Clinical trial NCT01747915
Conditions: Generalized Tonic Clonic Seizures
Keywords: Primary Generalized Tonic Clonic Seizures Epilepsy Safety Efficacy Tolerability Pregabalin Lyrica Adjunctive treatment Placebo Controlled Blinded
Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Start date: 2013-04-03; Completion date: 2019-02-20
Enrollment: 219 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to evaluate the safety, tolerability and efficacy of two doses of pregabalin as add-on treatment in pediatric and adult subjects with Primary Generalized Tonic-Clonic (PGTC) seizures as compared to placebo. It is hypothesized that both doses of pregabalin will demonstrated superior efficacy when compared to placebo by reducing PGTC 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, either liquid or capsule, dosed twice daily, escalated up to a maximum of 300 mg/day beginning at Randomization to Taper Phase, then tapered down to a maximum dose of 150 mg/day during 1 week Taper Phase to End of Study/Early Termination. intervention 2: Pregabalin, either liquid or capsule, dosed twice daily, escalated up to a maximum of 600 mg/day beginning at Randomization to Taper Phase, then tapered down to a maximum of 150 mg/day during 1 week Taper Phase to End of Study/Early Termination. intervention 3: Placebo, either liquid or capsule, dosed twice daily beginning at Randomization to End of Study/Early Termination.

Protocol documents:
Prot_001.pdf: 
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SAP_000.pdf: 
Protocol A0081105
Statistical Analysis Plan
Statistical Analysis Plan
Version 3.0
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Protocol A0081105
A randomized, double-blind, placebo-controlled, parallel group, multi-
center trial of pregabalin as adjunctive therapy in pediatric and adult 
subjects with primary generalized tonic-clonic seizures
Statistical Analysis Plan 
(SAP)
Version:
4.0
Author:
- New York, NY), and  
                        
