Clinical trial NCT00351611
Conditions: Epilepsies, Partial
Keywords: epilepsy partial seizure treatment with pregabalin or placebo vision testing
Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Start date: 2006-07-26; Completion date: 2020-02-04
Enrollment: 187 participants; Allocation: RANDOMIZED; Intervention model: 

Brief summary:
Patients with partial seizures currently taking 1-3 antiepileptic medications will have a 50:50 chance to receive Lyrica 300 mg per day or placebo (no active ingredients) added on to their current medications for 3 months. Neither the study doctor nor the patient will know the medication assignment. Vision testing will be performed prior to receiving the study treatment and at the end of the study to see if there are any changes.

Detailed description:

Arms: arm 1: Active drug arm 2: placebo comparator
Interventions: intervention 1: Lyrica (pregabalin) intervention 2: placebo
Intervention descriptions: intervention 1: 150 mg twice a day, oral administration intervention 2: Twice a day, oral administration

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL
PROSPECTIVE RANDOMIZED 12-WEEK CONTROLLED STUDY OF VISUAL 
FIELD CHANGE IN SUBJECTS WITH PARTIAL SEIZURES RECEIVING 
PREGABALIN OR PLACEBO
Compound:
PD-0144723; CI-1008
Compound Name (if applicable):
Pregabalin
EudraCT Number
2009-014269-25
US IND Number (if applicable):
49,393
Protocol Number:
A0081096
Phase:
Phase IV
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed 
to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it 
for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 5
25 September 2020
Sample size estimation changed based on the 
observed common standard deviation of mean 
deviation. Common SD changed from 5.6 dB 
based on literature at the time of the study design
to 1.3 dB based on observed blinded data from 
study A0081096.
Enrollment to be approximately 187.
The following statement has been added to the 
Section 9.4 of the protocol: the expectation is that 
the Per Protocol subset will be close in the 
number of subjects to the number of subjects 
randomized.
Amendment 4
15 December 2015
Single Reference Safety Document (SRSD) for 
this study was changed from the Core Data Sheet 
(CDS) to the Investigators Brochure (IB). The IB 
contains more extensive information about 
pregabalin than the CDS.
The protocol introduction was updated to include 
current marketing information on Lyrica.
The following changes were made to comply with 
FDA and Neuropsychiatric and Abuse Potential 
Advisory Council (NAPAC) Guidance:

Suicidality assessment: the Columbia-Suicide 
Severity Rating Scale (C-SSRS) will be 
performed instead of the Sheehan-Suicidality 
Tracking Scale (S-STS) for subjects screened 
following approval/initiation of 
Amendment 4. Subjects who are randomized 
under Amendment 3 will not switch to the 
C-SSRS. 

Suicidal Behaviors Questionnaire–Revised 
(SBQ-R) will be performed at screening.

Scoring instructions for the PHQ8 have been 
inserted as well as a reference to the 
Instruction Manual.
The following protocol exclusion has been 
inserted to increase subject safety:


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
Any subject at risk of suicide or self-harm 
based on investigator judgment and/or details 
of a mental health risk assessment (MHRA) 
by a qualified mental health professional.
Instructions for completion of the PHQ-8 have 
been included. The Instruction Manual has been 
referenced.
The following statement has been inserted into 
Section 4.3 to reinforce the requirement to 
include only subjects who have adequate baseline 
VFT.

Subjects may not be randomized prior to 
receiving confirmation of the validity of the 
Baseline VFT from the central reader.
Sections presenting the Visual Field Testing 
(VFT) procedures were revised to clarify 
procedures or to amend the procedures to make it 
easier for the investigator to comply with the 
protocol:

Repeat VFT should be performed as soon as 
possible and within 2 weeks following 
notification from the central reader.

Section has been updated to reflect the 
electronic submission of the VFT results with 
subsequent faster response times.
The number of sites to participate in the study has 
been deleted. This study has been ongoing for 
many years with waves of sites being initiated 
and terminated.
The following changes were made to comply with 
the current protocol template and required 
language/wording:

Abbreviation list moved to an Appendix.

Updated terms study drug and study 
medication to investigational product for 
consistency.

Inserted Lifestyle Guidelines which includes 
template contraception language.

Inserted Sponsors Medically Qualified 


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Personnel.

Updated Trial Treatments including insertion 
of new sections for Investigational Product 
Storage, Investigational Product 
Accountability and Destruction of 
Investigational Product Supplies.

Updated Drug Supplies.

Updated Investigational Product Storage.

Updated Quality Control and Quality 
Assurance.

Inserted Medication Errors.

Updated Exposure During Pregnancy.

Inserted Occupational Exposure.

Updated Publication of Results.
The following changes were made to clarify 
potentially confusing language or to streamline 
the protocol:
Clarified dose administration.
Deleted samples of S-STS and PHQ-8 from 
Appendices.
Subjects will be required to record all 
investigational product dosing in a dosing diary 
which is to be reviewed by site staff with the 
subject at each visit. This is expected to improve 
the ability of the investigative site to reconcile 
investigational product use.
Amendment 3
12 December 2011
To add new safety wording. To allow for 
rescreening of subjects. To add clarification 
around the timing of the visual field testing
(VFT) and handling of the primary endpoint as an 
AE.  Also clarification of prohibited and allowed
concomitant medications; and documentation of 
adverse events related to changes from entry in
vital signs, weight and on the physical exam.
Background & Rationale, PASS language added, 
Subject Selection, Compliance, DMC text added.
Amendment 2
12 August 2009
See Appendix 4.


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Amendment 1
17 October 2006
See Appendix 3.
Original 
protocol
25 May 2006
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country Health Authorities, IRB/ERB, etc.  


