousness, mental status, cranial nerve 
assessment, muscle strength and tone, reflexes, pin prick and vibratory sensation (the latter 
using a 128-Hz tuning fork), coordination and gait.
7.7. Electrocardiogram (ECG)
A 12-lead ECG will be performed at screening (Visit 1) and at the completion of the study
(Visit 7). A central ECG reader will be used for this study.  The following parameters will be 
assessed: PR interval, RR interval, QRS complex/duration, QT interval, QTc, and heart rate.
7.8. Imaging
MRI or CT scan with contrast will be performed at screening if not performed previously. 
Results must be available and reviewed as soon as possible and before the subject is 
randomized.
Note: in the event that a CT or MRI scan is needed, it must be performed as soon as possible 
after Visit 1 if it cannot be performed on the day of that visit. 
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
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For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer or its 
designated representative.  For all adverse events, sufficient information should be obtained 
by the investigator to determine the causality of the adverse event.  The investigator is 
required to assess causality.  Follow-up by the investigator may be required until the event or 
its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial. 
8.2. Reporting Period
For serious adverse events, the active reporting period to Pfizer or its designated 
representative begins from the time that the subject provides informed consent, which is 
obtained prior to the subject’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving investigational product, through and including 
28 calendar days after the last administration of the investigational product.  Serious adverse 
events occurring to a subject after the active reporting period has ended should be reported to 
the Sponsor if the investigator becomes aware of them; at a minimum, all serious adverse 
events that the investigator believes have at least a reasonable possibility of being related to 
study drug are to be reported to the Sponsor.

AEs (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of study treatment through last subject visit. 
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation subject
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;
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
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.5. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;
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
Is life-threatening (immediate risk of death);

Requires in subject hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject, or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.5.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section on Serious Adverse Event Reporting Requirements) 
8.5.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis 
and an alkaline phosphatase 2 X ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:
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
For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or 3 times the 
upper limit of normal (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/INR, and 
alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
subject, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted.  All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for liver function test (LFT)
abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs. Such potential Hy’s Law cases should be reported as serious 
adverse events.
8.6. Hospitalization
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria.  Admission also includes transfer within the hospital 
to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit).
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;
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
Routine emergency room admissions;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.7. Severity Assessment
As required on the adverse event case report forms, the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  
For purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
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Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious adverse event.  For example, a headache may be severe 
(interferes significantly with subject's usual function) but would not be classified as serious 
unless it met one of the criteria for serious adverse events, listed above.
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to
investigational product” for reporting purposes, as defined by the Sponsor (see section on 
Reporting Requirements).  If the investigator's causality assessment is "unknown but not 
related to investigational product", this should be clearly documented on study records. 
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.9. Withdrawal Due to Adverse Events (See also section on Subject Withdrawal)
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page. 
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.
8.10. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject’s/parent/legal guardian.  In addition, each study
subject’s/parent/legal guardian will be questioned about adverse events.
8.11. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.
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8.11.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator
awareness of the eventIn particular, if the serious adverse event is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available 
adverse event information.  This timeframe also applies to additional new information 
(follow-up) on previously forwarded serious adverse event reports.
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the adverse event case report form.  In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications and illnesses must be 
provided.  In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative. 
8.11.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the CRFs as well as 
on the form for collection of serious adverse event information.
8.11.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse events reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
Sample Size Justification:
A total of approximately 123 subjects was originally planned to be randomized in this study 
in a 2:2:1 ratio of placebo, Level 1 and Level 2. This randomization scheme was considered 
to allow a sufficient number of patients to be studied at each dose level for safety, while 
providing adequate power of the study to detect a significant effect for dose Levels 1 and 2.  
Randomization of 123 subjects accounted for a potential 10% discontinuation rate, with a 
resulting sample size of the necessary 110 subjects (44 placebo, 44 Level 1, and 22 Level 2).
The sample size rationale was based on the observed difference in loge (double-blind 24-hour 
seizure rate + 28
1 ) between pregabalin and placebo (Table 4).  A difference in the least 
squares means between pregabalin and placebo was estimated to be -0.668 and -0.448 for 
600- and 300 mg doses respectively, with a pooled standard deviation (SD) of 0.73.  This 
difference and pooled SD was obtained from a meta analysis of the -34, -11, -09 study data in 
adult subjects with partial onset seizures. 
For the purposes of this study, the same SD was also used to assess the power and sample 
size requirements for comparing each pregabalin group to placebo.  It was noted that while 
every effort will be put forth to minimize the variability in conducting this study, a larger 
than anticipated SD may actually be observed. To address this potential concern, a blinded 
sample size re-estimation procedure was planned to occur when approximately two thirds of 
the subjects that make up initial sample size had the opportunity to complete the study. 
Details of the sample size re-estimation procedure were included in the Statistical Analysis 
Plan.
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Table 4.
Power Calculations and Sample Size Assumptions for the Primary Endpoint 
(loge (24-hour seizure rate + 28
1 ; original constant)
Comparison
Log 
Transformed 
Difference 
from Placebo
Percent 
Difference 
from Placebo
Number of 
Pregabalin 
Subjects
Number of 
Placebo 
Subjects
SD (log 
transformed 
24-hour 
seizure rate)
Power
Expected difference1
between Level 2
-0.668
-48.7%
22
44
0.73
0.932
Expected difference1
between Level 1 
-0.448
-36.1%
44
44
0.73
0.812
1 Expected difference is the observed difference between the specified pregabalin dose minus placebo based on 
a meta analysis of studies -009, -011, and -034 based on the log transformed 24-hour seizure rate. 
Level 1 and Level 2 doses are anticipated to result in exposure that approximates 300 mg/day 
and 600 mg/day, respectively, achieved in adults. 
In order to address the primary analysis comparison between placebo and the Level 2 dose 
group, a sample size of 44 subjects in the placebo group and 22 subjects in the Level 2 dose 
group were anticipated to provide at least 90% power to detect a true difference of -0.668 
using a two-sided test at the 0.05 level of significance with a standard deviation of 0.73. 
In order to address the primary analysis comparison between placebo and the Level 1 dose 
group, a sample size of 44 in each of these two groups was anticipated to provide at least 
80% power to detect a true difference of -0.448 using a two-sided test at the 0.05 level of 
significance with a standard deviation of 0.73. 
Randomization will be stratified by subject age (Stratum 1: <1 year of age; 
Stratum 2: 1-2 years of age; Stratum 3: >2 years of age). Every reasonable effort will be 
made to enroll a minimum of 10 subjects in each of the 3 age strata.
The constant utilized in the log transformation of the 24-hour seizure rate for the primary 
analysis was changed while the study was ongoing, from “1/28” to “1” due to differences in 
the seizure rate distribution assumed during design of the study and the observed, blinded 
data distribution. Changing the constant to 1 provides a better approximation of a normal 
distribution of the seizure data. The constant “1/28” added variability to the data and 
decreased its normality. The planned difference for the blinded sample size re-estimation 
between pregabalin 7 mg/kg/day and placebo was -0.355 based on an update of the meta 
analysis referenced in Table 4, using the constant “1” in place of “1/28”. 
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Blinded Sample Size Re-estimation:
While every effort is being put forth to minimize the variability in conducting this study, a 
larger than anticipated SD may actually be observed.  To address this potential concern, a 
blinded sample size re-estimation procedure was applied when approximately two thirds of 
the subjects that make up initial sample size had the opportunity to complete the study (ie, no 
ongoing subjects were included in this sample size re-estimation procedure). 
The blinded sample size re-estimation procedure for this study originally did not allow for a 
reduction in the planned sample size of 123 subjects, nor did it pre-specify any cap to the 
suggested increase in sample.  The procedure was conducted by a statistician not associated 
with the study during its conduct or during the final analysis.  There was no penalty applied 
to the final analysis p-values or confidence intervals for assessing treatment difference from 
placebo due to this blinded sample size re-estimation procedure.  Details of the sample size 
re-estimation procedure are included in the Statistical Analysis Plan.
The blinded sample size re-estimation procedure utilized for this study was revised per 
Statistical Analysis Plan and did not allow for a reduction in the planned sample size of 123 
subjects total or require an increase in sample size greater than 150 subjects. The following 
decision rules were utilized for the blinded sample size re-estimation:
a.
If the recalculated sample size is less than or equal to the original sample size of 123 
subjects total, then the sample size will not be adjusted.
b. If the recalculated sample size is greater than the original sample size (123 subjects 
total) then the following information will be considered:

If the re-estimated sample size is between 123 and 150, then the sample size will 
be adjusted to the re-estimated sample size.