– Groton, CT), and
 - New York, NY)
Date:
18 March 2019
PPD
PPD
PPD
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TABLE OF CONTENTS
LIST OF TABLES.................................................................................................................... 3
1. AMENDMENTS FROM PREVIOUS VERSION(S) .......................................................... 4
2. INTRODUCTION ................................................................................................................ 7
2.1. Study Design ............................................................................................................ 7
2.2. Statistical Power and Sample Size ........................................................................... 8
2.3. Study Objectives..................................................................................................... 10
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING............................... 11
3.1. Interim Safety Analysis.......................................................................................... 11
3.2. Final Analysis and Unblinding............................................................................... 12
4. HYPOTHESES AND DECISION RULES........................................................................ 12
4.1. Statistical Hypotheses............................................................................................. 12
4.2. Statistical Decision Rules....................................................................................... 13
5. ANALYSIS SETS .............................................................................................................. 13
5.1. Full Analysis Set (Intent-to-Treat Population)....................................................... 13
5.2. ‘Per Protocol’ Analysis Set (PP Population).......................................................... 13
5.3. Safety Analysis Set................................................................................................. 13
5.4. Other Analysis Sets ................................................................................................ 13
5.5. Treatment Misallocations....................................................................................... 13
5.6. Protocol Deviations................................................................................................ 13
6. ENDPOINTS AND COVARIATES .................................................................................. 14
6.1. Efficacy Endpoint(s)............................................................................................... 14
6.1.1. Primary Endpoint....................................................................................... 14
6.1.2. Secondary Efficacy Endpoint .................................................................... 14
6.1.3. Exploratory Endpoints............................................................................... 15
6.1.3.1. Proportion of Seizure-Free Days.............................................. 15
6.1.3.2. Number of Seizure-Free Days Gained ..................................... 15
6.1.3.3. Proportion of Subjects with PGTC Seizure-Freedom .............. 15
6.1.3.4. Time to Nth Seizure .................................................................. 15
6.2. Safety Endpoints..................................................................................................... 16
6.2.1. Adverse Events .......................................................................................... 16
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6.2.2. Prior and Concomitant Treatments and Medications ................................ 16
6.2.3. Suicidal Ideation and Behavior Assessments During the Clinical 
Trial................................................................................................................. 16
6.3. Other Endpoints...................................................................................................... 17
6.3.1. PK/PD Endpoints....................................................................................... 17
6.4. Covariates............................................................................................................... 17
7. HANDLING OF MISSING VALUES ............................................................................... 18
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ......................... 20
8.1. Analysis of Primary Efficacy Endpoint.................................................................. 20
8.2. Analysis of Secondary Efficacy Endpoints............................................................ 23
8.3. Analysis of Exploratory Endpoints ........................................................................ 23
8.4. Safety Analyses ...................................................................................................... 24
8.4.1. Adverse Events .......................................................................................... 24
8.4.2. Suicidal Ideation and Behavior.................................................................. 25
8.5. Summary of Efficacy Analyses.............................................................................. 26
9. REFERENCES ................................................................................................................... 28
LIST OF TABLES
Table 1.
Power Calculations and Sample Size Assumptions with 56 
Subjects per Group for the Primary Endpoint (loge (28-day 
seizure rate + 1)......................................................................................... 9
APPENDICES
Appendix 1. Data Derivation Details...................................................................................... 29
Appendix 2. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events 
and Codes................................................................................................. 31
Appendix 3. Windowing for Study Months 1, 2 and 3........................................................... 32
Appendix 4. Analysis Strategy Using Multiple Imputations.................................................. 33
Appendix 5. Analysis Strategy Using a Poisson Model ......................................................... 37
Appendix 6. Blinded Sample Size Re-Estimation.................................................................. 38
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Status of the study when amendments were made: Study is still ongoing and blinded.
Final 
Date: 04-Jan-2013
Version 1.0
1. This is the first SAP for protocol 
A0081105.
1. N/A
Amendment 1
Date: 21-Apr-
2017
Version 2.0
2. Updated to the reference of the 
blinded sample size formula of 
Friede and Kieser (2011) to apply 
the latest methodology with 
considering covariate of continuous 
data under Section 2.2, References, 
and Appendix 6.
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.
3. Added the description to explain 
the procedure for final analysis and 
unblinding under Section 3.2.
4. Revised the analysis of pattern 
mixture model under Section 7, 
Reference, and Appendix 4.
5. Added to calculate odds ratio with 
95% confidence interval of 
responder rate and added the 
explanation of SAS code for p-
value calculation under Section 8.2.
2. To update the sample 
size re-estimation 
reference.
3. To match protocol 
procedure.
4. To replace multiple 
imputation analysis 
method consistent 
with A0081041 and 
A0081042.
5. To add detailed 
specification of the 
responder analysis 
with SAS code.
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Amendment 2
Date: 01-Mar-
2019
Version 3.0
1. Add the following equation in 
Section 6.1, Section 8.1, and 
Appendix 1 for additional 
presentation of percent reduction of 
treatment difference relative to 
placebo: 
2. Amended the seizure type for
evaluation from partial seizures to 
PGTC seizures under Section 
6.1.3.4.
3. Removed cognitive testing of safety 
endpoint under Section 6.2.
4. Added a sensitivity analysis with 
age group (5-16 years of age and 
17-65 years of age) as a covariate in 
Section 8.1.
5. Added a supplemental analysis with 
treatment-by-age group (5-16 years 
of age and 17-65 years of age) 
interaction term in the ANCOVA 
model in Section 8.1.
6. Updated geographical region 
definition under Section 6.4 with 
consideration of enrollment by 
country based on SSR dataset, and 
updated the definition to remain
consistent under Section 8.1.
7. Moved supplemental analysis detail 
from Section 7 to Section 8.
8. Updated a sensitivity analysis of 
pattern mixture model of multiple 
imputation under Section 8.1, 
Section 8.5 and Appendix 4.
9. Updated dependent variable of 
ranked ANCOVA and Wilcoxon-
Mann Whitney test from “log-
transformed 28 day seizure rate” to 
“change from baseline to double 
blind phase of log-transformed 28 
1. This back 
transformation was 
requested by FDA for 
A0081042. It is added 
to be consistent with 
A0081042.
2. Correction, consistent
with the protocol-
specified population.
3. Cognitive testing was 
not included in the 
study protocol.
4. To differentiate results 
in pediatric vs adult 
population.
5. Specified in the 
protocol.
6. Based on actual 
enrollment.
7. Editorial changes.
8. Added more details 
with multiple 
imputation.
9. To be consistent with 
A0081042 analyses
and to be able to adjust 
the model for any 
baseline seizure 
imbalance.
10. The plot is not 
necessary as the 
interaction is 
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day seizure rate” under Section 8.1.
10. Removed the possibility of forest 