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SUMMARY
Indication:
Epilepsy; adjunctive therapy in patients with partial seizures.
Rationale:
This study is being performed as a Phase IV commitment to assess visual fields in subjects 
taking pregabalin as compared to placebo when added to their existing antiepileptic therapy.
Objectives: 
To evaluate visual fields in subjects with partial epilepsy receiving 12 weeks treatment of 
pregabalin compared to placebo.
Trial Design:
This is a Phase IV, multicenter, randomized placebo-controlled trial to further characterize 
visual fields in subjects with partial epilepsy dosed for 13 weeks, including a 1 week up
titration and 1 week down titration from the target dose of pregabalin 300 mg/day versus 
placebo.  Comprehensive ophthalmologic testing will be done at pre-treatment baseline to 
exclude those with pre-existing eye disease.
Placebo
PGB 75mg
BID
Study Week
- 1
Study Week
2-12 
Screening
Treatment
Follow-up
Study Week
1
PGB 150 mg
BID
PGB 75 mg
BID
Study Week
15
Study Week
13 
Approximately 187 subjects will participate in the study. Subjects will be randomized 1:1 to 
pregabalin or placebo, with approximately 93 randomized to pregabalin and 93 to placebo.  
Study Week
-3 ~ -1
Study Week
1
Study Week
2 - 12
Study Week
13
Study Week
14 - 15


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Endpoints:
The primary endpoint is the proportion of subjects with a decrease in the threshold value 
from baseline to termination in five or more points (in either eye) at the p<.05 level repeated 
in the same five points on subsequent computerized automated perimetry testing 
(Humphrey 24-2 SITA standard).
Trial Treatments:
Subjects will receive oral pregabalin 75 mg twice daily (BID) (150 mg/day) or matching 
placebo for titration and taper.  Subjects will receive oral pregabalin 150 mg BID 
(300 mg/day) or matching placebo for the treatment phase.
Statistical Methods:
The primary endpoint will be analyzed using a non- inferiority analysis.  The difference in 
proportions between pregabalin and placebo in the per protocol population will be compared 
using a 2-sided 95% confidence interval (CI).  Non-inferiority will be demonstrated if the 
upper CI bound is less than 0.10 (10%).  The proposed sample size will have >90% power to 
detect non-inferiority on the primary endpoint, assuming a proportion of 1% for each group.
SCHEDULE OF ACTIVITIES
Protocol Activity
Screening Baseline
Wk 0 
Randomization
Wk 1 Wk 6
Wk 12
(Or ET)
Week 15
(Follow-Up)
Visit Numbern
1
2
3m
4
5
6
7
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
X
Review/document contraception use
X
History/Diagnosis/Demographics
X
Physical Examinationp
X
X
Concomitant Medication 
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
Vital Signs (Sitting BP/HR)
X
X
X
X
X
ECG (Singlet)
X
EEG
Xa
CT or MRI
Xb
Clinical
1) Hematologyc
X
X
Laboratory 2) Chemistryd
X
X
3) Urinalysise
X
X
Urine Pregnancy Testf
X
X
Urine Drug Screen
X
1) External Eye Exam
X
X
Xg
2) ETDRS Acuity
X
X
X
X
Xg
Ophthalmic 3) Intraocular Pressure
X
Examination 4) Dilated 
Funduscopic
X
5) VFT (24-2 SITA)
Xh,l
Xh,l
Xh
Xh
Xg,h
Patient assessment of seizure 
frequency
X


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Protocol Activity
Screening Baseline
Wk 0 
Randomization
Wk 1 Wk 6
Wk 12
(Or ET)
Week 15
(Follow-Up)
Investigational product Dispensing
Xi,j
Xk
Xk
Xj
Dispense Dosing Diary
X
X
Review Dosing Diary with subject
X
X
X
X
Sheehan-Suicidality Tracking Scale
(S-STS)o,r
X
X
X
X
X
X
X
Columbia-Suicide Severity Rating 
Scale (C-SSRS)o,r
X
X
X
X
X
X
X
Suicidal Behaviors Questionnaire –
Revised (SBQ-R)r
X
Patient Health Questionnaire–8 
(PHQ-8)
X
Assessment of need to complete a 
risk assessmentq
X
X
X
X
X
X
X
Adverse Events Report
X----------------------------------------------X
a.
Subjects who have not had a test within 2 years.  See inclusion criteria 1.
b.
Subjects who have not had a test within 3 years.  See inclusion criteria 4.
c.
Hemoglobin, hematocrit, RBC count, WBC count, platelet count.
d.
Electrolytes (Na, K, Ca, Cl, bicarbonate), creatinine, BUN, glucose, AST, ALT, alkaline phosphatase, 
bilirubin, CK, uric acid, albumin, total protein.
e.
Specific gravity, PH, Glucose (qual), Protein (qual), Blood (qual), Ketones, Nitrite and Microscopy if urine 
dipstick is positive for blood or protein.
f.
Childbearing potential female subjects only.
g.
Subjects who have had visual findings on Week 12 and subsequently confirmed.
h.
A repeat may be necessary upon the confirmation from central reader.
i.
Recommend subject to take first dose in the evening.
j.
Titration/tapering dose.
k.
Treatment dose.
l.
Conduct 2 tests.
m. Usually occur between the 3rd – 7th day after Baseline (Visit 2) when the verification of VFT is available.
n.
Screening procedures can be completed within 21 days prior to Baseline; Study Visits 4 – 7 have a 3 days 
window.
o.
The “Lifetime” assessment is completed at Screening and the “Since Last Visit” assessment is completed at 
all other visits.
p.
Including neurological exam at screening.
q.
A risk assessment must be performed and documented if the subject meets the criteria detailed in Protocol. 
r.
Subjects screened/randomized under Amendment 3 will continue the S-STS for assessment of suicidal 
ideation and behaviour. Subjects screened /randomized under Amendment 4 will have suicidal ideation and 
behaviour assessed by the C-SSRS and the SBQ-R.


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TABLE OF CONTENTS
SCHEDULE OF ACTIVITIES..................................................................................................7
LIST OF TABLES...................................................................................................................12
APPENDICES .........................................................................................................................12
1. INTRODUCTION ...............................................................................................................13
1.1. Background .............................................................................................................13
1.2. Rationale..................................................................................................................14
2. TRIAL OBJECTIVES AND ENDPOINTS ........................................................................14
2.1. Objective .................................................................................................................14
2.2. Endpoints.................................................................................................................14
3. TRIAL DESIGN..................................................................................................................14
4. SUBJECT SELECTION......................................................................................................15
4.1. Inclusion Criteria.....................................................................................................15
4.2. Exclusion Criteria....................................................................................................16
4.3. Randomization Criteria ...........................................................................................18
4.4. Lifestyle Guidelines ................................................................................................18
4.5. Sponsor’s Qualified Medical Personnel..................................................................19
5. TRIAL TREATMENTS ......................................................................................................20
5.1. Prohibited/Allowable Medications or Precautions..................................................20
5.2. Allocation to Treatment ..........................................................................................21
5.3. Breaking the Blind ..................................................................................................21
5.4. Drug Supplies..........................................................................................................21
5.4.1. Formulation and Packaging........................................................................21
5.4.2. Preparation and Dispensing ........................................................................21
5.4.3. Administration............................................................................................22
5.4.4. Compliance.................................................................................................22
5.5. Investigational Product Storage ..............................................................................22
5.6. Investigational Product Accountability...................................................................23
5.6.1. Destruction of Investigational Product Supplies ........................................24
6. TRIAL PROCEDURES.......................................................................................................24
6.1. Screening.................................................................................................................24
6.2. Trial Period..............................................................................................................25