If the re-estimated sample size exceeds 150 then the sample size will be increased 
to 150.
The blinded sample size re-estimation was conducted, and the sample size will be increased 
to approximately 150 subjects. 
9.2. Efficacy Analysis
The efficacy analyses will be performed on the modified intent to treat (mITT) population 
which consists of randomized subjects who took at least one dose of study drug during the 
double-blind treatment phase, have a baseline with at least one partial onset seizure identified 
by Video-EEG and a follow-up Video-EEG. Video-EEG assessments must include at least 
24 hours of evaluable monitoring to be eligible for the mITT population.
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9.2.1. Analysis of Primary Endpoint 
The primary analysis will be performed on the primary endpoint, loge (double blind 24-hour 
EEG seizure rate + 1), using a linear model with treatment, age stratum, and geographical 
region (ie, US, Europe, Asia, Rest of the World) as fixed factor effects, and loge (baseline 
24-hour EEG seizure rate + 1) as a continuous covariate. This linear model will include both
dose groups of pregabalin. Each dose of pregabalin and placebo will be compared using a 
sequential step-wise testing procedure outlined in Section 9.2.3.  Least square means will be 
calculated using the observed marginal distribution.
Two-sided 95% confidence intervals of the difference between the least square means will be 
calculated by using the appropriate least square means and their standard errors.  Results will 
be reported as “percent reduction in seizures” relative to placebo.  For example, a difference 
between one of the pregabalin doses and placebo of -0.400 on the log transformed scale for 
the 24-hour seizure rate, translates into a 33% reduction in the 24-hour seizure rate of the 
pregabalin group from the placebo group (ie, 100%*[exp-0.400-1]= -33%]). 
The change from baseline in 24-hour seizure rate, with and without log-transformation, will 
be analyzed descriptively for each treatment group using tables and plots.
9.2.2. Analysis of Secondary Endpoints
A key secondary efficacy parameters is Responder Rate, defined as subjects who have a 
50% reduction from baseline in partial seizure rate during the double-blind 48 hour 
Video-EEG period.  Subjects meeting this criterion will be considered responders.
Subjects who do not meet the favorable responder definition will be considered 
non-responders.  The dichotomized Responder variable will be analyzed using a logistic 
regression model via maximum likelihood estimation with the following covariates: 

treatment group, as a fixed effect;

age stratum, as a fixed effect;

geographical region (ie, US, Europe, Asia, Rest of the World as data allows) by 
pooling of investigator centers, as a fixed effect.
Comparisons will be performed for each pregabalin dose relative to placebo using a 
maximum likelihood tests and confidence intervals.  The definitive statistical summary for 
treatment group comparisons will be the odds ratios. 
The responder outcomes will be summarized descriptively by treatment group using counts 
and percentages. 
9.2.3. Multiple Testing Procedures
For the primary analysis which assesses the double blind 24-hour EEG seizure rate, the 
following step-wise testing procedure will be applied:
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
Step 1: Test the difference between the Level 2 group and placebo.

H01: Level 2 – Placebo = 0

Ha1: Level 2 – Placebo ≠ 0
If H01 is rejected (p 0.05) then move to step 2, otherwise claim no difference and 
stop.

Step 2: Test the difference between the Level 1 group and placebo.

H02: Level 1 – Placebo = 0

Ha2: Level1 – Placebo ≠ 0
If H02 is rejected (p 0.05) then claim a difference for all the comparisons, otherwise 
claim differences between 14 mg/kg/day and placebo only.
All other inferences will be performed at the nominal level, and may not control the type I 
experiment wise error rate at 0.05. 
9.3. Sensitivity Analysis to Assess the Impact of Missing Data
The primary analysis of the primary endpoint will be evaluated for violations to model 
assumptions.  A non-parametric analysis of covariance based on the rank transformed data 
will be performed and evaluated for efficacy results in combination with the primary 
analysis. 
Due to the use of Video-EEG assessments to collect seizure data (at baseline and the end of 
the double blind period), subjects who discontinue from the study may have no post-baseline 
efficacy data. If there is missing post-baseline 24-hour seizure rate for more than 5% of any 
treatment group, then multiple imputation techniques will be applied to the primary analysis 
model. The multiple imputation will consider age stratum and gender and will impute data 
using the method of propensity scores.
As a supplemental analysis, a generalized linear model assuming a Poisson distribution and 
canonical log link function will be applied to the raw seizure counts.5,6  The model will have
an off-set parameter for the amount of time (ie, loge(days)) the subject was in the double
blind treatment phase. Over-dispersion will be investigated, and if it appears to exist for this 
model, then the scale parameter will be set to the deviance in the Poisson model, and a 
negative binomial will be also be explored in addition to analyzing the data with a 
quasi-likelihood function. This analysis will assume missing completely at random, and will 
assess seizure frequency in relation to the amount of time each subject was at risk relative to 
their time on treatment. In addition, this analysis will not be subject to any potential 
extrapolation of applying the 24 hour seizure rate. 
Further details regarding sensitivity analyses will be provided in the statistical analysis plan. 
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9.4. Safety Analysis
Safety will be assessed by summarizing and reviewing the nature, frequency, relationship to 
study drug,  and severity of AEs, the results of physical and neurological examinations, 
weight, vital signs, ECG’s and the results of clinical laboratory tests including hematology, 
blood chemistry, and urinalysis. Subject listings of all laboratory data will be provided using 
a standard computer program for laboratory data display.  The listings will highlight values 
outside normal limits and those considered to be possible clinically important deviations.  
Medical history, physical exams, assessment of vital signs, and ECG will be displayed in 
standard listings and summary tables.
9.5. Interim Analysis
Two Interim Safety Analyses (ISA) will be conducted to assess safety.  The timing of the 
first interim analysis will be when approximately the first one-third of the subjects enrolled 
have had an opportunity to complete the study.  The second ISA will be performed when 
approximately two-thirds of the subjects have had an opportunity to complete the study.  A 
charter to delineate the safety parameters to be assessed and the general procedures to govern 
the ISA will be the subject of a separate document.
The ISA will involve the descriptive review of deaths, SAEs, and discontinuations due to 
AEs.
Since the ISA may include a review of the seizure data and the primary efficacy endpoint is a 
function of seizures, if the study is stopped for safety purposes then futility will be declared 
for efficacy. This strong rule does not require any type I error (alpha) spending penalty for 
the primary efficacy analysis. 
9.6. Data Monitoring Committee 
This study will use an External Data Monitoring Committee (EDMC). The DMC will be 
responsible for ongoing monitoring of the efficacy and safety of subjects in the study 
according to the Charter.  The recommendations made by the DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
which are not endpoints, to regulatory authorities, as appropriate. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
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It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonization (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
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If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  The 
investigator must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should 
be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 1996 & 
2008). 
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonization guideline on Good Clinical Practice, and applicable local 
regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
subject.
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
of subject personal data.
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The informed consent document(s) must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document used during the informed consent process must be reviewed 
by the sponsor, approved by the IRB/IEC, and available for inspection.
The investigator must ensure that each study subject’s legal representative is fully informed 
about the nature and objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from the subject's legal representative before any study-specific activity is 
performed. The investigator will retain the original of each subject's signed consent 
document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Other Participating Countries
End of Trial in all other participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of Pregabalin at any time.
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If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 1 week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov). Pfizer registers study 
protocols and posts Basic Results on ClincialTrials.gov for Pfizer-sponsored interventional 
studies in human subjects that evaluate the safety and/or efficacy of a Pfizer product; and for 
Pfizer-sponsored NI studies, regardless of design or data source, where the primary endpoint 
is to study whether a Pfizer product is associated with an increased incidence of a specific 
safety outcome.
The results are posted in a tabular format called Basic Results. 
For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, FDA-approved products, 
Pfizer posts results within one year of the primary completion date (PCD).  For 
studies involving products approved in any country, but not FDA approved, Pfizer 
posts results one year from last subject, last visit (LSLV);

For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of US regulatory approval, or 
one year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US);