plot to evaluate interaction by age 
under Section 8.1.
11. Updated the analysis with Poisson 
and negative binominal models 
with considering baseline seizure 
count as a covariate and Pearson as 
the scale parameter (Poisson model 
only) under Section 8.1, Section 8.5 
and Appendix 5.
12. Updated the analysis of the 
proportion of seizure-free days for 
each seizure type from logistic 
regression to ANCOVA analysis 
under Section 8.3. 
13. Clarified the definition of 
proportion of subjects with PGTC 
seizure-freedom in Section 6.1.3.3.
14. Added clarification regarding 
seizure free days and proportion of 
seizure free days in Section 6.1.3.1.
15. Clarified the definition of number 
of 12 week adjusted seizure free 
days gained in Section 6.1.3.2.
16. Added contingency plan in case the 
primary analysis model fails due to 
covariates of region and age strata
in Section 8.1.
17. Added a secondary analysis based 
on combined European Union and 
US
18. Added clarification of responder 
rate 
analytically checked 
by ANCOVA model
11. To be consistent with 
A0081042 analyses, to 
adjust for baseline 
seizure imbalance in 
the model (Pearson as 
the scale parameter).
12. To correct an error in 
the analysis model in 
the previous SAP.
13. To be consistent with 
adult PGTC seizure-
freedom definition
used in past pregabalin 
studies.
14. To add detailed 
specifications.
15. To add detailed 
specifications.
16. To make analysis 
viable in case small 
numbers of subjects in 
certain region(s)
and/or age strata cause 
any issue with analysis 
model.
17. Based on blinded 
number of subjects 
across countries, US 
enrolled only 5 
subjects
18. Make the definition of 
responder rate more 
clear
Date: 18-Mar-
2019
1. Revised responder definition in 
Appendix I
1. To make the definition 
of responder rate 
consistent with adult 
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Version 4.0
study’s definition.
2. INTRODUCTION
Protocol A0081105 is a randomized, double-blind, parallel-group, placebo-controlled, 
multi-center trial in subjects 5 to 65 years of age with PGTC seizures. This study will
evaluate the efficacy of 2 dose levels of pregabalin [Dose Level 1: pregabalin 
5 mg/kg/day (maximum 300 mg/day) or Dose Level 2: pregabalin 10 mg/kg/day 
(maximum 600 mg/day), administered BID] compared with placebo.
2.1. Study Design
This study will consist of an 8-week baseline phase, a 12-week double-blind assessment 
phase (including a 2-week double-blind dose escalation phase and a 10-week double-
blind fixed dose phase), and a 1-week double-blind taper phase.   Eligible subjects will be 
randomly assigned to receive double-blind treatment with 1 of 2 dose levels of pregabalin 
or placebo.  Study drug treatments are to be taken orally twice daily (BID) in equally 
divided doses for 12 weeks during the double-blind assessment phase and then 1 week 
double-blind taper.  Subjects who complete the double-blind phase of this trial may be 
eligible for screening for a 1-year open-label pregabalin safety study.
A total sample size of 168 subjects (ie, 56 subjects per group) is needed to have been 
randomized, received treatment and had a baseline and post baseline efficacy 
assessment. Randomization will be stratified by site and subject age (Stratum 1: 5-7 years 
of age; Stratum 2: 8-11 years of age; Stratum 3: 12-16 years of age; Stratum 4: 
17-65 years of age). Subjects in each age stratum within site will be randomized to a 
fixed dose of either placebo, Dose Level 1: pregabalin 5 mg/kg/day (maximum 
300 mg/day) or Dose Level 2: pregabalin 10 mg/kg/day (maximum 600 mg/day) in a 
1:1:1 ratio.  Approximately 30% of planned enrollment (approximately 50 subjects) will 
be subjects <17 years of age.  Every reasonable effort will be made to enroll a minimum 
of 12 subjects in each of the 4 age strata.
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Study Design Diagram:
Visit
V1
V2
V3 V4 V5 V6
V7
V8
V9 V10
Week    
-8
-4
0
1
2
3
6
9
12
13
Day 
-56
-28
1
8 15 22
43
64
85
92
Window (days) ±3
±3 
0 ±3 ±3 ±3 
±3 
±3 
±3 ±3
Randomization
Screening Visit / 
Baseline Phase
(8 weeks)
Dose Escalation Phase (2 weeks)
Fixed Dose Phase (10 weeks)
Double-Blind Taper Phase (1 week)
Placebo
Dose Level 1:
Pregabalin 5 mg/kg/day**
(maximum 300 mg/day)
Dose Level 2:
Pregabalin 10 mg/kg/day***
(maximum 600 mg/day)
Double-Blind Assessment Phase
(12 weeks)
*Optional Open-Label Study A0081106
*Eligible subjects may be assessed for a 1-year open-label pregabalin safety study (Study A0081106) and 
complete end of study activities for A0081105 at Visit 10 (V10).
** Dose Level 1: 7 mg/kg/day for pediatric subjects <30 kg and 300 mg/day for subjects 17 years of age.
*** Dose Level 2: 14 mg/kg/day for pediatric subjects <30 kg and 600 mg/day for subjects 17 years of 
age.
Phone visits are also scheduled for Study Days 3, 10, 17, and 89 (each with a ±3 day window).
2.2. Statistical Power and Sample Size
A total sample size estimate of 168 subjects allows for the evaluation of efficacy using the 
primary endpoint, loge (28-day seizure rate + 1), for making comparisons between 
placebo vs. 5 mg/kg/day pregabalin (maximum 300 mg/day; Dose Level 1), and placebo 
vs. 10 mg/kg/day (maximum 600 mg/day; Dose Level 2) pregabalin groups for the 
treatment period of the study.  The following sample size assumptions and corresponding 
power calculations are provided in Table 1 below.  This sample size will also allow for a 
general assessment of safety and tolerability.
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Table 1.
Power Calculations and Sample Size Assumptions with 56 Subjects per 
Group for the Primary Endpoint (loge (28-day seizure rate + 1)
Comparison
Log 
Transformed 
Difference from 
Placebo
Percent Difference 
from Placebo
SD (log 
transformed 28 
day seizure rate)
Power
Expected 
difference1 between 
600 mg/day and 
placebo
-0.534
-41.4%
0.73
0.67
0.970
0.984
Expected 
difference1 between 
300 mg/day and 
placebo
-0.358
-30.1%
0.73
0.67
0.742
0.800
1 
Expected difference is 80% of the observed difference between the specified pregabalin dose minus 
placebo based on a meta-analysis of Studies 1008-009, 1008-011, and 1008-034 based on the log 
transformed 28 day seizure rate, with 300 mg/day only in Study 1008 -034.
The primary statistical analysis will model the log transformed 28 day seizure rate, and 
compare each dose of pregabalin to placebo in a step-wise manner, starting with the 
highest dose of pregabalin.  Since there is a significant dose response of pregabalin, the 
power to detect expected differences for each pregabalin dose relative to placebo will be 
different.  Hence, this step-wise testing procedure will provide maximum power as well 
as control for multiplicity of testing at the desired 0.05 level of significance for the 
primary analysis.
Based on a meta-analysis of double-blind placebo controlled adult adjunctive therapy 
studies (Studies 1008-009, 1008-011, and 1008-034) using the log transformed 28 day 
seizure rate, the expected differences from placebo (ie, the difference in the observed 
least squares means after adjusting out the study-to-study differences and site clustering 
within study effects) were -0.668 (-48.7%) and -0.448 (-36.1%) for 600 mg/day 
(Dose Level 2) and 300 mg/day (Dose Level 1), respectively.  This study is powered on 
80% of these estimated treatment differences; -0.534 (-41.4%) and -0.358 (-30.1%) for 
600 mg/day (Dose Level 2) and 300 mg/day (Dose Level 1), respectively.
A meta-analysis of Studies 1008-009, 1008-011, and 1008-034 was used to estimate a 
pooled standard deviation of 0.73 on the log transformed 28 day seizure rate scale, with 
a 95% confidence interval of [0.70, 0.76].  For the purposes of this study, a smaller 
standard deviation of 0.67 was used to assess the power and initial sample size 
requirements for comparing the 2 pregabalin group to placebo.  The rationale for 
assuming the smaller SD of 0.67 is based on the Study 1008-034 data which included all 
three treatment groups of interest (i.e., placebo, 300 mg/day, and 600 mg/day).  This 
study had a point estimate for the standard deviation of 0.72 and a 95% confidence 
interval for the standard deviation of [0.67, 0.77].
To ensure that the sample size is reasonably sufficient using an assumed pooled standard
deviation of 0.67 on the loge scale, in order to provide at least 80% power to detect a 
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treatment difference of 0.358 on the loge scale a blinded sample size re-estimation 
procedure (Friede and Keiser, 2011)3 based upon a residual variance of ANCOVA under 
the null hypothesis will be applied when approximately the first 110 subjects in total have 
had 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 56 subjects per 
group or an increase in sample size greater than 65 subjects per group (195 subjects 
total).  This represents the sample size required to provide 80% power to detect a 
treatment difference of -0.358 on the log scale with a standard deviation of 0.72.  The 
sample size also allows for operational feasibility. Details regarding the statistical 
methodology of the blinded sample size re-estimation procedure will be documented in 
Appendix 6.  This blinded sample size re-estimation procedure will be conducted by a 
statistician who is not associated with the conduct or final analysis of the study.
There will be no penalty applied to the p-values or confidence intervals for assessing 
treatment difference from placebo due to this blinded sample size re-estimation 
procedure.
2.3. Study Objectives 
Primary Objective:

To demonstrate superior efficacy of pregabalin compared to placebo for treatment of 
PGTC seizures as measured by the 28 day seizure rate.
Safety Objectives:

To assess the safety and tolerability of pregabalin relative to placebo in pediatric and 
adult subjects with PGTC seizures.
Secondary Objectives:

To demonstrate superior efficacy of pregabalin compared to placebo for PGTC 
seizures as determined by responder rate.
Exploratory Efficacy Objectives:

To demonstrate superior efficacy of pregabalin compared to placebo as 
determined by seizure-free days for PGTC, myoclonic, tonic/atonic, absence, and 
clonic seizures.
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
To demonstrate superior efficacy of pregabalin compared to placebo as 
determined by seizure-freedom of PGTC seizures over the last 28 days of the 
double-blind assessment phase and over the entire double-blind assessment 
phase.  In those subjects with myoclonic, tonic/atonic, absence, or clonic seizures 
at baseline, seizure freedom over the last 28 days of the study and over the entire 
double-blind assessment phase will be summarized descriptively.

To demonstrate superior efficacy of pregabalin compared to placebo as 
determined by the time to experience the same total number of PGTC seizures in 
the 12-week double-blind assessment phase that was observed during the baseline 
phase for each subject (referred to as ‘Time to Nth Seizure’). This analysis will be 
reported separately from the main clinical study report.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
3.1. Interim Safety Analysis
In additional to the regular review of blinded safety data during the conduct of the study, 
as described in the “Safety Analysis” section, 2 unblinded Interim Safety Analyses (ISA) 
to be reviewed by an E-DMC will be conducted to further assess safety.  The timing of the 
first ISA will be when the first one-third of the subjects enrolled (randomized) has had an 
opportunity to complete the study.  The second ISA will be performed when 
approximately two-thirds of the subjects enrolled (randomized) have had an opportunity 
to complete the study.  
The ISA will involve the descriptive review of deaths, SAEs, discontinuations due to 
AEs, and discontinuations due to the following 4 events:
1. An episode of status epilepticus during the 12-week double-blind assessment 
phase.
2. A 28-day seizure rate for all PGTC seizures during the 12-week double-blind 
assessment phase that is greater than 2-times the maximum 28-day study seizure 
rate during the baseline phase (a 28-day period is defined as 4 consecutive study 
weeks).
3. An episode of a newly emergent generalized seizure type during the 12-week 
double-blind assessment phase.
4. An increase in the rate or intensity of PGTC or other generalized seizure activity 
during the 12-week double-blind assessment phase that, according to the 
investigator, is clinically significant.
The ISA will not include any analysis for efficacy and therefore no type I error (alpha) 
spending penalty applies.
An External Data Monitoring Committee (E-DMC) will conduct this unblinded interim 
safety analysis and provide recommendation to the sponsor.  An E-DMC Charter will 
specify the details of how the safety interim analyses are to be conducted, and how 
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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.
3.2. Final Analysis and Unblinding 
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 appropriate case report form.
The unblinding for the final analysis will follow standard Pfizer procedures. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses
There will be 2 pair-wise comparisons of interest: 
a) Dose Level 2: pregabalin 10 mg/kg/day (maximum 600 mg/day) - placebo, and
b) Dose Level 1: pregabalin 5 mg/kg/day (maximum 300 mg/day) - placebo.
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.
1) The first step will test the null hypothesis of equal treatment effect of Dose Level 2 vs. 
placebo at =0.05 2-sided for the primary endpoint.
H01:  µPGB Dose Level 2 - µPBO = 0
Ha1:  µPGB Dose Level 2 - µPBO ≠ 0
2) The second step will test the null hypothesis of equal treatment effect of Dose Level 
1 vs. placebo at =0.05 2-sided for the primary endpoint.
H02:  µPGB Dose Level 1 - µPBO = 0
Ha2:  µPGB Dose Level 1 - µPBO ≠ 0
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4.2. Statistical Decision Rules
If the null hypothesis (H01) of the first step is rejected, then proceed to the second step 
(H02), otherwise, accept the null hypothesis of the first step (H01), stop further testing, and 
claim no treatment effect.
If the null hypothesis of the second step (H02) is rejected, then claim a treatment 
difference for both dose groups of pregabalin [Dose Level 2: 10 mg/kg/day (maximum 
600 mg/day) and Dose Level 1: 5 mg/kg/day (maximum 300 mg/day)] from the placebo 
group for the primary endpoint only; otherwise accept the null hypothesis of the second 
step (H02), stop further testing, and claim a treatment difference for only pregabalin Dose 
Level 2: 10 mg/kg/day (maximum 600 mg/day) from placebo for the primary endpoint 
only.
5. ANALYSIS SETS
5.1. Full Analysis Set (Intent-to-Treat Population)
The efficacy analyses will be performed on the intent to treat (ITT) population which 
consists of randomized subjects who took at least 1 dose of investigational product 
during the double-blind assessment phase, have a baseline value and at least 1 post-
baseline efficacy assessment (diary entry).
5.2. ‘Per Protocol’ Analysis Set (PP Population)
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 
randomized subjects who took at least one dose of the investigational product. 
5.4. Other Analysis Sets
Not applicable.
5.5. Treatment Misallocations 
If a subject was randomized but took incorrect treatment, then they will be reported under 
their randomized treatment group for the efficacy analyses, but will be 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.
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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
For all 28-day log seizure endpoints, the 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 28-day seizure rate 
translates into a 33% reduction in the 28-day seizure rate of the pregabalin group from 
the placebo group (ie, 100%*[exp-0.400-1]= -33%).  The “percent reduction in seizures” 
will be calculated for changes versus placebo on the following statistics: the two-sided 
95% confidence intervals, the least square means and their standard errors.
An additional back transformation will be calculated for percent reduction in seizures for 
each pregabalin treatment group relative to placebo for presentation as follows: 
6.1.1. Primary Endpoint 
The primary endpoint will be the log-transformed (loge) 28-day seizure rate for all PGTC 
seizures collected during the double-blind assessment phase (not including the 1-week 
double-blind taper phase).  The 28-day seizure rate will be calculated as follows for the 
double-blind assessment phase:
28-day seizure rate
=
# of seizures in the double-blind assessment phase of study
28
[# of days in period - # of missing diary days in period]
When the log-transformation is used, the quantity “1” is added to the 28-day seizure rate 
for all subjects to account for any possible "0" seizure incidence.  This will result in the 
following primary efficacy endpoint: loge(28-day seizure rate + 1). 
The 28-day seizure rate for all PGTC seizures collected during the baseline phase will be 
calculated similarly.
6.1.2. Secondary Efficacy Endpoint
Responder Rate, defined as subjects who have a 50% reduction in the 28-day seizure 
rate for all PGTC seizures during the double-blind assessment phase, as measured from 
baseline (data collected during the 8-week baseline phase) will be defined as a responder, 
otherwise they be considered as a non-responder.
The responder rate will be based on the percentage change from baseline in the 12-week 
double-blind treatment phase 28-day seizure rate, which is defined as follows:
% Change = [(28-day seizure ratet – 28-day seizure rateb) / 28-day seizure rateb] × 100%,
where t is the 12-week double-blind treatment phase and b is for the 8-week baseline 
phase.
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6.1.3. Exploratory Endpoints
6.1.3.1. Proportion of Seizure-Free Days
The proportion of seizure-free days for each seizure type: PGTC, myoclonic, tonic/atonic, 
absence, and clonic seizures will be computed. Proportion of PGTC seizure-free days is 
defined as number of seizure-free days in a period divided by “number of days in a period
- number of missing Seizure diary days”.
6.1.3.2. Number of Seizure-Free Days Gained
The number of seizure-free days gained for each seizure type: PGTC, myoclonic, 
tonic/atonic, absence, and clonic seizures will be calculated.  The number of seizure-free 
days will be adjusted to a per 12 weeks value (ie, 84 days) for the baseline and 12-week 
double-blind assessment phases.  Changes from baseline are to be computed and the 
analysis performed accordingly. The 12 week adjusted number of seizure-free days is 
defined as follows:
number of seizure-free days in a period * 84 / (number of days in a period – number of 
missing diary days in a period) .
Period refers to the length time in baseline, and in DB.  The 12 week adjusted number of 
seizure-free days will be calculated for baseline and DB; change from baseline will also 
be calculated.
6.1.3.3. Proportion of Subjects with PGTC Seizure-Freedom
The proportion of subjects with PGTC seizure-freedom will be computed.  The numerator 
for seizure-freedom is defined as the number of subjects that experience no PGTC 
seizures over the last 28 days of the double-blind assessment phase (must be a minimum 
of 4 weeks), patient must have received at least 42 days (2 weeks + 28 days) of study 
medication and have a minimum of 21 of the last 28 days as non-missing diary (ignore 
the first 2 weeks from dose escalation phase). The denominator is the number of subjects 
in the ITT population with 42 days (2 weeks + 28 days) of study medication.
The proportion of subjects with PGTC seizure-freedom over the entire double blind fixed 
dose assessment phase will also be computed. The numerator for seizure-freedom is 
defined as the number of subjects that experience no PGTC seizures over the fixed dose 
phase, patient must have received at least 84 days (2 weeks + 14 +28 +28 days) dosing
and have a minimum of 11 of the 14 days and 21 of each of the two 28 day periods with 
non-missing seizure diary (ignore the first 2 weeks from dose escalation phase). The 
denominator is the number of subjects in the ITT population with 84 days of study 
medication.
6.1.3.4. Time to Nth Seizure
The time to experience the same total number of PGTC seizures in the double-blind phase 
that were observed during the baseline phase for each subject, referred to as ‘Time to Nth
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Seizure’ will be assessed as an exploratory endpoint and will be described and conducted 
according to a separate exploratory statistical analysis plan (ESAP) for endpoint 
development, and reported separate from the main clinical study report.
6.2. Safety Endpoints
Safety endpoints include adverse event data (eg, occurrence, nature, intensity, and 
relationship to study drug), Hy’s law, vital signs, weight, clinical laboratory assessments, 
ECG, neurological examination, physical examination, prior and concomitant 
medications, suicidal ideation and behavior assessments (as age appropriate).
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 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). 
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.
6.2.3. Suicidal Ideation and Behavior Assessments During the Clinical Trial
C-SSRS responses will be mapped to the Columbia Classification Algorithm of Suicide 
Assessment (C-CASA). (see Appendix 2)
The following 3 endpoints are for suicidality data analysis and evaluation: 

Suicidal Behavior;

Suicidal Ideation;

Suicidal Behavior or Ideation.
Suicidal behavior: A subject is said to have suicidal behavior if the subject has 
experienced any of the following events (C-CASA event codes 1-3): 

Completed suicide;