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6.2.1. Baseline.......................................................................................................25
6.2.2. Randomization (Week 0) Visit ...................................................................26
6.2.3. Week 1 Visit ...............................................................................................26
6.2.4. Procedures During the Investigational product Treatment Period 
(Weeks 6 and 12) .............................................................................................27
6.2.4.1. The Following will be Performed at Weeks 6 and 12 
Visits..................................................................................................27
6.2.4.2. The Following Additional Assessments will be Performed 
on Week 12 Only...............................................................................27
6.3. Follow-up Visit (Week 15 Visit).............................................................................28
6.4. Subject Withdrawal.................................................................................................28
7. ASSESSMENTS..................................................................................................................30
7.1. Ophthalmic Examination Procedures......................................................................30
7.1.1. External Eye Examinations.........................................................................30
7.1.2. Direct and Indirect Funduscopy..................................................................30
7.1.3. Best Corrected Visual Acuity.....................................................................30
7.1.4. Visual Field Test.........................................................................................30
7.2. Clinical Laboratory Tests........................................................................................31
7.3. Vital Sign, Body Weight and Physical Examination ..............................................33
7.4. Electrocardiogram (ECG)........................................................................................34
7.5. Assessment of Suicidal Ideation and Behavior.......................................................34
7.5.1. Sheehan-Suicidality Tracking Scale (S-STS).............................................34
7.5.2. Columbia-Suicidality Severity Rating Scale (C-SSRS) .............................34
7.5.3. Suicide Behaviors Questionnaire – Revised (SBQ-R) ...............................35
7.5.4. Patient Health Questionnaire-8 (PHQ) .......................................................35
7.5.5. Assessment of Suicidal Ideation and Behavior During Screening .............35
7.5.6. Assessment of Suicidal Behavior and Ideation During the Clinical 
Trial..................................................................................................................36
7.6. Patient Assessment of Seizure Frequency...............................................................37
8. ADVERSE EVENT REPORTING......................................................................................37
8.1. Adverse Events........................................................................................................37
8.2. Reporting Period .....................................................................................................37
8.3. Definition of an Adverse Event...............................................................................38


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8.4. Medication Errors....................................................................................................39
8.5. Abnormal Test Findings..........................................................................................39
8.6. Serious Adverse Events...........................................................................................39
8.6.1. Protocol-Specified Serious Adverse Events ...............................................40
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................40
8.7. Hospitalization ........................................................................................................41
8.8. Severity Assessment................................................................................................42
8.9. Causality Assessment..............................................................................................43
8.10. Exposure During Pregnancy..................................................................................43
8.11. Occupational Exposure .........................................................................................44
8.12. Withdrawal Due to Adverse Events (See Also Section 6.4 Subject 
Withdrawal)...............................................................................................................44
8.13. Eliciting Adverse Event Information ....................................................................45
8.14. Reporting Requirements........................................................................................45
8.14.1. Serious Adverse Event Reporting Requirements .....................................45
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................45
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities ...................46
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................46
9.1. Sample Size Determination.....................................................................................46
9.2. Efficacy Analysis ....................................................................................................46
9.3. Analysis of Other Endpoints ...................................................................................47
9.4. Safety Analysis........................................................................................................47
9.4.1. Analysis of Primary Endpoint ....................................................................47
9.4.2. Analysis of Secondary Endpoints...............................................................47
9.4.3. Mean Deviation ..........................................................................................47
9.4.4. Visual Acuity..............................................................................................48
9.4.5. Other Safety Measurements........................................................................48
9.5. Interim Analysis ......................................................................................................48
9.6. Data Monitoring Committee ...................................................................................48
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................48
11. DATA HANDLING AND RECORD KEEPING .............................................................49
11.1. Case Report Forms/Electronic Data Record .........................................................49


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11.2. Record Retention...................................................................................................50
12. ETHICS..............................................................................................................................50
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............50
12.2. Ethical Conduct of the Trial..................................................................................50
12.3. Subject Information and Consent..........................................................................50
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................51
13. DEFINITION OF END OF TRIAL...................................................................................51
13.1. End of Trial in all Participating Countries ............................................................51
13.2. End of Trial in a Member State of European Union .............................................51
14. SPONSOR DISCONTINUATION CRITERIA ................................................................51
15. PUBLICATION OF TRIAL RESULTS............................................................................52
15.1. Communication of Results by Pfizer ....................................................................52
15.2. Publications by Investigators ................................................................................52
16. REFERENCES ..................................................................................................................54
LIST OF TABLES
Table 1.
Study 1096 Sample Size and Power for the Secondary Endpoint........................46
Table 2.
Study 1096 Sample Size and Power for the Primary Endpoint............................46
APPENDICES
Appendix 1. Abbreviations/Definitions...................................................................................56
Appendix 2. Special Notes about Visual Field Testing...........................................................57
Appendix 3. Clinical Protocol Amendment 1..........................................................................59
Appendix 4. Clinical Protocol Amendment 2..........................................................................61