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year of discontinuation of the program (if 
there are no plans for outlicensing or within two years if outlicensing plans have not 
completed).
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
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15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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16. REFERENCES
1.
Hermann BP, Austin J. Psychosocial status of children with epilepsy and the effects of 
epilepsy surgery. In: Wylie E, editor. The treatment of epilepsy: principles and 
practices. Philadelphia: Lea & Febiger; 1993: p. 1141-8.
2.
Ott D, Siddarth P, Gurbani S, et al. Behavioral disorders in pediatric epilepsy: unmet 
psychiatric need. Epilepsia 2003; 44(4):591-7.
3.
Berg AT, Berkovic SF, Brodie MJ, et al. Revised Terminology and Concepts for 
Organization of Seizures and Epilepsies. Epilepsia 2010; 51: 676-685.
4.
Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel J. Glossary 
of Descriptive Terminology for Ictal Semiology: Report of the ILAE Task Force on 
Classification and Terminology. Epilepsia 2001 42(9): 1212-1218. 
5.
McCullagh, P. and Nelder, J.A. (1989). Generalized Linear Models, Second Edition, 
New York: Chapman & Hall/CRC. 
6.
Stokes, M.E., Davis, C.S., and Koch, G.G. (2000). Categorical Data Analysis Using the 
SAS System, Second Edition, Cary, NC: SAS Institute.
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Appendix 1. International League Against Epilepsy 2010 and Revised 1981 
Classification
2010 ILAE criteria:
"Descriptors of focal seizures. For pragmatic reasons and to facilitate continuity with the 
1981 classification of seizures, descriptors of focal seizures may be used, individually or in 
combination with other features depending on the purpose.  We have listed examples chosen 
to facilitate continuity with the 1981 seizure document and which have been drawn from the 
glossary of ictal semiology (Blume et al 20014) (Table 2).
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Revised 1981 criteria:
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Appendix 2. Clinical Dosing Instructions for Liquid Oral Solution: 
Liquid Oral Solution
Pregabalin 20 mg/mL and matching placebo oral solutions are provided as clear, colorless, 
flavored solutions in bottles.  To accommodate the broad dose range that may be encountered 
during clinical studies, pregabalin 20 mg/mL and matching placebo oral solutions can be 
administered using a variety of oral dosing syringes.  An example of the syringes are 
provided in this document for reference. 
Subjects/parents/guardians will receive training on dose preparation, administration, storage, 
and disposal prior to release for outpatient dosing.  Parent/caregivers will need to 
demonstrate proper use of dosing supplies to site personnel at Visits 3, 4 and 5 and sites will 
be required to document training and demonstration.
DOSING:
Dosing is accommodated by the use of either a 0.5, 1.0, 3.0, or 10.0 mL oral dosing syringe 
depending on the required dose.  The 1 mL oral dosing syringe can accommodate 0.1-1 mL 
doses in 0.1 mL increments.  The 3 mL oral dosing syringe can accommodate doses from 
1.25-3.0 mL in 0.25 mL increments. The 10 mL oral dosing syringe can accommodate doses 
from 3.5-10 mL in 0.5 mL increments.
Illustrations of the oral dosing syringes are provided in Figure 1.
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Figure 1.
Liquid Oral Dosing Syringes (1, 3, and 10 mL left to right)
LIQUID ORAL DOSING AND ADMINISTRATION PROCEDURE:
1. Insert the appropriate oral dosing syringe into the bottle.
2. Pull back on the plunger of the oral dosing syringe to the appropriate measurement 
mark on the oral dosing syringe barrel.
3. Measure the dose by aligning the fin on the plunger to the appropriate marking on the 
barrel (Figure 2). 
4. Place the oral dosing syringe down onto a clean surface and securely close the bottle.
5. Deliver the dose by placing the tip of the oral dosing syringe into the mouth of the 
subject with the subjects head tilted slightly back and pushing the plunger to expel the 
liquid.  Be careful to not expel the dose directly into the back of the throat, to avoid 
choking.  Alternatively dose can be transferred into a cup for administration.
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6. Remove the plunger from the oral dosing syringe and rinse the barrel and plunger 
under warm water.  Allow the plunger and barrel to air dry or use a fresh paper towel 
or clean cloth to dry.  When dry, push the plunger back into the barrel prior to the 
next dose. 
Figure 2.
Liquid Oral Dosing Example
LIQUID DOSING SUPPLIES:
Subjects should be supplied with a suitable oral dosing syringe for self-administration. 
Examples of oral dosing syringes are provided in Figure 1.
STABILITY AND STORAGE:
A single dose that has been prepared in an oral dosing syringe should be administered within 
1 hr.  Bottles containing the dosing solution should be stored at room temperature.
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Appendix 3. List of Abbreviations
A
AE
Adverse Event
AED
Antiepileptic Drug
2-
Alpha-2-Delta
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
Area under the curve
B
B12
Vitamin B12
BID
Twice Daily
BP
Blood Pressure
C
CI
Confidence Interval
CLcr
Creatinine Clearance
Cmax
Maximum Concentration
CNS
Central Nervous System
CP
Complex Partial
CR
Controlled Release
CRF
Case Report Form
CT
CAT Scan (Computerized 
Tomography Scan)
CTA
Clinical Trial Application or Clinical 
Study Application
D
DMC
Data Monitoring Committee
DPN
Diabetic Peripheral Neuropathy
DSM-IV
Diagnostic and Statistical Manual of 
Mental Disorders, Version IV
E
ECG
Electrocardiogram
EEG
Electroencephalogram
ET
Early Termination
EMA
European Medicines Agency
F
FDA
Food and Drug Administration
FSFV
First Subject First Visit
G
GCP
Good Clinical Practice
GI
Gastrointestinal
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H
HEENT
Examination of Head, Ears, Eyes, 
Nose, and Throat
I
ISA
Interim Safety Analysis
IB
Investigator’s Brochure
ICH
International Conference on 
Harmonisation
IEC
Independent Ethics Committee
IND
Initial New Drug
IRB
Institutional Review Board
L
LFT
Liver Function Test
LSLV
Last Subject Last Visit
M
MHP
Mental Health Professional
mL
Milliliter
mITT
Modified Intention to Treat
MRI
Magnetic Resonance Imaging
N
N/A
Not applicable
NONMEM
Nonlinear Mixed Effects Modeling
Numeric rating scale
NSAID
Nonsteroidal anti-inflammatory drug
P
PBO
Placebo
PD
Pharmacodynamic
PHN
Postherpetic Neuropathy
PI
Principal Investigator
PK
Pharmacokinetic/Pharmacokinetics
PP
Per Protocol
R
RBC
Red Blood Cell
RDC
Research Diagnostic Criteria
S
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SD
Standard Deviation
SE
Status Epilepticus
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SGTC
Secondarily Generalized Tonic-Clonic 
Seizures (a type of Partial Epilepsy
Seizure)
SP 
Simple Partial
SRSD
Single Reference Safety Document
SSID
Single Subject Identification Number
T
TID
Three Times A Day
U
US
United States
V
V
Visit
VNS
Vagus Nerve Stimulation
W
WBC
White Blood Cell
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SAP_000.pdf: 
Protocol A0081042 Statistical Analysis Plan
Page 1
Protocol A0081042
A DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP,
MULTICENTER STUDY OF THE EFFICACY AND SAFETY OF PREGABALIN AS
ADJUNCTIVE THERAPY IN CHILDREN 1 MONTH THROUGH <4 YEARS OF
AGE WITH PARTIAL ONSET SEIZURES
Statistical Analysis Plan
(SAP)
Version:
1 (Final) Author:
 (inVentiv Health Clinical, LLC)
Date:
12-FEB-2014
Version
2 (Amendment 1) Final
By  
Date:
03-Mar-2017
Version
3 (Amendment 2) Final
By  
Date:
09-Aug-2017
Version 
4 (Amendment 3) Final
By
Date 
02-Mar-2018
Version 
5 (Amendment 4) Final
By
Date 
06-Apr-2018
PPD
PPD
PPD
PPD
PPD
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Protocol A0081042 Statistical Analysis Plan
Page 2
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................9
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................9
3.1. Blinded Sample Size Re-estimation..........................................................................9
3.2. Interim Safety Analyses ..........................................................................................10
3.3. Unblinding and Final Analysis................................................................................10
4. HYPOTHESES AND DECISION RULES.........................................................................11
4.1. Statistical Hypotheses .............................................................................................11
4.2. Statistical Decision Rules........................................................................................11
5. ANALYSIS SETS ...............................................................................................................11
5.1. Full Analysis Set (mITT) ........................................................................................11
5.2. ‘Per Protocol’ Analysis Set .....................................................................................12
5.3. Safety Analysis Set..................................................................................................12
5.4. Other Analysis Sets .................................................................................................12
5.4.1. ITT Analysis Set.........................................................................................12
5.5. Treatment Misallocations........................................................................................12
5.6. Protocol Deviations.................................................................................................12
6. ENDPOINTS AND COVARIATES ...................................................................................12
6.1. Efficacy Endpoint(s) ...............................................................................................12
6.1.1. Primary Efficacy Endpoint .........................................................................12
6.1.2. Secondary Efficacy Endpoints....................................................................13
6.2. Safety Endpoints .....................................................................................................13
6.2.1. Adverse Events...........................................................................................13
6.2.2. Prior and Concomitant Treatments and Medications .................................14
6.4. Covariates................................................................................................................14
7. HANDLING OF MISSING VALUES ................................................................................15
CCI
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Protocol A0081042 Statistical Analysis Plan
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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................15
8.1. Statistical Methods ..................................................................................................15
8.1.1. Analyses for Continuous Data....................................................................15
8.1.2. Analyses for Count Data.............................................................................15
8.1.3. Analyses for Binary Endpoints...................................................................16
8.2. Statistical Analyses .................................................................................................16
8.2.1. Analysis of Primary Endpoints...................................................................16
8.2.2. Analysis of Secondary Endpoints...............................................................18
8.2.3. Analysis of Safety Data ..............................................................................18
8.2.3.1. Adverse Events..........................................................................18
8.2.3.2. Laboratory Data (Hy’s Law).....................................................19
8.2.4. Summary of Efficacy Analyses ..................................................................21
9. REFERENCES ....................................................................................................................23
10. APPENDICES ...................................................................................................................24
LIST OF TABLES
Table 1.
Power Calculations and Sample Size Assumptions for the Primary 
Endpoint (loge (24-hour seizure rate + 28
1 ))..........................................................8
Table 2.
Description of Stratifying Factors and Their Levels ............................................15
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................24
Appendix 2. STATISTICAL METHODOLOGY DETAILS..................................................25
Appendix 2.1. Further Details of Interim Analyses.................................................................25
Appendix 2.1.1. Blinded Sample Size Re-estimation..............................................................25
Appendix 2.2. Further Details of the Statistical Methods........................................................26
Appendix 2.2.1. Analysis Strategy Using Multiple Imputations.............................................26
Appendix 2.2.2. Analysis Strategy Using a Poisson Model ....................................................29
Appendix 2.2.3. Pooling ..........................................................................................................30
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Protocol A0081042 Statistical Analysis Plan
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1. AMENDMENTS FROM PREVIOUS VERSION(S)
Status of the study when amendments were made: Study is still ongoing and blinded. 
Amendment 
1
Date: 
03-Mar-201
7
Version 2
1. The following statement added in 
Section 3.1 Blinded Sample size 
re-estimation section:
Pfizer and FDA agreed on a proposed sample 
size of no more than 150 subjects.
2. Reference Section Changed:
From: Kieser, M. and Friede, T. (2003). 
Simple Procedures for Blinded Sample 
Size Adjustment that Do Not Affect the 
Type I Error Rate. Statistics in Medicine,
32: 3571-3581.
To: Friede, T and Kieser, M. (2011).  
Blinded Sample Size Recalculation for 
Clinical Trials with Normal Data and 
Baseline Adjusted Analysis. Pharmaceut. 
Statist., 10: 8-13.
1. To add the cap on 
sample size of N=150 
based on FDA 
agreement with Pfizer.  
For study A0081042, 
FDA agrees with 
Pfizer’s study sample 
size cap proposal: 
Archive Record: 
US20020055 -
pregabalin, Pediatric; 
Post Approval 
Commitment dated 
14-Oct-2016. 
2. To update the sample 
size re-estimation 
reference.
Amendment 
2
Dated 
09-Aug-201
7
Version 3
1. In the Statistical Power and Sample Size
section the following statement was added 
NOTE: Because the following sample size 
work occurred prior to study conduct and 
prior to review of blinded data, this section 
remains unchanged with respect to the 
constant 1/28 in the log transformation of 
the 24-hour seizure rate data and the 
differences between pregabalin and placebo.
2. In sections 6.1.1, 6.4, 8.2.1, Appendix 1, 
and Appendix 2.2.1, the constant in the log 
transformation of 24 hour seizure data is 
changed from “1/28” to “1”.
3. Appendix 2.1.1 Blinded Sample Size 
Re-estimation changed 
From: is the planned difference 
(ie, 7 mg/kg/day and placebo) as specified in 
the protocol (ie, -0.448). 
To: = -0.355 is the planned difference 
(ie, 7 mg/kg/day and placebo) for the sample 
1. Pfizer and FDA agreed 
to change the 
transformation of the 
primary endpoint due to 
distributional properties of 
the endpoint as follows: 
Add the constant “1” 
rather than “1/28” to the 
loge (24-hour seizure rate)
both in the sample size 
re-estimation (SSRE) plan 
and the study statistical 
analysis plan for the
primary analysis.
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Protocol A0081042 Statistical Analysis Plan
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size re-estimation.  The details for deriving this 
delta are in the SSRE plan.
Amendment 
3
Dated 
02-Mar-201
8
Version 4
Table 2, pooling of region has changed from:
Region
Countries
North 
America
United States
Europe
Belgium, Bulgaria, Croatia, 
France, Germany, Greece, 
Hungary, Italy, Netherlands, 
Poland, Portugal, Romania, 
Spain, United Kingdom
Asia 
Pacific
China, Malaysia, Philippines, 
Singapore, South Korea, Taiwan, 
Thailand
Rest Of 
World
Israel, South Africa, Serbia, 
Turkey, Ukraine
To:
Region
Countries
Asia Pacific
China, Malaysia, 
Philippines, South Korea, 
Taiwan, Thailand
Rest of the 
world 
Russia, Ukraine
North 
America + 
Europe + 
Middle East
United States, Belgium, 
Bulgaria, Germany, Spain, 
France, Greece, Hungary, 
Romania, Belarus, Israel, 
Lebanon, Serbia, Turkey 
In a blinded manner, due 
to enrolment and 
distribution of subjects in
each country, region
pooling needs adjustment
to ensure that each region 
includes a minimally
appropriate number of 
subjects for each 
treatment.
Section 8.1.1, 8.1.3 and 8.2.2 has been revised 
regarding region to reflect table 2 on the 
revised SAP.
Adjustment made to 
account for treatment 
representation. See 
previous note.
Appendix 2.2.3 also has been simplified 
regarding region pooling
See previous note.
Appendix 2.2.1 has been updated to add 
programming code for Multiple Imputation 
Details added to aid in 
programming.
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algorithm.
Section 8.1.3 was updated to allow for the 
removing of any non-treatment factor, from the 
responder analysis (key secondary endpoint)
model if that factor causes non-convergence of 
the model.
Allowance to remove 
factor added to ensure 
program can run.
Section 8.2.1 (other analyses) and 
Appendix 2.2.2 were updated to use the 
appropriate off-set time (V-EEG monitoring 
time – evaluable time).
Corrected to match with 
the numerator count time 
used in the sensitivity 
analysis.
Amendment 
4
Dated 
06-Apr-201
8
Version 5
Add the following equation in section 6.1.1, 
8.2.1 & Appendix 1 for additional presentation
of percent reduction of treatment difference 
relative to placebo
Based on FDA 
recommendation
(IND 49393: Pediatric 
Protocol A0081042 
Statistical Analysis Plan), 
for percent reduction
relative to placebo (back 
transformation estimated 
treatment difference) for 
the primary endpoint the 
SAP will be updated to 
add additional treatment 
difference relative to 
placebo estimation.
The changes in this SAP regarding the use of the constant “1” in the log transformation 
of the seizure rates supersede the references to “1/28” used in the protocol. In 
particular, the transformation used for the primary endpoint in the protocol is now 
replaced in the primary analysis by the transformation used in this SAP. This SAP 
serves as the final documentation of the transformation used for the primary endpoint 
and analysis – loge(double blind 24-hour EEG seizure rate +1).
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicized.  The current 
protocol version is dated 30 December 2013 (Original).
2.1. Study Design
Study A0081042 is a double-blind, placebo-controlled, randomized, parallel group, 
multicenter study to evaluate efficacy and safety of two dose levels of pregabalin compared 
to placebo administered TID as adjunctive therapy in pediatric subjects 1 month (44 weeks 
gestational age) through <4 years of age with partial onset seizures with or without 
secondary generalization.
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The study is composed of 4 phases:

Video-Electroencephalographic (EEG) baseline phase with a target minimum of 
48 hours.  To ensure that the target minimum of 48 hours of Video-EEG is obtained, 
the total duration of the Video-EEG baseline phase will be up to 72 hours.

5 day double-blind dose escalation phase.

9 day double-blind fixed dose treatment phase, which includes a Video-EEG 
evaluation over the final 3 days at the end of this 9-day phase with a target minimum 
of 48 hours and a total recording duration of up to 72 hours.  For subjects who 
successfully complete the target 48 hour Video-EEG or must terminate the 
Video-EEG recording before the end of this 9-day phase, fixed dosing will continue 
until beginning the taper phase.

7 day double-blind taper phase.
The total double-blind treatment phase is 21 days.
Study Design Diagram:
14.0 mg/kg/day pregabalinc
  Screen
Randomization
Dose 
Escalation 
Fixed dose 
Taper
End of study/
Screen for A0081106
Visit V1           V2        V3                      V4                                             V5     V6                V7*
Day -14            -3           1                         6
              12      15                 22
7.0 mg/kg/dayc pregabalinb
Placebo
7.0 b
mg/kg/day
pregabalin
3.5 a
mg/kg/day 
pregabalin
Baseline
Video 
EEG
48
Hours
Video 
EEG
48
Hours
Study treatment + current AEDs
* Eligible subjects may be assessed for screening into study A0081106 and complete end of 
study activities for A0081042 at Visit 7 (V7)
a [3 mg/kg/day for subjects 1 to 3 months of age]; 
b [6 mg/kg/day for subjects 1 to 3 months of age]; 
c [12 mg/kg/day for subjects 1 to 3 months of age]
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Statistical Power and Sample Size
NOTE: Because the following sample size work occurred prior to study conduct and 
prior to review of blinded data, this section remains unchanged with respect to the 
constant 1/28 in the log transformation of the 24-hour seizure rate data and the 
differences between pregabalin and placebo.
A total of approximately 123 subjects will be randomized in this study in a 2:2:1 ratio of 
placebo, Level 1 and Level 2.  This randomization scheme will allow a sufficient number of 
patients to be studied at each dose level for safety, while providing adequate power of the 
study to detect a significant effect for dose Levels 1 and 2.  Randomization of 123 subjects 
accounts for a 10% discontinuation rate, with a resulting sample size of the necessary 
110 subjects (44 placebo, 44 Level 1, and 22 Level 2).
The sample size rationale is based on the observed difference in loge (double-blind 24-hour 
seizure rate +
) between pregabalin and placebo.  A difference in the least squares means 
between pregabalin and placebo was estimated to be -0.668 and -0.448 for 600- and 300 mg 
doses respectively, with a pooled standard deviation (SD) of 0.73.  This difference and 
pooled SD was obtained from a meta analysis of the -34, -11, -09 study data in adult subjects 
with partial onset seizures. 
For the purposes of this study, the same SD is also used to assess the power and sample size 
requirements for comparing each pregabalin group to placebo.  While every effort will be 
put forth to minimize the variability in conducting this study, a larger than anticipated SD 
may actually be observed.  To address this potential concern, a blinded sample size 
re-estimation procedure will be applied when approximately two thirds of the subjects that 
make up initial sample size have the opportunity to complete the study. Details of the sample 
size re-estimation procedure will be included in Appendix 2.1.1.
Table 1.
Power Calculations and Sample Size Assumptions for the Primary Endpoint 
(loge (24-hour seizure rate + 28
1 ))
Comparison
Log 
Transformed 
Difference 
from Placebo
Percent 
Difference 
from Placebo
Number of 
Pregabalin 
Subjects
Number of 
Placebo 
Subjects
SD (log 
transformed 
24-hour 
seizure rate)
Power
Expected difference1
between Level 2 
-0.668
-48.7%
22
44
0.73
0.932
Expected difference1
between Level 1 
-0.448
-36.1%
44
44
0.73
0.812
1 Expected difference is the observed difference between the specified pregabalin dose minus placebo based on 
a meta analysis of studies -009, -011, and -034 based on the log transformed 24-hour seizure rate. 
Level 1 and Level 2 doses are anticipated to result in exposure that approximates 
300 mg/day and 600 mg/day, respectively, achieved in adults. 
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In order to address the primary analysis comparison between placebo and the Level 2 dose 
group, a sample size of 44 subjects in the placebo group and 22 subjects in the Level 2 dose 
group will provide at least 90% power to detect a true difference of -0.668 using a two-sided 
test at the 0.05 level of significance with a standard deviation of 0.73. 
In order to address the primary analysis comparison between placebo and the Level 1 dose 
group, a sample size of 44 in each of these two groups will provide at least 80% power to 
detect a true difference of -0.448 using a two-sided test at the 0.05 level of significance with 
a standard deviation of 0.73. 
Randomization will be stratified by subject age (Stratum 1: <1 year of age; Stratum 2: 1-2 
years of age; Stratum 3: >2 years of age).  Subjects in each age stratum within the site will 
be randomized to either placebo or 1 of 2 fixed doses of pregabalin divided TID, Dose Level 
1: pregabalin 7 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age] or Dose Level 2: 
pregabalin 14 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age] in a 2:2:1 ratio.  
Every reasonable effort will be made to enroll a minimum of 10 subjects in each of the 3 age 
strata.
2.2. Study Objectives
Primary Efficacy Objective

The primary objective of this study is to evaluate the efficacy of two dose levels of 
pregabalin compared to placebo as an adjunctive treatment in reducing the frequency 
of partial onset seizures in pediatric subjects 1 month through <4 years of age. 
Secondary Efficacy Objective

To evaluate the efficacy of pregabalin compared to placebo on the frequency of 
partial onset seizures as determined by responder rate in pediatric subjects 1 month 
through <4 years of age.