Suicide attempt; or

Preparatory acts toward imminent suicidal behavior.
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Suicidal ideation: Any observed suicidal ideation maps to a single C-CASA category.   
The C-SSRS, for example, includes five ideation questions (that map to C-CASA 
category 4) with increasing severity.    
Subjects with new onset suicidal ideation and behavior: A subject will be considered to 
have a new onset of suicidal ideation and behavior if the subject reported no ideation and 
no behavior at the baseline assessment (note that self-injurious behavior, no suicidal 
intent [C-CASA code 7] is not considered to be suicidal ideation or behavior) and 
reported any behavior or ideation post-baseline.  Data observed at screening is not 
considered in the definition of new onset.
Subjects with worsening suicidal ideation and behavior relative to baseline: A subject 
will be considered to have a worsening of suicidal ideation and behavior if the subject 
moved to a lower numbered C-CASA category (observed in categories 1-4) than was 
reported at baseline.  Movement within C-CASA categories 5-9 would not be considered 
worsening.  In addition, worsening will be considered within the suicide ideation 
C-CASA category 4 if there is an increase in severity identified in the C-SSRS which 
captures additional granularity on suicide ideation. A subject who reports only ideation at 
baseline and who reports any behavior post-baseline is considered to have worsened.  
Data observed at screening is not considered in the definition of worsening.
6.3. Other Endpoints 
6.3.1. PK/PD Endpoints 
PK/PD endpoints and analyses will be described in a separate document created by 
Clinical Pharmacology.
6.4. Covariates 
Log-transformed 28-day seizure rate [loge(28-days seizure rateb + 1)] at baseline will be 
utilized as a covariate in the linear model used in the primary analysis, and for secondary 
analyses utilizing a similar model. 
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 
below).
Two covariates about age are defined as follows.  
Age strata will be defined as Stratum 1: 5-7 years of age; Stratum 2: 8-11 years of age; 
Stratum 3: 12-16 years of age; or Stratum 4; 17-65 years of age. This covariate is applied 
to primary analysis.
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Age group will be defined as: group 1, 5-16 years of age (at randomization); group 2: 17-
65 years of age (at randomization).  This covariate is applied to the analysis of primary 
efficacy endpoint as a sensitivity analysis. This age group definition will also be used to 
investigate treatment-by-age interaction for the primary efficacy endpoint.
Age will be defined as subjects’ age at randomization. If a subject turns 66 at 
randomization after screening, he/she will be counted in the 17-65 age group.
Region will be defined as follows (Upon closing of the randomization, region 
determinations will be further evaluated-See contingency plan):

United States (US): Subjects who participate in the U.S. or Puerto Rico centers 
will be pooled together;

European Union: All subjects who participate in European Union (eg, Austria, 
Belgium, Denmark, France, Germany, Greece, Italy, Netherlands, Portugal, 
Spain, Sweden, United Kingdom, Bulgaria, Croatia, Czech Republic, Estonia,
Hungary, Lithuania, Poland, Romania, and Slovakia, ) centers will be pooled 
together. The member countries of European Union are explained in more detail 
at https://europa.eu/european-union/about-eu/countries_en;

Asia-Pacific: All subjects participating in Asia-Pacific (China, India, Korea, 
Malaysia, Philippines, Singapore) centers will be pooled together;

Others: All subjects not participating in above three regions (eg, Russian 
Federation, Ukraine, Belarus, Bosnia and Herzegovina, Serbia, Montenegro,
Turkey) centers will be pooled together.
Any region not enrolling any subjects will not be included in the analysis.
7. HANDLING OF MISSING VALUES
Missing data will be handled based on the nature of the endpoint and the proposed 
statistical methods for analyzing the data.  
For all endpoints that include seizure rate, days with missing seizure diary data will be 
subtracted from the seizure rate calculations. If seizure rate for any phase cannot be 
calculated for a subject due to missing information, the endpoint that involves seizure rate 
during that phase will be also missing for that subject.
For scales used in this study, scores will be imputed according to the imputation rules and 
algorithms for missing component scores that are provided in the data standard 
documents. Partial dates for AEs and concomitant medications will be imputed 
according to Pfizer standard algorithms. 
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The assessment of missing data for the primary endpoint will require the construction of 
the following windows and drop-out categories:

Windowing for each subject will be constructed for the 1st month, 2nd month, and 
3rd month the subject was in the study. Thus a 28-day seizure rate will be 
determined for each windowed month for which seizure data exist, otherwise the 
seizure data will be considered missing with a corresponding reason for it being 
missing. Specific details are provided in Appendix 3.

Drop-out patterns will be constructed based on the reason the seizure data is 
missing for the corresponding windowed month. Hence, the following drop-out 
patterns will be defined for three specific categories of related to lack of efficacy 
or adverse event or other reason:

Completed study as planned.

Drop-out due to lack of efficacy:

Drop-out at month 1 due to lack of efficacy;

Drop-out at month 2 due lack of efficacy;

Drop-out at month 3 due to lack of efficacy.

Drop-out due to an adverse event:

Drop-out at month 1 due to an adverse event;

Drop-out at month 2 due to an adverse event;

Drop-out at month 3 due to an adverse event.

Drop-out due to other reason:

Drop-out at month 1 due to other reason;

Drop-out at month 2 due to other reason;

Drop-out at month 3 due to other reason.
Other reason includes any drop-outs excluding efficacy and adverse event.
These drop-out patterns will be summarized by treatment group to assess any imbalance 
using frequency counts. If there is a significant amount of missing data, then multiple 
imputation techniques will also be applied to the primary analysis model. However, if the 
amount of missing data is not significant (ie, less than 5% across all treatment groups), 
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then the assessment of missing data will not include multiple imputation techniques 
applied to the primary analysis model. 
Further details regarding the statistical strategy of assessing missing data will be 
provided in AppendicesAppendix 4, Appendix 5, and Appendix 6.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
The ITT 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. Analysis of Primary Efficacy Endpoint
The primary efficacy analysis of the primary endpoint, loge(28-days seizure ratet + 1) as 
defined in Section 6.1 of this document, will utilize a linear model with the following 
fixed effect terms:

A loge transformed baseline seizure rate loge(28-days seizure rateb + 1) for all 
PGTC seizures, as a continuous covariate;

Age strata (Stratum 1: 5-7 years of age; Stratum 2: 8-11 years of age; Stratum 3: 
12-16 years of age; Stratum 4; 17-65 years of age);

Geographic region (See Section 6.4) by pooling of investigator centers;

Treatment group [placebo, Dose Level 1: pregabalin 5 mg/kg/day (maximum 
300 mg/day), Dose Level 2: pregabalin 10 mg/kg/day (maximum 600 mg/day)].
There will be two pair-wise comparisons of interest: 
1) Dose Level 2: pregabalin 10 mg/kg/day (maximum 600 mg/day) - placebo, and
2) Dose Level 1: pregabalin 5 mg/kg/day (maximum 300 mg/day) - placebo.
The difference in the least squares means and their standard errors for these two pair-wise 
comparisons will be used for constructing test statistics and two sided 95% confidence 
intervals. 
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:
1. The first step will test the null hypothesis of equal treatment effect of Dose Level 2 
vs. placebo at =0.05 2-sided for the primary endpoint. 
If the null hypothesis of the first step is rejected, then proceed to the second step, 
otherwise accept the null hypothesis of the first step, stop further testing, and 
claim no treatment effect.
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2. The second step will test the null hypothesis of equal treatment effect of 
Dose Level 1 vs. placebo at =0.05 2-sided for the primary endpoint.
If the null hypothesis of the second step is rejected, then claim a treatment difference 
for both dose groups of pregabalin [Dose Level 2: 10 mg/kg/day (maximum 
600 mg/day) and Dose Level 1: 5 mg/kg/day (maximum 300 mg/day)] from the 
placebo group for the primary endpoint only; otherwise accept the null hypothesis of 
the second step, stop further testing, and claim a treatment difference for only 
pregabalin Dose Level 2: 10 mg/kg/day (maximum 600 mg/day) from placebo for the 
primary endpoint only.
The difference in the least squares means and their standard errors for these 2 
pair-wise comparisons will be used for constructing test statistics and 2-sided 95% 
confidence intervals.  Results will be reported as “percent reduction in seizures from 
baseline” relative to placebo.  For example, a difference between 1 of the pregabalin 
doses and placebo of -0.358 on the log-transformed scale for the 28-day seizure rate, 
translates into a 30.1% reduction in the 28-day seizure rate of the pregabalin group 
from the placebo group (ie, 100%*[exp-0.358-1] = -30.1%]).
An additional back transformation will be calculated for percent reduction in seizures 
for each pregabalin treatment group relative to placebo for presentation as follows:
The 28-day seizure rate of log scale in the double-blind treatment phase will be 
summarized by each month and the entire 12-weeks double-blind period for each 
treatment group, age group [pediatrics overall (<17 years) and adults (17-65 years)], 
and geographic region.
Contingency plan for the primary ANCOVA analysis model
If after unblinding, the primary ANCOVA analysis model as described above performs 
well without any issues, the primary analysis model will stay as described above. 
However, in case of ANCOVA analysis issues, for example, with convergence or missing 
cells in a particular treatment within a region or within an age strata, the cause of the 
analysis model issues will be mitigated, for example, as follows:

If a small region, say US region, causes the model issue alone, the small region 
(say US region) will be pooled with European Union; Other ANCOVA model 
terms will stay as is;

If age strata causes the model issue alone, the age group (5-16 years of age and 
17-65 years of age) as described in Section 6.4 will be used instead of the age 
strata; Other ANCOVA model terms will stay as is;
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
If both a small region and age strata cause the model issue, then ANCOVA 
analysis will be performed with the small region (say US region) pooled with 
European Union and age group (instead of age strata), Other ANCOVA model 
terms will stay as is.
Other analyses of continuous dependent variables with ANCOVA model will follow the 
same procedure as the primary efficacy endpoint analysis. Responder rates and any other 
binary variables that use the same planned model as primary efficacy endpoint analysis 
will similarly be adjusted as needed.
Sensitivity Analysis
As a sensitivity analysis of the primary endpoint, multiple imputation methods will be 
used to evaluate the impact of missing data (See Appendix 4). 
Subjects who discontinue the study for insufficient clinical response, adverse event, or 
death will be imputed based on the observed placebo distribution, regardless of 
randomized treatment assignment.  Imputation will be based on baseline loge(28-days 
seizure rateb +1), geographical region, baseline weight (continuous), and age strata.
Subjects who discontinue the study for other reasons, or who complete the study but have 
a missing double blind seizure rate, will be imputed based on observed subjects in the 
same randomized treatment group.  Imputation will be based on treatment group, baseline 
loge(28-days seizure rateb +1), geographical region, baseline weight (continuous), and age 
strata.
A sensitivity analysis will be performed using the same linear model as the primary 
efficacy analysis except for the age covariate, which will be applied for the 2 age groups
(5-16 years of age; 17-65 years of age). 
An additional sensitivity analysis will be performed using the same linear model as the 
primary efficacy analysis with two age groups covariate as well as pooled region of US 
and European Union.
A ranked ANCOVA will be performed for the change from baseline to double blind phase
of log-transformed (loge) 28-day seizure rate for all PGTC seizures, including age strata, 
treatment group, and region.
A Wilcoxon-Mann Whitney test will also be performed and reported for the change from 
baseline to double blind phase of log-transformed (loge) 28-day seizure rate for all PGTC 
seizures.
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Supplemental Analysis
A supplemental analysis will be performed to investigate generalizability of the treatment 
difference with respect to the 2 age categories (ie, a possible treatment-by-age 
interaction that is statistically and clinically relevant). The estimated seizure rate, 
standard error and the corresponding 95% confidence interval in addition to the treatment 
difference between each pregabalin treatment group and placebo will be calculated for 
both pediatric (5-16 years of age) and adult population (17-65 years of age).  This 
supplemental analysis will also be a re-evaluation of the primary analysis model with an 
interaction term for treatment-by-age.  This model will not replace the primary model.    
As a supplemental analysis, a generalized linear model assuming a Poisson and negative 
binomial distributions and canonical log link function will be applied to the raw seizure 
counts.1, 2  The model will have an off-set parameter for the amount of time (i.e., 
loge(days ) ) the subject was in the double blind treatment phase. A scale parameter of 
Pearson will be specified to fit the Poisson distribution.
The analyses with Poisson and negative binomial models will be performed with baseline 
seizure count as covariate. 
The raw 28-day seizure rate will be summarized overall, and separately by age group of
pediatrics overall (<17 years) and adults (17-65 years).
8.2. Analysis of Secondary Efficacy Endpoints
The secondary efficacy endpoint will be the responder rate, defined as the proportion of 
subjects who had at least a 50% reduction in the 28-day seizure rate for all PGTC 
seizures during the double-blind assessment phase, as measured from baseline (data 
collected during the 8-week baseline phase) on the ITT population.  This secondary 
endpoint will be analyzed using a logistic regression model with the following fixed 
covariate terms: treatment, age stratum, and geographical region.  No adjustments for 
multiplicity will be taken, and nominal p-values from 2-sided tests and the 
correspondence odds ratio with 95% confidence interval will be reported.
NOTE: The “PARAM=GLM” option in CLASS statement of SAS will be applied for 
logistic regression. 
The responders and non-responders will be summarized descriptively by treatment using 
counts and percentages, and additionally by treatment group, age strata. Descriptive 
statistics for responder will also be provide for pediatrics overall (<17 years) and adults 
(17-65 years) and geographical region.
8.3. Analysis of Exploratory Endpoints
The proportion of seizure-free days for each seizure type: PGTC, myoclonic, tonic/atonic, 
absence, and clonic seizures will utilize ANCOVA model.
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The number of seizure-free days gained for each seizure type: PGTC, myoclonic, 
tonic/atonic, absence, and clonic seizures will be analyzed utilizing a linear model 
similar to the primary analysis.  
The proportion of subjects with PGTC seizure-freedom will utilize a logistic regression 
model similar to the responder rate analysis. 
No adjustments for multiplicity will be taken and nominal p-values from 2-sided tests will 
be reported.
The exploratory endpoints will additionally be presented descriptively overall, and 
separately by age group of pediatrics overall (<17 years) and adults (17-65 years).
8.4. Safety Analyses
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 a baseline.
No inferential safety analyses are planned. Pfizer safety reporting standards will be 
utilized for all safety endpoints.
All safety analyses will be presented overall, and separately by age group of pediatrics 
overall (<17 years) and adults (17-65 years).
8.4.1. 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 from the first day of study treatment through 
and including 28 calendar days after the last administration of the study drug will be 
considered treatment emergent AEs (TEAEs). An overall summary of treatment-
emergent AEs will be provided.  TEAEs will also be summarized by system organ class, 
preferred term, severity, and relationship to study drug. TEAEs will be presented overall, 
and separately by age group of pediatrics overall (<17 years) and adults (17-65 years).
Summaries and listings of all AEs, SAEs and treatment-related AEs will be presented in 
accordance with the current Pfizer Standard Operating Procedures (SOPs) and standards.
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
Tier 3: Standard safety output (no new outputs-see above)
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The Tier 2 and 3 AEs will be presented overall, and separately by age group of   
pediatrics overall (<17 years) and adults (17-65 years).
8.4.2. Suicidal Ideation and Behavior
C-CASA/C-SSRS
The denominator used in the percentages will be the number of subjects assessed for 
suicidal ideation and behavior.  For worsening, the denominator would include the subset 
of subjects who had any level of suicidal ideation and behavior reported at baseline.  For 
new onset, the denominator would include the subset of subjects with no suicidal ideation 
and behavior reported at baseline.