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1. INTRODUCTION
1.1. Background
Pregabalin (Lyrica) has been approved in over 130 countries to date for varying neuropathic 
pain indications and for adjunctive treatment of patients with partial seizures and for 
generalized anxiety disorder.  Lyrica is approved in the United States for management of 
neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia, for 
the adjunctive treatment of adult patients with partial onset seizures, and for management of 
fibromyalgia.1  Lyrica is approved in European Union countries for the treatment of 
peripheral neuropathic pain, adjunctive treatment of partial seizures with or without 
secondary generalization, and for the treatment of generalized anxiety disorder.2  Since initial 
market approval of Lyrica in 2004 through 2014, it is estimated that more than 28.5 million
patient years of exposure will have accumulated worldwide.  More detailed information, 
including efficacy results in adults and the possible risks associated with administration of 
pregabalin, can be found in the current Investigator Brochure (IB).
Prospectively planned ophthalmologic assessments, including visual acuity testing, formal 
visual field testing and dilated funduscopic examination, were performed in the pregabalin 
clinical development program for all of the initial indications.
Formal visual field testing was conducted in over 2400 patients treated with pregabalin for 
neuropathic pain, chronic pain syndromes, intractable epilepsy, or generalized anxiety 
disorder in randomized controlled clinical trials of up to 3 months in duration and in over 
3600 patients in open-label trials of up to 4 years in duration.  Ophthalmologic assessments 
were included in the program due to concerns expressed at the time on emerging reports of 
visual field disturbances with the anticonvulsant vigabatrin, a gamma-aminobutyric acid 
(GABA)-transaminase inhibitor.3-11  The mechanism of the visual field defects with 
vigabatrin is unknown but was considered as possibly related to its GABA mechanism.  As a 
structural derivative of GABA, regulatory agencies considered similarity of pregabalin to 
vigabatrin as possible.  Subsequently, it became clearer that the mechanism of action of 
pregabalin was not related to GABA-transaminase inhibition or to a GABA related 
mechanism.  While the mechanism of action of pregabalin is not completely understood, 
results in animal models indicate that binding to the alpha-2-delta subunit of voltage-gated 
calcium channels may be involved in the activity of pregabalin.
In controlled pregabalin studies, a higher proportion of patients treated with pregabalin 
reported blurred vision (6%) than did patients treated with placebo (2%), which resolved in 
the majority of patients during treatment.  In patients assessed with prospectively planned 
ophthalmologic testing, visual acuity was reduced in 7% of patients treated with pregabalin, 
and 5% of placebo-treated patients.  Visual field changes were detected in 13% of 
pregabalin-treated, and 12% of placebo-treated patients.  Funduscopic changes were 
observed in 2% of pregabalin-treated and 2% of placebo-treated patients.
This study is a Post-Authorization Safety Studies (PASS).  It is being conducted as a 
commitment agreed upon with the United States Federal Drug Administration (FDA) 
regulatory agency.


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1.2. Rationale
This study is being performed to further characterize visual fields with pregabalin as 
compared to placebo when added to their existing antiepileptic therapy. In this study, 
standardized test equipment, program and test procedures across all study sites will be used 
to optimize the data quality and the sensitivity of the test.  Threshold visual fields will be 
performed using computerized static perimetry.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the pregabalin Investigator’s Brochure (IB).  The 
SRSD will be used in determining expected versus unexpected adverse events.
2. TRIAL OBJECTIVES AND ENDPOINTS
2.1. Objective
To evaluate visual fields in subjects with partial epilepsy receiving 12 weeks treatment of 
pregabalin compared to placebo.
2.2. Endpoints
Primary endpoint: 

The proportion of subjects with a decrease in the threshold value from baseline to 
termination in five or more points (in either eye) at the p<.05 level repeated in the 
same five points on subsequent computerized automated perimetry testing 
(Humphrey 24-2 SITA standard).
Secondary endpoints:

Change in mean deviation score from baseline to Week 12 from the Humphrey 
threshold test;

Change in visual acuity from Baseline to Week 12 expressed by number identified in 
ETDRS visual acuity assessment.
3. TRIAL DESIGN
This is a Phase IV, multicenter, double-blind, randomized, placebo-controlled trial to 
measure visual field sensitivity in subjects with partial epilepsy dosed with pregabalin or 
placebo.  Pregabalin will be dosed at 300 mg/day for 11 weeks after one-week initiation with 
150 mg/day, followed by one-week tapering of 150 mg/day.  Total treatment period will be 
13 weeks.  Comprehensive ophthalmologic testing will be done at pre-treatment baseline to 
exclude subjects with pre-existing eye disease.  
A central reader will assure the quality of all visual field test results with pre-specified 
criteria.  Any field failing this quality assurance criteria either due to poor subject compliance 
or due to failure to follow testing procedures will be repeated as soon as possible within 
2 weeks following notification from the central reader.  Prior to randomization subjects must 


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meet the pre-specified quality assurance criteria. Subjects failing to meet this criteria at 
Baseline either due to poor subject compliance or due to failure to follow testing procedures 
can be re-screened one additional time after 3 months and will keep their previously assigned
ID number. Rescreening may also be allowed for subjects with non-lesional epilepsy who 
may have been screen failed for reasons other than those specified above, if correctable. 
Approximately 187 subjects will participate in the study. Subjects will be randomized 1:1 to 
pregabalin or placebo, with approximately 93 randomized to pregabalin and 93 to placebo.  
4. SUBJECT SELECTION
This clinical trial 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
Subjects must meet the following criteria to be eligible to participate in the study:
1. Diagnosis of epilepsy with partial seizures (as defined in the International League 
Against Epilepsy Classification of Seizures).  Diagnosis must be established by 
subject’s medical history (eg, seizures), family history, and the results of 
electroencephalogram testing done within 2 years prior to baseline (if none available, 
must be taken during Screening).  Results must be consistent with the diagnosis of 
focal-onset epilepsy;
2. Seizures should not have occurred within 2 weeks of an acute neurological event 
(eg, a stroke);
3. Be currently taking 1 to 3 antiepileptic drugs (AEDs). Vagus nerve stimulator (VNS) 
device also will be considered an AED.  AED should be continued without alteration 
of current dose during the study.  Benzodiazepines and barbiturates will not be 
allowed as treatment regardless of indication;
4. Have magnetic resonance imaging (MRI) or computed tomography (CT) scan with 
contrast of the head within 3 years prior to randomization (if none available, must be 
taken during Screening) that demonstrates no progressive structural abnormality and
non-lesional epilepsy;  
5. Subjects who, in the opinion of the investigator, may benefit from treatment with 
pregabalin; 
6. Be 18 to 65 years old;