To assess the safety and tolerability of pregabalin in pediatric subjects 1 month 
(44 weeks gestational age) through <4 years of age with partial onset seizures.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
3.1. Blinded Sample Size Re-estimation
While every effort will be put forth to minimize the variability in conducting this study, a 
larger than anticipated SD may actually be observed.  To address this potential concern, a 
blinded sample size re-estimation procedure will be applied when approximately two thirds 
of the subjects that make up initial sample size have the opportunity to complete the study 
(ie, no ongoing subjects will be included in this sample size re-estimation procedure). 
The blinded sample size re-estimation procedure for this study will not allow for a reduction 
in the planned sample size of 123 subjects, however Pfizer and FDA agreed on a proposed 
sample size of no more than 150 subjects.  The procedure will be conducted by a statistician 
who is not associated with the study during its conduct or during the final analysis.  There 
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will be no penalty applied to the final analysis p-values or confidence intervals for assessing 
treatment difference from placebo due to this blinded sample size re-estimation procedure.  
Details of the sample size re-estimation procedure will be included in Appendix 2.1.1.
3.2. Interim Safety Analyses
Two Interim Safety Analyses (ISA) will be conducted to assess safety.  The timing of the first 
interim analysis will be when approximately the first one-third of the subjects enrolled 
(randomized) have had an opportunity to complete the study.  The second ISA will be 
performed when approximately two-thirds of the subjects have had an opportunity to 
complete the study.  A charter to delineate the safety parameters to be assessed and the 
general procedures to govern the ISA will be the subject of a separate document.
The ISA will involve the descriptive review of deaths, SAEs, and discontinuations due to AEs.
Since the ISA may include a review of the seizure data and the primary efficacy endpoint is a 
function of seizures, if the study is stopped for safety purposes then futility will be declared 
for efficacy.  This strong rule does not require any type I error (alpha) spending penalty for 
the primary efficacy analysis.
This study will use an External Data Monitoring Committee (EDMC).  The DMC will be 
responsible for conducting these unblinded ISAs and for ongoing monitoring of the efficacy 
and safety of subjects in the study according to the Charter.  An E-DMC Charter will specify 
the details of how the safety interim analyses are to be conducted, and how communications 
between the sponsor and the E-DMC will take place through open and closed meeting 
sessions.  Additionally, the Charter will address the confidentiality of the interim safety 
information and appropriate measures will be taken to minimize bias so that the integrity of 
the study is protected. The recommendations made by the DMC to alter the conduct of the 
study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
which are not endpoints, to regulatory authorities, as appropriate.
3.3. Unblinding and Final Analysis
Blinding codes should only be used for an individual subject and the blind broken only in an 
emergency situation or when it is critical to guide treatment and care of a given subject for 
reasons of subject safety.  At the initiation of the study, the study site will be instructed on the 
method for breaking the blind for an individual subject.  The method will be either a manual 
or electronic process.  When breaking the blind is required the investigator should contact 
Pfizer before breaking the blind if possible.  When the blinding code is broken for a subject, 
the reason must be fully documented and entered on the subject's case report form.
Final analyses will be conducted after the database is released. 
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4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There will be 2 pair-wise comparisons of interest: 

Level 1: 7.0 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of age] – Placebo 
and, 

Level 2: 14 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months of age] – Placebo.
For the primary analysis which assesses the double blind 24-hour EEG seizure rate, the 
following step-wise testing procedure will be applied:

Step 1: Test the difference between the Level 2 group and placebo.

H01: Level 2 – Placebo = 0

Ha1: Level 2 – Placebo ≠ 0

Step 2: Test the difference between the Level 1 group and placebo.

H02: Level1 – Placebo = 0

Ha2: Level1 – Placebo ≠ 0
4.2. Statistical Decision Rules
Each dose of pregabalin will be compared to placebo in a pair-wise manner using a 
sequential step-wise testing procedure to control for multiplicity of testing such that the 
experiment-wise type I error rate will not exceed the 5% level of significance.  If H01 is 
rejected (p 0.05) then move to step 2, otherwise claim no difference and stop.  If H02 is 
rejected (p 0.05) then claim a difference for all the comparisons, otherwise claim 
differences between 14 mg/kg/day and placebo only. 
All other endpoints inferences will be performed at the nominal level, and may not control 
the type I experiment wise error rate at 0.05.
5. ANALYSIS SETS
5.1. Full Analysis Set (mITT)
The efficacy analyses will be performed on the modified intent to treat (mITT) population 
which consists of randomized subjects who took at least one dose of study drug during the 
double-blind treatment phase, have a baseline with at least one partial onset seizure 
identified by Video-EEG and a follow-up Video-EEG.  Video-EEG assessments must include 
at least 24 hours of evaluable monitoring to be eligible for the mITT population.  This will be 
the primary efficacy population.
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5.2. ‘Per Protocol’ Analysis Set 
None.  Protocol Deviations will be addressed (See Section 5.6) but no PP analyses are 
planned.
5.3. Safety Analysis Set
The primary analysis set for safety will be the safety population which will include subjects 
who took at least one dose of the investigational product.
5.4. Other Analysis Sets
5.4.1. ITT Analysis Set
Sensitivity analyses include evaluation of missing data, so the ITT population will include 
additional subjects not included in mITT, those without a follow-up Video-EEG.  The intent 
to treat (ITT) population will consist of randomized subjects who took at least one dose of 
study drug during the double-blind treatment phase and have a baseline with at least one 
partial onset seizure identified by Video-EEG.
5.5. Treatment Misallocations 
If a subject was:

Randomized but not treated, then they are by definition excluded from the efficacy 
and safety analyses as actual treatment is missing.

Treated but not randomized, then by definition they will be excluded from the 
efficacy analyses since randomized treatment is missing, but will be reported under 
the treatment they actually received for all safety analyses.

Randomized but took incorrect treatment, then they will be reported under their 
randomized treatment group for all efficacy analyses, but will reported under the 
treatment they actually received for all safety analyses.
5.6. Protocol Deviations
The list of protocol deviations will be compiled prior to database closure and study 
unblinding.  All deviations will be reviewed and decisions for handling each of the deviations 
will be made prior to unblinding of the study.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
6.1.1. Primary Efficacy Endpoint

The primary endpoint will be the log transformed double blind 24 hr seizure rate for 
all partial onset seizures collected at Visit 6 (48 hour Video-EEG assessment phase) 
during the double blind phase as determined by the central reader.  This 24-hour 
seizure rate will be calculated as follows for the double-blind period:
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24
monitoring
EEG
-
Video
of
hours
of
#
phase
assessment
hr
-
48
blind
double
in
seizures
of
#
rate
seizure
EEG
hr
-
24
Blind
Double



When the log-transformation is used, the quantity 1 is added to the double blind 24-hr 
EEG seizure rate for all subjects to account for any possible "0" seizure incidence.  
This will result in the following primary efficacy measure: loge (double blind 24-hr 
EEG seizure rate +1).  Results will be reported as “percent change in seizures” 
relative to placebo.  For example, a difference between one of the pregabalin doses 
and placebo of -0.400 on the log transformed scale for the double blind 24-hr seizure 
rate, translates into a 33% reduction in the double blind 24-hour EEG seizure rate of 
the pregabalin group from the placebo group (ie, 100%*[exp-0.400-1]=-33%]). 

An additional back transformation will be calculated for percent reduction in seizures 
for each pregabalin treatment group relative to placebo for presentation in the CSR as 
follows: 

A minimum of 24 hours of evaluable Video-EEG will be required to utilize the EEG.  
In cases where there is less than 24 hours of evaluable Video-EEG, the seizure rate 
will be set to missing.