A subject listing of C-CASA categories as well as the underlying C-SSRS scale data will 
be presented.  
In addition, a summary table with the number and percent of subjects within each C-
CASA category by treatment group at screening, baseline, and at any time post-baseline 
without regard to baseline will be reported.   
C-CASA will be presented overall, and separately by age group of   pediatrics overall 
(<17 years) and adults (17-65 years).
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8.5. Summary of Efficacy Analyses 
Endpoint (Key 
Summary 
Metrics)
Analysis 
Set
Statistical 
Method 
Model/ 
Covariates/ 
Strata
Missing Data
Interpretation
Loge 28-day 
PGTC seizure 
rate 
(N, LS Mean
Diff/SE)
ITT
ANCOVA Treatment, 
region, age 
strata, 
baseline 
seizure rate
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Primary Analysis
Note: age strata is 
protocol defined age 
strata. Baseline is the 
log of 28-day PGTC 
rate at baseline
Key summary statistics will be presented for the Loge 28-day PGTC seizure rate and for the back 
transformed “percent reduction in seizures” relative to placebo. 
Loge 28-day 
PGTC seizure 
rate 
(N, LS Mean 
Diff/SE)
(treatment-by-
age p-value)
ITT
ANCOVA Treatment, 
region, age 
group, 
treatment-by-
age group
interaction, 
baseline 
seizure rate
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Supplemental Analysis
Note: age groups are 
Age< 17 yrs and Age>= 
17 yrs. Baseline is the 
log of 28-day PGTC 
rate at baseline.
Key summary statistics will be presented for the Loge 28-day PGTC seizure rate and for the back 
transformed “percent reduction in seizures” relative to placebo. 
Responder rate
(%)
ITT
Logistic 
regression
Treatment, 
region, age 
strata
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Secondary Analysis
Proportion 
Seizure-free 
days
(%)
ITT
ANCOVA
Treatment, 
region, age 
strata, 
baseline
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Exploratory Analysis
Each seizure type: 
PGTC, myoclonic, 
tonic/atonic, absence, 
and clonic seizures.  
Baseline for this 
endpoint is the 
proportion of seizure
free days at baseline.
Number of 
seizure-free 
days gained 
(N, Mean, SE)
ITT
ANCOVA Treatment, 
region, age 
strata, 
baseline 
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Exploratory Analysis
Each seizure type: 
PGTC, myoclonic, 
tonic/atonic, absence, 
and clonic seizures.
Baseline for this 
endpoint is the number 
of adjusted seizure free 
days at baseline.
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Proportion 
PGTC Seizure-
freedom
(%)
ITT
Logistic 
regression
Treatment, 
region, age 
strata 
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Exploratory Analysis
Loge 28-day 
PGTC seizure 
rate 
(N, LS Mean 
Diff/SE)
ITT
ANCOVA Treatment, 
region, age 
strata, 
baseline 
Multiple 
imputation will 
be applied.
Sensitivity Analysis.  
Baseline is the log of 
28-day PGTC rate at 
baseline.
Loge 28-day 
PGTC seizure 
rate 
(N, LS Mean 
Diff/SE)
ITT
ANCOVA Treatment, 
region, 2 age 
groups, 
baseline 
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Sensitivity Analysis
Note: age group are 
Age< 17 yrs and Age>= 
17 yrs.  Baseline is the 
log of 28-day PGTC 
rate at baseline
Loge 28-day 
PGTC seizure 
rate 
(N, LS Mean 
Diff/SE)
ITT
ANCOVA Treatment, 
pooled 
region, 2 age 
groups, 
baseline 
Days missing 
from Seizure 
Diary will be 
subtracted from 
rate calculations
Sensitivity Analysis
Note: age group are 
Age< 17 yrs and Age>= 
17 yrs. US and 
European Union will be 
pooled in the region 
class. Baseline is the 
log of 28-day PGTC 
rate at baseline
Change from 
baseline to 
double blind 
phase of Loge 
28-day PGTC 
seizure rate 
ITT
Rank
ANCOVA
Treatment, 
region, age 
strata, region 
and ranked 
log-BL
Sensitivity Analysis
(Log-Scale). Baseline 
is the ranked log of 28-
day PGTC rate at 
baseline.
Change from 
baseline to 
double blind 
phase of Loge 
28-day PGTC 
seizure rate 
(DB Phase)
ITT
Wilcoxon-
Mann 
Whitney 
Test
Sensitivity Analysis
(Log-Scale)
Raw Seizure 
Count
ITT
GENMOD, 
Poisson 
and 
negative 
binomial 
distribution 
with log 
link
Treatment, 
and baseline
scale parameter = 
Pearson for the Poisson 
model. Baseline for this 
endpoint is seizure 
count at baseline.
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
All efficacy endpoints will be presented descriptively overall, and separately as by 
age group of pediatrics overall (<17 years) and adults (17-65 years).
9. REFERENCES
1.
McCullagh, P. and Nelder, J.A. (1989). Generalized Linear Models, Second Edition, 
New York: Chapman & Hall/CRC.
2.
Stokes, M.E., Davis, C.S., and Koch, G.G. (2000). Categorical Data Analysis Using 
the SAS System, Second Edition, Cary, NC: SAS Institute.
3.
Friede, T. and Keiser, M. (2011). “Blinded sample size recalculation for clinical 
trials with normal data and baseline adjusted anlaysis” Pharmaceutical Statistics,
10: 8-13.
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APPENDICES 
Appendix 1. Data Derivation Details 
This table describes how seizure related endpoints have been defined. 
Endpoint 
Derivation
8-week baseline phase (b) 
28-day seizure rate 
28-day seizure rateb= [(# of seizuresb) ÷ (#of daysb - # of 
missing diaryb)] × 28, where #of daysb is defined as (first dose 
date-1) – screening date +1.
12-week double-blind 
treatment phase (t) 28-day 
seizure rate 
28-day seizure ratet = [(# of seizurest) ÷ (#of dayst- # of 
missing diaryt)] × 28, where #of dayst is defined as date of 
last dose in phase – date of first dose in phase +1.
Primary endpoint: Loge of 
28-day seizure rate during 
12-week double-blind 
treatment phase
Loge (28-day seizure ratet +1)
“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 28-day seizure rate translates into a 33% reduction 
in the 28-day 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: 
Percent change from 
baseline in 12-week 28-day 
seizure rate
% Change = [28-day seizure ratet -28-day seizure rateb)/ 28-
day seizure rateb] × 100%
Responders 
50% reduction in the 28-day seizure rate from baseline 
during the 12-week double-blind treatment phase, then
response = 1 (responder) otherwise response = 0 (non-
responder).
The response status will be set as missing if the baseline 
seizure rate is missing. If baseline seizure rate is non-missing 
but there are no double-blind phase seizure rates, then the 
response status will be set as non-response
Proportion Seizure-free 
days
The numerator for seizure-free days is defined as the 
number of days the subject experience no seizures over the 
double-blind assessment phase.
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Number of seizure-free 
days gained
The number of seizure-free days will be adjusted to a per 
12 weeks value (ie, 84 days) for the baseline and 12-week 
double-blind assessment phases.  Changes from baseline 
are to be computed and the analysis performed accordingly.
Number of 12 week adjusted seizure free days is defined as 
follows:
Number of seizure free days in a period x 84 / number of 
days in a period.
Proportion PGTC Seizure-
freedom
The numerator for seizure-freedom is defined as the 
number of subjects that experience no PGTC seizures over 
the last 28 days of the double-blind assessment phase 
(Patient must have received at least 42 days (2 weeks + 28 
days) of study medication and have a minimum of 21 of the 
last 28 days as non-missing diary). The denominator is the 
ITT population with 42 days (2 weeks + 28 days) of study 
medication.
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Appendix 2. C-SSRS Mapped to C-CASA - Suicidal Ideation and Behavior Events 
and Codes
C-CASA 
Event Code
C-CASA Event
C-SSRS Response
1
Completed suicide
As captured in the safety database
2
Suicide attempt
“Yes” on “Actual Attempt”
3
Preparatory acts towards 
imminent suicidal behavior
“Yes” on any of the following:

“Aborted attempt”, or

“Interrupted attempt”, or

“Preparatory Acts or Behavior”
4
Suicidal ideation
“Yes” on any of the following:

“Wish to be dead”, or

“Non-Specific Active Suicidal 
Thoughts”, or

“Active Suicidal Ideation with Any 
Methods (Not Plan) without Intent to 
Act”, or

“Active Suicidal Ideation with Some 
Intent to Act, without Specific Plan”, 
or

“Active Suicidal Ideation with 
Specific Plan and Intent”
7
Self-injurious behavior, no 
suicidal intent
“Yes” on “Has subject engaged in Non-suicidal 
Self-Injurious Behavior?”
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Appendix 3. Windowing for Study Months 1, 2 and 3
A 28-day seizure rate will be determined for each windowed month for which seizure 
data exist. Assignment of seizure data to visits during the Double-Blind Treatment Phase 
will use visit windows based on the day of the assessment relative to the date of the start 
of the double blind treatment phase. The following visit windows will be defined for 
statistical outputs:
Visit Windows 
Month
Time Interval
(Days)
Month 1
1 to 28
Month 2
29 to 56
Month 3
57 to 90
Derive study day as the (assessment date-date of start of double blind treatment phase) 
+ 1. A subject must have at least 24 diary days to be counted in any monthly visit 
window data. Any data collected after Day 90 will be excluded from the monthly visit 
window calculations. 
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Appendix 4. Analysis Strategy Using Multiple Imputations
If the amount of missing data is not significant in the primary endpoint (ie, less than 5% 
within each treatment groups), then the multiple imputation analysis will not be 
performed.
Concept of multiple imputation strategy
Multiple imputation procedure is used under the assumption of missing at random (MAR) 
data and under the assumption of a monotone missing data pattern. In general, let Y be 
the response data (monthly seizure rate) 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.
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, we will let m take on the value 100.
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 
imputation. 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:
Yj = β0 + β1*Y1 + β2*Y2 + … + β(j-1) Y(j-1).
The fitted model has parameter estimates (b0, b1, b2, …, b(j-1)) and the associated 
covariance matrix s2
jVj, where Vj is the usual XTX matrix from the intercept and 
variables Y1, Y2, …, Y(j-1). 
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For each imputation, new parameters (β*
0, β*
1, β*
2, …, β*
(j-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:
β*
0 + β*
1*y1 + β*
2*y2 + … + β*
(j-1)*y(j-1) + zi**2
where y1, y2, …, y(j-1) are covariates values for the first (j-1) variables 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. 
SAS sample programs for multiple imputation strategy for this study
A pattern mixture model of multiple imputation is applied, and sample SAS programs are 
described as below.  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 (See covariates Section 6.4).

TRT: Treatment group (Placebo, Pregabalin Level 1, Pregabalin Level 2).

LN_BSZRT: A loge transformed baseline seizure rate loge(28-days seizure rateb
+1).

LN_SZRATE: A loge transformed double-blind seizure rate loge(28-days 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, 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 
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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';
*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;
   else 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 = 100;
   class region age_strata;
   var region age_strata ln_bszrt ln_szrate weight;
   monotone regression(ln_szrate = ln_bszrt region age_strata weight);
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 = 101 ;
class region age_strata trt ;
   var region age _strata trt ln_bszrt ln_szrate weight;
   monotone regression(ln_szrate = trt ln_bszrt region age_strata weight) ;
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 Level 1, and Pregabalin Level 2 ;
proc glm data=main; 
  by _imputation_ ;
  class region age_strata trt ;
  model ln_szrate = trt region age_strata ln_bszrt;
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lsmeans trt / diff=control('Placebo') tdiff pdiff cl ;
  estimate ‘Pregabalin Level 1 vs Placebo’ trt -1 1 0 ;
  estimate ‘Pregabalin Level 2 vs Placebo’ trt -1 0 1 ;
  ods output lsmeans=lsm diffs=lsdiff estimates=estdiffs ;
run ;
quit ;
*integrated summary of results of imputed datasets;
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 ;
  by parameter ;
  modeleffects estimate ;
  stderr stderr ;
run ;
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Appendix 5. 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 time (T) in the Model 

Off-setting the exposure time by ln(T)

ln(/T) = +X

= T·exp(+X)

Adjust for unequal exposure times among treatment groups
Exposure time T is derived in months as study day/28, where study day is derived as the 
(assessment date-date of start of double blind treatment phase) + 1.  Eg, if the subject 
dropped out at day 26, the exposure time would be 26/28=0.93 months.
The scale parameter will be set to Pearson in the Poisson model.
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Appendix 6. Blinded Sample Size Re-Estimation
The proposed sample size re-estimation formula (Friede and Keiser, 2011)3 is the 
following:




2
2
2
2
1
2
/
1
2
*
1
)
(
1
















z
z
n
where,
*n is the revised total sample size of two treatment groups for this estimation;
is the ratio of the estimated sample size of two treatment groups;
2
/
1 

z
is a percentile from a standard normal cdf with α/2=0.025; 


1z
is a percentile from a standard normal cdf with β=0.20;
2

is the blinded estimate of pooled variance for outcome variable at the interim review;
is the blinded estimate for the correlation between an outcome and a covariate variable;
is the clinically meaningful difference between Dose Level 1: pregabalin 5 mg/kg/day 
(maximum 300 mg/day) and placebo (i.e., 0.358) as specified in the protocol. 
For this study, the ratio of estimated sample size of two treatment group () is assumed 
as one due to 1:1 randomization with respect to placebo versus dose level 1.  In addition, 
the estimates for correlation ( ) and pooled variance (
2
) is estimated based on the 
residual variance of ANCOVA.  Therefore, the simplified equation for this study is: 
2
2
2
1
2
/
1
*
~
)
(
4







s
z
z
n


where, 
2
~s is the blinded estimate of the residual variance based on ANCOVA at the interim 
review.  
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
110 subjects have had the opportunity to complete the study. Since baseline 28 day 
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 
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estimate of the variance under the null hypothesis will be biased upwards, this bias is 
negligible when the overall sample is reasonably large. Results from a thorough 
simulation study indicated that the re-estimated sample size using the uncorrected pooled 
variance required only 2 -to-3 more subjects per group relative to using a corrected 
pooled variance estimate. 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=195). 
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