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7. Be male, or nonpregnant, nonlactating female who is postmenopausal, surgically 
sterilized, or premenopausal using a reliable method of contraception (including 
barrier or hormonal method) and have a confirmed negative urine pregnancy test prior 
to randomization;
8. Have a 12-lead electrocardiogram prior to randomization without clinically
significant abnormal findings;
9. On both screening and baseline visual field exam, any eye has <20% false positives, 
<30% false negatives, <30% fixation loss;
10. Difference in mean deviation between screening and baseline visual field exams must 
be ≤2 decibels (dB) of mean deviation (MD) on both eyes;
11. Provide written informed consent signed by subject or legal guardian prior to entering 
the study;
12. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other trial procedures.
4.2. Exclusion Criteria
Subjects may not participate in the study if they meet any of the following criteria:

Known previous or current serious ophthalmologic disease (including uncorrected 
cataracts or history of cataract surgery <8 days), serious eye trauma or intra ocular or 
ocular surgery other than refractive (ie, lasik, cataract) surgery, or ophthalmologic 
finding that could affect the visual field;

Amblyopia;

Ptosis;

Manifest nystagmus in primary gaze;

On medications that could affect the visual field or pupil eg, chloroquine or miotics;

Refractive error in either eye exceeding 5 D (sphere) or 2.5 D (cylinder);

Best corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity 
worse than 20/25 in either eye;

Intra ocular pressure (IOP) >22 mmHg in either eye at Screening;


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
Have clinically significant abnormal findings on ophthalmologic examinations 
including external eye examination, visual acuity test, intraocular pressure, 
funduscopy and repeated visual field test (VFT).  Repeat any test if there is a finding
that is uncertain.  For VFT – if one test is normal and another one abnormal a third 
test may be performed.  Two of the three tests being normal is acceptable; 

Subjects with glaucoma or a history of glaucoma;

Family history of inherited retinal or optic nerve disorders;

Subject with a history of intolerability to pregabalin, or with a history of insufficient 
response (based on investigator’s clinical judgment) to pregabalin in the treatment of 
partial seizure, or subjects with current pregabalin treatment; 

Subjects who currently have poorly controlled epileptic seizures which could interfere 
with test procedures;

Childbearing potential female who is unable to take adequate contraceptive 
precautions, has a positive pregnancy test result within 24 hours prior to study entry, 
is otherwise known to be pregnant, plans to become pregnant in the next 3 months or 
is currently breastfeeding an infant;

Creatinine clearance 60 mL/min (estimated from serum creatinine);

Have a history or clinical evidence of cardiovascular, hematologic, hepatic, or renal 
disease (ALT, AST, bilirubin, urea, or creatinine values above twice the upper limit 
of normal [ULN] at Screening) or any physical conditions that, in the opinion of the 
investigator, would compromise participation in the study;

With a mental condition rendering the subject unable to be cooperative with and 
complete study requirements;

Have a significant psychiatric disorder, recurrent episodes of severe depression (any 
pharmacologic treatment or hospitalization for the illness within 1 year prior to 
Screening), or subjects with serious suicidal risk per criteria described in the 
Section 7.5.1 of the protocol.  Subjects with mild, chronic depression without recent
hospitalization who are being maintained on a stable dose of a single antidepressant 
are acceptable;

Has received any investigational drug during the previous 60 days prior to first dose;

Hypersensitivity to pregabalin or gabapentin;

Meets criteria for alcohol or drug abuse within the past year;


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
Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with trial participation or 
investigational product administration or may interfere with the interpretation of trial 
results and, in the judgment of the investigator, would make the subject inappropriate 
for entry into this trial;

Any subject at risk of suicide or self harm based on investigator judgment and/or 
details of a mental health risk assessment (MHRA) by a qualified mental health 
professional, as specified in Section 7.5.
4.3. Randomization Criteria 
Subjects will complete visual field testing (VFT) at baseline.  Once the central reader 
confirms the validity of the VFT, the subjects will return to the site to be randomized to 
treatment and to receive the investigational product. Subjects may not be randomized prior 
to receiving confirmation of the validity of the Baseline VFT from the central reader.
4.4. Lifestyle Guidelines
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for at least 28 days after the last dose of investigational product.  The 
investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
or her partner from the permitted list of contraception methods (see below) and instruct the 
subject in its consistent and correct use.  Subjects need to affirm that they meet the criteria 
for correct use of at least 1 of the selected methods of contraception.  The investigator or 
his/her designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the schedule of activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:

Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.

Correctly placed copper-containing intrauterine device (IUD). 


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
Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.

Male sterilization with absence of sperm in the postvasectomy ejaculate.

Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).

Female partner who meets the criteria for non-childbearing potential, as described 
below:
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle stimulating hormone (FSH) level 
confirming the post-menopausal state.
All other female subjects (including females with tubal ligations) will be considered 
to be of childbearing potential.
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center 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 
subject’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigational 


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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 the study team 
for advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.
5. TRIAL TREATMENTS
Equal number of subjects will receive oral pregabalin or matching placebo.  Pregabalin 
treatment period will be 11 weeks at the dose of 300 mg/day (150 mg BID).  A one-week 
titration and one-week taper at 150 mg/day (75 mg BID) will be given prior to and following 
the 11 week period (total 13 weeks).
If the subject cannot tolerate 300 mg/day dose, they will be discontinued from the study.  No 
down-titration on the dose is allowed.
It is recommended that the first dose of pregabalin be taken in the evening.
On the day of the ophthalmic testing it is recommended that the visual field test be performed 
in the morning (or when the subject is most alert). It is also recommended that the subject 
withholds the morning dose of investigational product until the ophthalmic tests are 
completed to reduce any potential effects of CNS events that may occur (eg, somnolence) 
with pregabalin which may interfere with testing. If the subject has taken the morning study 
dose of medication, testing should be performed when the subject is least probably affected 
by any potential CNS events that may occur to ensure the subject is optimally alert during the
test.
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Prohibited/Allowable Medications or Precautions
Apart from the background antiepileptics, administration of psychotropic compounds is 
prohibited during the trial, with the exception of a single antidepressant.  Benzodiazepine and 
barbiturate usage are not allowed in this study. Concurrent treatment with other 
investigational agents or devices is not allowed during the study. The prior or current use of 
vigabatrin is prohibited in this trial.
If it is necessary to alleviate insomnia during the study, zolpidem 10 mg or another non 
benzodiazepine hypnotic is permitted on an as needed (PRN) basis, but must not be taken for 
more than 4 nights per week, and must not be taken on a night before an ophthalmologic
study visit.