The baseline 24-hr EEG seizure rate will be calculated in the same respective 
manner. 
6.1.2. Secondary Efficacy Endpoints
Responder Rate, defined as subjects who have a 50% reduction from baseline in partial 
seizure rate during the double-blind 48 hour Video-EEG phase.  Subjects meeting this 
criterion will be considered responders.
6.2. Safety Endpoints
The evaluation of safety will include adverse event (AE) data (occurrence, nature, intensity, 
and relationship to study drug), assessment of clinical laboratory data and the results of 
physical examinations, vital signs, weight, neurological examinations, and 
electrocardiograms (ECGs).
6.2.1. Adverse Events
All AEs occurring during the course of the study will be coded using the MedDRA coding 
dictionary. 
All AEs (serious and non-serious) reported during the course of this study from the first day 
of study treatment through and including 999 calendar days after the last administration of 
the study drug will be considered treatment emergent AEs (TEAEs).  Only AEs captured in 
this study will be included, and not AEs captured in the 1-year open label safety study.
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A 3-tier approach will be used to summarize AEs.  Under this approach, AEs are classified 
into 1 of 3 tiers.  Different analyses will be performed for different tiers (See
Section 8.2.3.1). 
6.2.2. Prior and Concomitant Treatments and Medications
Concomitant and prior medications, defined as medications stopped, ongoing or started on or 
after the first day of study treatment up to the last dose of study treatment, will be 
summarized, using the WHO-drug coding dictionary.  In addition, concomitant and prior 
non-drug treatments/procedures will be summarized using the MedDRA coding dictionary.
 
 
 
 
 
6.4. Covariates 
Log-transformed 24-hour seizure rate [loge(24-hour seizure rateb + 1)] at baseline will be 
utilized as a covariate in the linear model used in the primary analysis, and for parametric 
sensitivity analyses utilizing a similar model.  Regarding a non-parametric analysis of 
covariance based on the rank transformed data, ranked Log-Transformed 24-hour seizure rate 
at baseline will also be utilized as covariate. 
Additional terms considered in the primary analysis and included in the responder rate 
analysis are age strata and geographic region.  Because it is anticipated that this study will 
have many investigator centers having very few subjects in each treatment group, age strata, 
and geographic region combination; a pre-specified pooling will take place (See
Appendix 2.2.3).
Age strata will be defined as Stratum 1: <1 year of age; Stratum 2: 1-2 years of age; Stratum 
3: >2 years of age.
Region pooling will be defined as follows (Upon closing of the randomization, region 
determinations will be further evaluated-See Appendix 2.2.3):
CCI
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Table 2.
Description of Stratifying Factors and Their Levels
Region
Countries
Asia Pacific
China, Malaysia, Philippines, South Korea, Taiwan, Thailand
Rest of the world 
Russia, Ukraine
North America + Europe 
+ Middle East
United States, Belgium, Bulgaria, Germany, Spain, France, 
Greece, Hungary, Romania, Belarus, Israel, Lebanon, Serbia, 
Turkey 
7. HANDLING OF MISSING VALUES
Due to the use of Video-EEG assessments to collect seizure data (at baseline and the end of 
the double blind period), subjects who discontinue from the study may have no post-baseline 
efficacy data.  If there is missing post-baseline 24-hour seizure rate for more than 5% of any 
treatment group, then multiple imputation techniques will be applied to the primary analysis
model.  Specific details are provided in Appendix 2.2.1.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
The mITT population will be used in the analyses of the primary efficacy endpoint, and for 
all other efficacy endpoints.  The Safety population will be used in the analyses of the safety 
data.
8.1. Statistical Methods 
8.1.1. Analyses for Continuous Data
ANCOVA methods will use a linear model with treatment, age stratum, and geographical 
region (as defined in Table 2 above) as fixed factor effects, and baseline as a continuous 
covariate.  This linear model will include both dose groups of pregabalin. 

Least square means will be calculated using the observed marginal distribution.  
Two-sided 95% confidence intervals of the difference between the least square means 
will be calculated by using the appropriate least square means and their standard 
errors.
Sensitivity analyses will include non-parametric analyses including analysis of covariance 
based on the rank transformed data, and a Wilcoxon-Mann Whitney test; and handling of 
missing data using multiple imputation methods (See Appendix 2.2.1).
8.1.2. Analyses for Count Data 
A generalized linear model assuming a Poisson distribution and canonical log link function 
will be applied to the raw seizure counts (McCullagh and Nelder, 1989 and Stokes et al., 
2000).2,3  Further details will be provided in Appendix 2.2.2.
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8.1.3. Analyses for Binary Endpoints
A logistic regression model via maximum likelihood estimation with the following covariates
will be performed: 

treatment group, as a fixed effect;

age stratum, as a fixed effect;

geographical region (as defined in Table 2 above) by pooling of investigator centers, 
as a fixed effect.  If any non-treatment factor causes non-convergence of the model, 
that factor will be dropped from the model.
Comparisons will be performed for each pregabalin dose relative to placebo using a 
maximum likelihood tests and confidence intervals.  The definitive statistical summary for 
treatment group comparisons will be the odds ratios.
8.2. Statistical Analyses 
8.2.1. Analysis of Primary Endpoints
The primary analysis will be performed on the primary endpoint, loge (double blind 24-hour 
EEG seizure rate +1), using a linear model with treatment, age stratum, and geographical 
region (as defined in Table 2 above) as fixed factor effects, and loge (baseline 24-hour EEG 
seizure rate +1) as a continuous covariate.  This linear model will include both dose groups 
of pregabalin.  This analysis will be applied for all subjects who satisfy mITT criteria and for 
data of observed case. 
Each dose of pregabalin and placebo will be compared using a sequential step-wise testing 
procedure.  For this analysis, the following steps will be applied:

Step 1: Test the difference between the Level 2 group and placebo.

H01: Level 2 – Placebo = 0

Ha1: Level 2 – Placebo ≠ 0

Step 2: Test the difference between the Level 1 group and placebo.

H02: Level1 – Placebo = 0

Ha2: Level1 – Placebo ≠ 0
If H01 is rejected (p 0.05) then move to step 2, otherwise claim no difference and stop.If H02
is rejected (p 0.05) then claim a difference for all the comparisons, otherwise claim 
differences between 14 mg/kg/day and placebo only. 
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Least square means will be calculated using the observed marginal distribution.  Two-sided 
95% confidence intervals of the difference between the least square means will be calculated 
by using the appropriate least square means and their standard errors.  Results will be 
reported as “percent reduction in seizures” relative to placebo.  For example, a difference 
between one of the pregabalin doses and placebo of -0.400 on the log transformed scale for 
the 24-hour seizure rate, translates into a 33% reduction in the 24-hour seizure rate of the 
pregabalin group from the placebo group (ie, 100%*[exp-0.400-1]= -33%]).
An additional back transformation will be calculated for percent reduction in seizures for 
each pregabalin treatment group relative to placebo for presentation in the CSR as 
follows: 
Sensitivity Analysis
The same analysis as the primary, except for missing data imputation and analysis set, will be 
performed as a sensitivity analysis.  In this analysis, a multiple imputation technique for 
missing data will be applied for the ITT population.  This sensitivity analysis will only be
applied for the ITT analysis set, and all other efficacy analyses will be applied for the mITT
analysis set.
A non-parametric analysis of covariance based on the rank transformed data will be 
performed and evaluated for efficacy results in combination with the primary analysis.
A Wilcoxon-Mann Whitney test will also be performed and reported for the primary 
endpoint.
Other Supplemental Analyses 
The primary analysis of the primary endpoint will be evaluated for violations to model 
assumptions based on descriptive statistics, box plots and residual plots. 
The change from baseline in 24-hour seizure rate, with and without log-transformation, will 
be analyzed descriptively for each treatment group using tables and plots.
A generalized linear model assuming a Poisson distribution and canonical log link function 
will be applied to the raw seizure counts (McCullagh and Nelder, 1989 and Stokes et al., 
2000).2,3  The model will have an off-set parameter for the amount of evaluable time 
(ie, loge(time monitored)) the subject was with V-EEG.  Over-dispersion will be investigated, 
and if it appears to exist for this model, then the scale parameter will be set to the deviance 
in the Poisson model, and a negative binomial will be also be explored in addition to 
analyzing the data with a quasi-likelihood function.  This analysis will assume missing 
completely at random, and will assess seizure frequency in relation to the amount of time 
each subject was at risk relative to their evaluable hours of V-EEG monitoring.  In addition, 
this analysis will not be subject to any potential extrapolation of applying the 24 hour seizure 
rate.  Further details will be provided in Appendix 2.2.2.
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8.2.2. Analysis of Secondary Endpoints
A secondary efficacy parameter is Responder Rate, defined as subjects who have a 50% 
reduction from baseline in partial seizure rate during the double-blind 48 hour Video-EEG 
period.  Subjects meeting this criterion will be considered responders.
Subjects who do not meet the favorable responder definition will be considered 
non-responders.  The dichotomized Responder variable will be analyzed using a logistic 
regression model via maximum likelihood estimation with the following covariates: 

treatment group, as a fixed effect;

age stratum, as a fixed effect;

geographical region (as defined in Table 2 above) by pooling of investigator centers, 
as a fixed effect.  If any non-treatment factor causes non-convergence of the model, 
that factor will be dropped from the model.
Comparisons will be performed for each pregabalin dose relative to placebo using a 
maximum likelihood tests and confidence intervals.  The definitive statistical summary for 
treatment group comparisons will be the odds ratios. 
The responder outcomes will be summarized descriptively by treatment group using counts 
and percentages.
8.2.3. Analysis of Safety Data
All subjects with at least 1 dose of study medication will be included in the safety analyses.  
Baseline assessments are done at Day 1 (Visit 3).  If Visit 3 data is missing the last available 
observation prior to start of study treatment is considered as baseline.
No inferential safety analyses are planned.  Pfizer safety reporting standards will be utilized 
for all safety endpoints.
In addition, a summary of the number of days in the study will be presented for each 
treatment group.
8.2.3.1. Adverse Events
All AEs occurring during the course of the study will be coded using MedDRA coding 
dictionary. 
All AEs (serious and non-serious) reported during the course of this study from the first day 
of study treatment through and including 999 calendar days after the last administration of 
the study drug will be considered treatment emergent AEs (TEAEs).  Only AEs captured in 
this study will be included, and not AEs captured in the 1-year open label safety study.
An overall summary of treatment-emergent AEs will be provided.  Treatment-emergent AEs 
will also be summarized by system organ class, preferred term, severity, and relationship to 
study drug.  Summaries and listings of all AEs, SAEs and treatment-related AEs will be 
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Protocol A0081042 Statistical Analysis Plan
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presented in accordance with the current Pfizer Standard Operating Procedures (SOPs) and 
Best Practices.
The 3-tier Approach for summarizing AEs will be implemented, and events (MedDRA PTs) 
will be classified into the following tier definitions:
Tier 1: None 
Tier 2: Targeted Medical Events (TMEs) identified in the Lyrica Safety Review Plan

Point estimates and confidence intervals for the risk difference.  Risk Difference is 
computed as Level 1 versus Placebo and as Level 2 versus Placebo.