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5.2. Allocation to Treatment
Following the Baseline visit and after confirmation of the validity of the VFTs from the 
central reader, subjects will be randomized to receive either pregabalin or placebo.  Subjects 
will be randomly assigned to treatment regimens in a 1:1 ratio according to a
computer-generated random code.  Each subject will receive the lowest randomization 
number available at the site.
5.3. Breaking the Blind 
At the initiation of the trial, the trial site will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process.  Blinding codes should only 
be broken in emergency situations for reasons of subject safety.  The investigator should 
contact Pfizer before breaking the blind.  When the blinding code is broken, the reason must 
be fully documented and entered on the case report form.  With the exception of such 
emergency code breaks, the blind for the study will be broken only after all subjects have 
completed or terminated from the study, data issues have been resolved, and the per protocol 
population has been determined.
5.4. Drug Supplies
5.4.1. Formulation and Packaging
Pregabalin capsules (75 mg and 150 mg) and matching placebo will be supplied by Pfizer.  
Investigational product will be assigned according to a randomization code prepared from 
specifications provided by the Clinical Statistics department.
Investigational product is formulated into size 0 grey/grey capsules and packaged into 
high-density polyethylene child-resistant bottles.
5.4.2. Preparation and Dispensing
The Sponsor will provide the investigational product that will be dispensed according to 
randomization code.  The investigator must verify and acknowledge the receipt of clinical 
drug supplies and retain related documentation.  A set of detailed dispensing instructions will 
be provided.
At Randomization, each subject will receive 1 bottle of investigational product capsules with 
the titration dose for the first week (pregabalin 75 mg BID (150 mg/day) or placebo BID).
At Week 1, the subject will receive 5 bottles containing capsules of the treatment dose
(pregabalin 150 mg BID (300 mg/day) or placebo BID).  At Week 6, the subject will receive 
6 bottles containing capsules of treatment dose (pregabalin 150 mg BID (300 mg/day) or 
placebo BID).  At Week 12, the subject will receive 1 bottle containing capsules for the taper
(pregabalin 75 mg BID (150 mg/day) or placebo BID).  All bottles will contain 3 days 
overage except the taper bottle that will contain only enough capsules for seven days.


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5.4.3. Administration
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the 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).
The subjects will be recommended to take their first dose of investigational product the 
evening of their randomization visit. Dosing is BID, therefore subjects should take one 
capsule 2 times per day, except on Day 1 when the subject should take their first capsule in 
the evening. 
Subjects are to take a single capsule of investigational product from a single bottle at each 
dose. Subjects must not take more than 1 capsule per dose.  Subjects should take study 
capsules only from one bottle at a time. Doses should be administered at approximately the 
same time of day, without regard to meals, preferably as close to 12 hours apart as possible.  
All doses should be taken with 6 to 8 ounces of water.  Subjects must swallow the capsules 
intact.  Blinding will be maintained within each group by administering the same number of 
capsules of investigational product per day and by the fact that all capsules are identical in 
appearance.
Subjects will document each dose in a diary at the time of the dose. Reasons for any missed 
doses should also be recorded in the diary. The dosing diary is to be brought to each study 
visit and reviewed by the study team at the site and any correction should be made by the 
subject while they are at the site. 
5.4.4. Compliance
Subjects who are not fully compliant with investigational product as intended (<80% or 
>120% of doses taken) will be evaluated by the investigator for possible discontinuation 
from the study.  If the subject fails to take investigational product for 7 consecutive days the 
subject should be considered non compliant, and the investigator should consider 
discontinuing the subject from the study after confirming the decision with Pfizer.
5.5. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.


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Investigational product should be stored in its original container and in accordance with the 
label. See the Investigational Product Manual for storage conditions of the product.
Pregabalin is a controlled substance in the United States and must be handled and stored in 
accordance with state and federal regulations for controlled substances.
Storage conditions stated in the single reference safety document (SRSD) (eg, investigator’s 
brochure [IB]) will be superseded by the storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the sponsor approves the use of the investigational 
product after the temperature excursion.  Use of the investigational product prior to sponsor 
approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  Subjects should bring all 
Investigational Product bottles to each study visit for review and accounting. Bottles no 
longer needed will be retained by the site. By the completion of the study all Investigational 
Product bottles are to be returned to the site. Do not transfer the investigational product from 
one bottle to another. 


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5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
6. TRIAL PROCEDURES
6.1. Screening
At the Screening Visit (up to 21 days prior to Baseline), subjects will be eligible for the study 
after verification of the inclusion/exclusion criteria and the study has been explained to them.  
The following procedures will be completed at the screening visit:

Obtain written informed consent (must be signed prior to the initiation of any study 
related activities);

Verify inclusion/exclusion criteria;

Record demographic information, medical history, and diagnosis;

Record concomitant medications;

Perform physical exam including neurologic exam;

Collect vital signs (sitting blood pressure, heart rate);

Perform electrocardiograph;

Prescribe/perform EEG, CT and MRI if necessary (inclusion criteria 1 and 4);

Collect body weight;

Collect blood samples for clinical laboratories;

Blood chemistry;

Hematology;

Urinalysis including drug screen; 

Urine pregnancy test (females of child-bearing-potential);

Columbia-Suicide Severity Rating Scale (C-SSRS) Lifetime Assessment;

Suicide Behaviors Questionnaire-Revised (SBQ-R);


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
Patient Health Questionnaire – 8 (PHQ-8);

Determine if mental health risk assessment (MHRA) is required (refer to Section 7.5);

Ophthalmic Examination.
1. External eye examinations.
2. Best corrected ETDRS visual acuity.
3. Intraocular pressure to be measured by a calibrated applanation tonometer such as
Goldmann, Perkins, or Tonopen.If more than one tonometer is available at the 
site, the same one should be used consistently throughout the study.
4. Computerized automated perimetry (Humphrey 24-2 SITA standard) 2 times on 
both eyes with a minimum 5 minute break between each eye tested and minimum 
10 minutes (may take longer break if needed) between 2 tests.
5. Dilated funduscopic examination. Recommend subject to wear sunglasses for at
least one hour after this procedure and to bring someone along for driving home.
6.2. Trial Period
6.2.1. Baseline 
The following procedures will be completed at this visit:

Verify inclusion/exclusion criteria;

Vital signs (sitting blood pressure, heart rate);

Body weight;

Best corrected ETDRS visual acuity;

Computerized automated perimetry (Humphrey 24-2 SITA standard) 2 times on both 
eyes with a 5 minute break between each eye tested and 10 minutes between 2 tests.  
A longer break may be taken if needed;

Concomitant medications;

Adverse events;

C-SSRS Since Last Visit assessment (or C-SSRS Lifetime assessment if not 
completed at screening);

SBQ-R if not completed at screening;

Review C-SSRS to determine if a MHRA is required;


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
Subjects who fail the VFT due to poor subject compliance or due to failure to follow 
the testing protocol can be re-screened one additional time after 3 months and will 
keep their previously assigned ID number.  Rescreening may also be allowed for 
subjects with non-lesional epilepsy who may have been screen failed for reasons 
other than those specified above, if correctable.
6.2.2. Randomization (Week 0) Visit
At this visit, subjects will be randomized after verification that they continue to meet the 
inclusion/exclusion criteria.  This visit occurs after the central reader confirms the validity of 
the VFTs, ie, usually between 3 and 7 days after the Baseline visit.
The following procedures will be completed prior to randomization:

Verify inclusion/exclusion criteria;

Confirmation from Central Reader that VFTs are valid and useable prior to dosing;

Concomitant medications;

Adverse events;

Complete C-SSRS Since Last Visit assessment (or C-SSRS Lifetime assessment if 
not completed at prior visit);

Complete SBQ-R if not completed at a prior visit;

Determine if MHRA is required based on results of screening and subsequent 
assessments of suicidal ideation and behavior.  No subject can be randomized until a 
risk assessment has been completed and documents eligibility to participate in the 
study in applicable subjects (refer to Section 7.5.5).

Dispense investigational product (titration dose).  Recommend subject take the first 
dose that evening.

Provide dosing diary and instructions for use to the subject.
6.2.3. Week 1 Visit

Review Dosing Diary with subject and assess dosing compliance;

Dispense investigational product (treatment dose);

Concomitant medications;

Adverse events;

Body weight;


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
Vital signs (sitting blood pressure, heart rate);

Complete C-SSRS Since Last Visit assessment;

Review C-SSRS to determine if a MHRA is required.
6.2.4. Procedures During the Investigational product Treatment Period (Weeks 6 
and 12)
Subjects will have the following assessments performed at 6 and 12 weeks following 
randomization (or at Early Termination if subject does not complete 12 weeks of study).
6.2.4.1. The Following will be Performed at Weeks 6 and 12 Visits

Best corrected ETDRS visual acuity;

Computerized automated perimetry (Humphrey 24-2 SITA) on both eyes with a 
5 minute break between each eye tested;

Body weight;

Vital signs (sitting blood pressure, heart rate);

Review Dosing Diary with subject and assess dosing compliance;

Concomitant medications;

Adverse events; 

Complete C-SSRS Since Last Visit assessment;

Review C-SSRS to determine if a MHRA is required;

Dispense Dosing Diary (Week 6);

Dispense investigational product (treatment dose at Week 6, taper dose at Week 12).
6.2.4.2. The Following Additional Assessments will be Performed on Week 12 Only

Physical exam;

External eye exam;

Collect blood samples for clinical laboratories.
Blood chemistry.
Hematology.


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
Urinalysis;

Urine pregnancy test (females of child-bearing-potential);

Patient assessment of seizure frequency;

Subjects will be recommended to withhold their morning dose of investigational 
product on testing days until ophthalmologic testing is completed.
6.3. Follow-up Visit (Week 15 Visit)
Subjects will have the following assessments performed 15 weeks following randomization 
(or 2 weeks after final dose of investigational product).

Review Dosing Diary and assess dosing compliance;

Concomitant medication;

Adverse events; 

Body weight;

Complete C-SSRS Since Last Visit assessment;

Review C-SSRS to determine if a MHRA is required.
Subjects who have had visual findings on Week 12 and subsequently confirmed will also 
have ophthalmologic tests done at this visit.

Ophthalmic Examination.
External eye examinations;
Best corrected ETDRS visual acuity;
Computerized automated perimetry (Humphrey 24-2 SITA standard) on both eyes 
with 5 minutes break between 2 eyes.
Visual findings that require follow-up beyond Week 15 will be supported by Pfizer.
6.4. Subject Withdrawal
Subjects may withdraw from the trial at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons.  If a subject does not return for a scheduled visit, every effort 
should be made to contact the subject.  In any circumstance, every effort should be made to 
document subject outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request the subject to return all unused investigational product(s), request the 


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subject to return for a final visit, if applicable, and follow-up with the subject regarding any 
unresolved adverse events.
If the subject withdraws from the trial and 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. If the subject withdraws early, all Week 12 activities are to be 
conducted:

External eye exam;

Best corrected ETDRS visual acuity;

Computerized automated perimetry (Humphrey 24-2 SITA) on both eyes with 
5 minutes break between 2 eyes; 

Body weight;

Review Dosing Diary and assess dosing compliance;

Concomitant medications;

Adverse events; 

Physical exam;

Vital signs (sitting blood pressure, heart rate);

Collect blood samples for clinical laboratories.
Blood chemistry;
Hematology;

Urinalysis;

Urine pregnancy test (females of child-bearing-potential);

Complete C-SSRS Since Last Visit assessment;

Review C-SSRS to determine if a MHRA is required.