AEs will be arranged sorted in descending point estimate of the risk measure.
Tier 3: Standard safety output (no new outputs-see above).
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events.  Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification.  As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation.  The 3-tier approach facilitates this exploratory analysis.
8.2.3.2. Laboratory Data (Hy’s Law)
A listing of subjects who meet the criteria for Hy’s law will be presented. 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below 
in the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events.

Subjects with AST or ALT and total bilirubin baseline values within the normal range
who subsequently present with AST or ALT 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis
and an alkaline phosphatase ≤2 X ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the upper
limit of normal, the following threshold values should be used in the definition
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller).
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
Concurrent with

For subjects with pre-existing values of total bilirubin above the normal 
range: Total bilirubin increased by one time the upper limit of normal or 
3 times the upper limit of normal (whichever is smaller).
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8.2.4. Summary of Efficacy Analyses 
Endpoint
Analysis
Set
Statistical 
Method
Model/ Covariates/ 
Strata
Output
Missing 
Data
Interpretation
Loge (24-hour seizure rate +1)
(DB Phase)
mITT
ANCOVA
Treatment, age strata, 
region and log-BL
log-BL = Loge
(24-hour seizure rate 
+1) at baseline
Log-Scale
- LS mean and 95% CI by 
   treatment group, 
- LS mean difference from 
   placebo, SE, 95% CI and 
p-value
Original (Back Transformed)
- LS Mean and 95% CI by 
  treatment group
- “Percent Change in Seizures” 
   Relative to Placebo
OC
Primary 
Analysis
Loge (24-hour seizure rate +1)
(DB Phase)
ITT
ANCOVA
Treatment, age strata, 
region and log-BL
Log-Scale
- LS mean and 95% CI by 
   treatment group, 
- LS mean difference from 
   placebo, SE, 95% CI and 
   p-value
Original (Back Transformed)
- LS Mean and 95% CI by 
   treatment group
- “Percent Change in Seizures” 
  Relative to Placebo
MI
Sensitivity 
Analysis
Loge (24-hour seizure rate +1)
(DB Phase)
mITT
Rank 
ANCOVA
Treatment, age strata, 
region and ranked 
log-BL
Log-Scale
- Median by treatment group
- LS mean difference from 
   placebo, SE, 95% CI and 
   p-value
OC
Sensitivity 
Analysis
Loge (24-hour seizure rate +1)
(DB Phase)
mITT
Wilcoxon-Mann 
Whitney Test
Log-Scale
N, Mean, SD, Median, Min, 
Max, 25%, 75%, Test 
Statistics and 
p-value
OC
Sensitivity 
Analysis
Loge (24-hour seizure rate +1)
mITT
Descriptive 
N, Mean, SD, Median, Min, 
OC
Evaluation for 
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Endpoint
Analysis
Set
Statistical 
Method
Model/ Covariates/ 
Strata
Output
Missing 
Data
Interpretation
(BL, DB and Chg. from BL)
Statistics
Max, 25%, 75%, Skewness 
and Kurtosis
violations to 
model 
assumption
Loge (24-hour seizure rate +1)
(BL, DB and Chg. from BL)
mITT
Plot
Box Plot and Histogram of 
endpoint by Treatment Group
OC
Evaluation for 
violations to 
model 
assumption
Loge (24-hour seizure rate +1)
(DB Phase)
mITT
ANCOVA
(Plot)
Treatment, age strata, 
region and log-BL
Residual Plot of Primary 
Analysis
OC
Evaluation for 
violations to 
model 
assumption
Responder Rate
mITT
Logistic 
Regression
Treatment, age strata, 
and region
Odds Ratio, 95% CI and 
p-value
OC
Secondary 
Endpoint
Responder Rate
mITT
Descriptive 
Statistics
N1, n2 and %
OC
Secondary 
Endpoint
Raw Seizure Count
mITT
GLM
Assumption of a 
Poisson distribution 
and canonical log link 
function
Goodness of Fit, maximum 
likelihood estimates, least 
squares means, and p-values
OC
Supplemental 
Analysis
BL: Baseline, DB: Double Blind, OC: Observed Case, MI: Multiple Imputation, GLM: Generalized Linear Model 
1: N is number of mITT subjects.
2: n is number of responder subjects.
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9. REFERENCES 
1.
Friede, T and Kieser, M. (2011). Blinded Sample Size Recalculation for Clinical Trials 
with Normal Data and Baseline Adjusted Analysis. Pharmaceut. Statist., 10: 8-13.
2.
McCullagh, P. and Nelder, J.A. (1989). Generalized Linear Models, Second Edition, 
New York: Chapman & Hall/CRC. 
3.
Stokes, M.E., Davis, C.S., and Koch, G.G. (2000). Categorical Data Analysis Using the 
SAS System, Second Edition, Cary, NC: SAS Institute.
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10. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Endpoint 
Derivation
24-hour seizure rate at baseline 
(b) phase (Count/24 hours)
24-hour seizure rateb= [(# of seizuresb) ÷ (#of hoursb of Video- EEG 
monitoring)] × 24
24-hour seizure rate at 
double-blind treatment (t) phase 
(Count/24 hours)
24-hour seizure ratet= [(# of seizurest) ÷ (#of hourst of Video- EEG 
monitoring)] × 24
Primary endpoint: Loge of 
24-hour seizure rate at 
double-blind treatment phase
Loge (24-hour seizure ratet +1)
Log transformed baseline 24-hour 
seizure rate
Loge (24-hour seizure rate +1) at baseline
“Percent reduction in seizures” 
relative to placebo
Example: A difference between one of the pregabalin doses and placebo 
of -0.400 on the log transformed scale for the 24-hour seizure rate 
translates into a 33% reduction in the 24-hour seizure rate of the 
pregabalin group from the placebo group
(ie, 100%*[exp-0.400 -1]= -33%)
An additional back transformation will be calculated for 
the percent reduction in seizures for each pregabalin 
treatment group relative to placebo for presentation in 
the CSR as follows: 
Change from baseline in 24-hour 
seizure rate
Change = 24-hour seizure ratet -24-hour seizure rateb.
Percent change from baseline in 
24-hour seizure rate for 
calculation of responders
% Change = [24-hour seizure ratet -24-hour seizure rateb)/24-hour 
seizure rateb] × 100
Responders 
50% reduction in the 24-hour seizure rate from baseline during the 
double-blind 48 hour Video EEG period, then response = 1 (responder) 
otherwise response = 0 (non-responder)
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Appendix 2. STATISTICAL METHODOLOGY DETAILS 
Appendix 2.1. Further Details of Interim Analyses
Appendix 2.1.1. Blinded Sample Size Re-estimation
The sample size re-estimation formula of Friede and Keiser (2011)1 for this study is the 
following:
N = 
where,
N=NA + NB, NB= γ* NA and zp is the p-quantile of the standard normal distribution;
2
/
1 

z
is a 
percentile from a standard normal cdf with /2=0.025; =1 assumes equal sample sizes; for 
this study the two groups are placebo and 7 mg/kg/day which are in 1:1 ratio.


1z
is a percentile from a standard normal cdf with =0.20;
= correlation between primary endpoint and baseline; 
is the unbiased estimate of 2, which can be shown to equal the residual variance.
= -0.355 is the planned difference (ie, 7 mg/kg/day and placebo) for the sample size 
re-estimation.  The details for deriving this delta are in the SSRE plan. 
The Guenther adjustment for equal sample sizes per group, leads to the final computation:
NG = N + 
n* = NG/2; where n* is the number of subjects per group (rounded to the nearest integer) for 
Pregabalin 7 mg/kg/day and placebo.  Since the randomization ratio for this study is 2:2:1 for 
(Placebo: pregabalin 7 mg/kg/day: pregabalin 14 mg/kg/day), the number of subjects for 
pregabalin 14 mg/kg/day will be n*/2, and 2.5 x n* is the total subjects.
The pooled blinded estimate of the variance, 
2
~s , will be based in a blinded manner without 
making any correction for possible treatment group differences after the 1st approximately
2/3 of the planned 123 subjects have had the opportunity to complete the study.  Since 
baseline 24-hour seizure rate, age strata, and geographical region are important pre-specified 
modeling terms that explain sources of variability in the data, the estimate 
2
~s will take into 
consideration these three modeling terms as the mean squared error.  While this pooled 
estimate of the variance under the null hypothesis will be biased upwards, this bias is 
negligible when the overall sample is reasonably large.  The proposed blinded sample size 
re-estimation procedure will only allow for a new sample size (nNew) to be increased beyond 
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the initial targeted sample size (nInitial).  The nNew is estimated to keep at least the power of 
0.8 for comparison of between Dose Level 1 and Placebo when estimated SD is larger than 
initial SD.  In addition, the nNew is also estimated to keep the randomization ratio of Placebo, 
Dose Level l, Dose Level 2 in 2:2:1.  The proposed blinded sample size re-estimation 
procedure will only allow for a new sample size (nNew) to be increased beyond the initial 
targeted sample size (nInitial), but not beyond the pre-determined maximum sample size 
(nMax=150). 
Appendix 2.2. Further Details of the Statistical Methods
Appendix 2.2.1. Analysis Strategy Using Multiple Imputations
Multiple imputation procedure is used under the assumption of missing at random (MAR) 
data.  The goal of the imputation strategy is to produce a completed dataset.  This dataset has 
two time points, baseline and on study.  The pattern of missing data is implicitly, monotone.  
It is likely that little or no data is missing at baseline.  In general, let Y be the response data 
[loge(double blind 24-hour EEG seizure rate +1)] where that part of Y which is missing is 
denoted by Ymis, and that part of Y which is observed is denoted by Yobs. A data pattern is 
said to have a missing monotone data pattern when the variable Yj for an individual subject is 
missing at time point j, and all subsequent variables for that individual are also missing for 
Yk in which k>j.  In this data there are only two assessment time points, baseline and the 
on-study measurement. 
The three steps for conducting statistical inferences using a multiple imputation procedure 
consist of the following:
Imputation step: Missing data are filled in m times to generate m complete data sets, where 
m >1; for this study, m will take on the value 5.
Analysis step: The m complete data sets are analyzed using standard procedures.
Combination step: The results from the m complete data sets are combined for the final 
statistical inference.
The imputation step is perhaps the most critical, since it relies upon assumptions regarding 
the missing data mechanism.  The goal of the imputation is to account for the relationships 
between the unobserved and observed variables, while taking into account the uncertainty of 
the imputation.  The MAR assumption is key to the validity of multiple imputations.  Use of 
this assumption allows the analyst to generate imputations (Y{1},Y{2}, . . .Y{m}) from the 
distribution f(Ymis|Yobs), since after conditioning on Yobs, the missingness is assumed to be 
due to chance and is considered ignorable.  In this application, we will use the regression 
method in which the variable Yj with missing values is fitted with non-missing observations 
as the dependent variables.  This allows for the following regression model to be employed:
Y0 = 0; and Y1 = 0 + 1*Y1.
The fitted model has parameter estimates (b0, b1) and the associated covariance matrix s2
jVj, 
where Vj is the usual XTX matrix from the intercept and variable Y1. 
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For each imputation, new parameters (*
0, *
1; and *2) are drawn from a posterior predictive 
distribution of the missing data.  The missing values of Yj are then replaced with the 
predicted values using the following equation:
*
0 + *
1*y1 + zi**2
where y1 is the covariate value for the first variable and zi a simulated standard normal 
deviate for the ith individual. 
The next step is to carry out the analysis of interest for each of the m imputed 
complete-observation datasets, storing the parameter vector and standard error estimates.
Finally, the results are combined using results from Rubin (1987) to calculate estimates of 
the within imputation and between imputation variability.  These statistics account for the 
variability of the imputations and assuming that the imputation model is correct, provide 
consistent estimates of the parameters and their standard errors.  The imputation model need
not be exactly correct and the MI will provide these consistent estimates.  The following are 
additional information and suggested code that can be used for MI:
In this appendix, we will assume that data are stored in a SAS dataset, with the following 
variables.  Note that the variable names/labels are suggestions only and the actual 
names/labels and code levels should be consistent with current sponsor reporting standards. 
SUBJID: subject identification number.
REGION and AGE_STRATA.
TRT: Treatment group (Placebo, Pregabalin 7.0 mg/kg/day, Pregabalin 14.0 mg/kg/day).
LN_BSZRT: A loge transformed baseline seizure rate loge(Baseline 24-hour seizure 
rateb +1).
LN_SZRATE: A loge transformed double-blind seizure rate loge(Double blind 24-hour 
seizure ratet +1).
IMPSTAT: Impstat = 1 if DC due to AE, death, or insufficient clinical response.  
Impstat = 2 otherwise.
MISS: Miss = 1 if ln_szrate is missing.  Miss = 0 otherwise.
In order to impute missing data at the singular time point and based on the definition of the 
link function, first prepare an input dataset, making sure that it will contain only the intended 
donor and recipient patterns.  Separate the input dataset <efficacy> into two datasets: IMP, 
containing all placebo subjects and those subjects from the pregabalin arms that have missing 
LN_SZRATE [Miss=1] and Impstat=1; and REST, containing the rest of the subjects from 
the pregabalin arms (those with non-missing LN_SZRATE [Miss=0] or Impstat=2).
title1 'Pattern Imputation based on reason for DC';
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*these sets are exhaustive and mutually exclusive;
data IMP REST;
   set <efficacy>;
   if trt ne “Placebo” and (impstat = 2 or   miss = 0) then output REST;
   if trt =   “Placebo” or   (impstat = 1 and miss = 1) then output IMP;
run;
Call PROC MI to impute missing data at the time point using dataset IMP as input.
*order of variables matters in proc mi;
proc mi data = IMP out = impout nimpute=100 seed = 233;
   class region age_strata;
   var region age_strata ln_bszrt ln_szrate;
   monotone regression(ln_szrate = ln_bszrt region age_strata);
run;
Call PROC MI to impute missing data at the time point using dataset REST as input.
*impute like randomized trt for active who are 'ignorably missing';
proc mi data = REST out = restout nimpute=100 seed = 238 ;
   class region age_strata trt ;
   var region age_strata trt ln_bszrt ln_szrate ;
   monotone regression(ln_szrate = trt ln_bszrt region age_strata) ;
run;
Assemble back a dataset containing all subjects.
*fully imputed integrated dataset;
data main ;
  set impout restout ;
run ;
proc sort data = main ;
  by _imputation_ trt ;
run ;
*Analysis of imputed data sets;
* Confirm the ordering of the trt variable for specifying the vector.  Here it is assumed 
Placebo, Pregabalin 7.0 mg/kg/day, and Pregabalin 14.0 mg/kg/day ;
proc glm data=main; 
  by _imputation_ ;
  class region age_strata trt ;
  model ln_szrate = trt region age_strata ln_bszrt ;
  lsmeans trt / diff=control('Placebo') tdiff pdiff cl;
  estimate ‘Pregabalin 7.0 mg/kg/day vs Placebo’ trt -1 1 0 ;
  estimate ‘Pregabalin 14.0 mg/kg/day vs Placebo’ trt -1 0 1 ;
  ods output lsmeans=lsm diffs=lsdiff estimates=estdiffs ;
run ;
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quit ;
*integrated summary of results of imputed datasets, please note the degree of freedom 
(XXX) should come from MSE of GLM model above;
proc mianalyze parms(classvar=full)=lsm  edf=XXX;
  class trt ;
  modeleffects trt ;
run ;
proc sort data = estdiffs ;
  by parameter _imputation_ ;
run ;
proc mianalyze data=estdiffs edf=XXX;
  by parameter ;
  modeleffects estimate ;
  stderr stderr ;
run ;
Appendix 2.2.2. Analysis Strategy Using a Poisson Model
Poisson Distributions often arise from a Counting process

Seizure counts as a random variable Y
The expected value of the seizure counts is E(Y) = 
The variance of the seizure counts is Var(Y) = 
Generalized Linear Model for Seizure Counts with equal duration

g() = ln() = +X
Distribution is Poisson
Link function g() is the natural log 
In other words = exp(+X)
Incorporating exposure/V-EEG monitoring time (T) in the Model 

Off-setting the exposure/V-EEG monitoring time by ln(T)

ln(/T) = +X

= T·exp(+X)

Adjust for unequal exposure/V-EEG monitoring times among treatment groups
Exposure/V-EEG monitoring time, T, is based on observed V-EEG monitoring time 
(evaluable hours).
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If the ‘Criteria For Assessing Goodness Of Fit’ section of the output indicates that the 
value/df for both deviance and Pearson Chi-Square statistics is numerically much higher than 
1 (ie, value/df >1.5), then Poisson model is not quite adequate to describe the counts of
seizures.  This lack of fit is termed over-dispersion, and it indicates that the data contains 
more variability than what the model is explaining.  While the maximum likelihood 
estimators for the fixed effect from the Poisson model are still consistent when 
over-dispersion is present, the variance is biased downward.  Thus, statistical tests may lead 
to higher type I error rates (ie, p-values are smaller than what they should be) if 
over-dispersion was not present.
If over-dispersion is determined based on the threshold criteria above, a common statistical 
strategy of fitting quasi-likelihood and negative binomial models will be employed.  A scale 
parameter (Scale=deviance, the dispersion parameter is estimated by the deviance divided by 
its degrees of freedom) will be specified to fit the overdispersed Poisson and negative 
binomial distributions, if warranted.
Appendix 2.2.3. Pooling 
Pooling of sites will be determined prior to unblinding of the study.  Any investigator center 
having less than 2 subjects in any given treatment group or efficacy outcome category within 
each strata will be defined as a ‘small’ center.  The pooling of small centers will be based on 
the total number of subjects randomized at each center.  Small centers will be pooled to large
centers within the same country.  When there are only small centers within a given country, 
small centers will be pooled to large centers within the same region.
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