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7. ASSESSMENTS
7.1. Ophthalmic Examination Procedures 
7.1.1. External Eye Examinations 
An external eye examination will be performed to assess the general appearance of the eye.  
It will look at ocular motility to detect deviations from strabismus or a convergence defect.
The external eye examination will be conducted at the Screening (Visit 1) and Week 12
(Visit 6) visits, and at the Week 15 (Follow-up, Visit 7) visits if deemed necessary.
7.1.2. Direct and Indirect Funduscopy 
At Screening visit, direct and indirect funduscopy will be used to look at retinal morphology 
(dilated eyes).  Indirect funduscopy will be performed using a biomicroscope (slit lamp) and 
a Volk 90 diopter lens allowing evaluation of maculae and optic nerve. A 20 or 28 diopter 
lens can be used to evaluate the peripheral fundus and providing an overall view of the 
pigment epithelium.  Direct funduscopy may be performed using a manual ophthalmoscope 
and will examine the macular ocular disc vessels, looking especially for edema and 
alterations of the macular reflex.  Results will be collected on the Case Report Form (CRF).
Funduscopy will be conducted at Screening visit.
7.1.3. Best Corrected Visual Acuity
The best corrected visual acuity (with glasses or best possible glasses prescription) will be 
measured using the ETDRS charts.  The letters on chart A are read using the right eye and 
chart B using the left eye.
The subject starts the top of the chart and begins to read down the chart.  The subject reads 
down the chart until they reach a row where a minimum of three letters on a line cannot be 
read.  The subject is scored by how many letters could be correctly identified.
The number of correct letters identified by each eye will be collected into the CRF. 
Visual acuity will be measured at Screening (Visit 1), Baseline (Visit 2), Week 6 (Visit 5), 
and Week 12 (Visit 6) visits, and at Week 15 (Follow-up, Visit 7) visit if deemed necessary.  
The best corrected visual acuity should be obtained at each scheduled visit or repeat visit.  It 
should not be copied from a previous visit.
7.1.4. Visual Field Test
All investigators will receive extensive training at the investigator’s meeting and periodically 
throughout the study to improve the reliability of measurements by monitoring subject 
compliance and recognizing artifact in visual field examination.  Investigators should 
repeat/reschedule sessions when subjects have poor compliance or any difficulties which 
interferes with visual field testing. Ophthalmologists/ VFT technician should inquire prior to 
testing when the subject’s last seizure occurred to assess the possibility of ictal or post-ictal 
state to avoid interference with testing; the time of last dose of investigational product (it is 


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recommended that the subject withholds the morning dose of investigational product until 
after the VFT has been completed to reduce any potential effects of CNS events that may 
occur (eg, somnolence) with pregabalin which may interfere with testing).  If the subject has 
taken the morning study dose of medication, testing should be performed when the subject is 
least probably affected by any potential CNS events that may occur to ensure the subject is 
optimally alert during the test.
Prior to performing the computerized automated perimetry (Humphrey 24-2 SITA), pupil 
size will be measured and recorded and must be 3 mm or greater for VFT, otherwise the 
pupil must be dilated.  Visual fields will be measured using the Humphrey 24-2 SITA and 
analyzed using STATPAC according to the guidelines.  A detailed guideline is provided in 
the Appendix 2 of this document.  Because visual field results are strongly affected by 
experience, visual field tests will be repeated on two occasions at Screening and at Baseline 
visits.  A pre-test is recommended for all subjects who have never performed VFT.
All automated perimetry results will be read by a central reader within 3 working days of the 
examination.  If the central reader assesses the visual field exam to be of poor quality, the 
exam should be repeated as soon as possible within 2 weeks of being notified.  The repeat 
test will be performed only on the eye whose test was considered to give a poor result. 
Any subject who has a new loss of sensitivity at the p<.05 level in five or more points in the 
visual field will have a repeat exam as soon as possible within 2 weeks of receiving 
confirmation from the central reader.
VFT will be conducted at the Screening (Visit 1), Baseline (Visit 2), Week 6 (Visit 5), and 
Week 12 (Visit 6) visits as well as at the Week 15 (follow-up, Visit 7) visit if deemed 
necessary.
If a subject complains about their vision at the site it should be recorded as an adverse event 
like every other adverse event regardless of central reading.
If the subject does not complain about the vision and the central reader shows confirmed
deterioration based on the VFT this should not be collected as an adverse event because this 
is the study endpoint. 
7.2. Clinical Laboratory Tests
Laboratory
The following safety laboratory tests will be performed at the Screening (Visit 1) and 
Week 12 (Visit 6).


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Safety Laboratory
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC Count
Platelet Count
WBC Count
Creatinine
BUN
Glucose
Ca++
Na+, K+, Cl-
Total CO2
(Bicarbonate)
AST, ALT
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Creatine 
phosphokinase
PH
Color
Clarity
Specific gravity
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Microscopyb
Urine Pregnancy testa
Urine drug testingc
(amphetamines, 
antidepressants, 
barbiturates, 
benzodiazepines, 
canabinoids, cocaine, 
methadone, 
methaqualone, 
opiates, 
phenothiazines, 
propoxyphene and 
alcohol)
a
Childbearing potential females only.
b
Only if urine dipstick is positive for blood or protein.
c
Only at Screening.
Results of the urine drug tests at screening (V1) must be negative for the subject to receive 
trial medication on Day 1.  

Safety laboratory tests from Screening must have no clinically significant findings, as 
judged by the investigator, in order for a subject to receive trial medication on Day 1.

CLcr (must be >60 ml/min) will be estimated from serum creatinine at screening 
to determine eligibility using the equations that follow.13  
Creatinine
Serum
72
(kg)
Weight
Body
age)
(140
CLcr
Male




0.85
Creatinine
Serum
72
(kg)
Weight
Body
age)
(140
Female









CLcr


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In order to use SI units for creatinine (µmol/L), use the following formulas:
Creatinine
Serum
(kg)
Weight
Body
age)
(140
CLcr
Male



x   1.23 
(mL/min)
Creatinine
Serum
(kg)
Weight
Body
age)
(140
1.23








Female
CLcr
(mL/min)
0.85

7.3. Vital Sign, Body Weight and Physical Examination
Vital signs (sitting heart rate and blood pressure) will be obtained at Screening (Visit 1), 
Baseline (Visit 2), Week 1 (Visit 4), Week 6 (Visit 5), Week 12 (Visit 6) and Early 
Termination (ET). BP will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mm Hg.  The same arm (preferably the dominant arm) will 
be used throughout the trial. BP and heart rate will be measured after at least 5 minutes in 
sitting position.  When done manually, heart rate will be measured in the brachial/radial 
artery for at least 30 seconds.  The use of automated devices for measuring BP and heart rate 
are also acceptable.  Any clinically significant negative changes (increase or decrease) in 
vital signs from the entry examination should be recorded as an adverse event and/or based 
on the clinical judgment of the PI.
Body weight will be collected at Screening (Visit 1), Baseline (Visit 2), Week 1 (Visit 4), 
Week 6 (Visit 5), Week 12 (Visit 6), Week 15 (Visit 7) and Early Termination (ET). Any 
clinically significant negative changes (increase or decrease) from the entry examination 
should be recorded as an adverse event for weight and/or based on the clinical judgment of 
the PI.  
To reduce measurement variability of body weight, subjects should be weighed on the same 
scale at each visit that body weight is assessed; should not carry extraneous items such as
purses, blackberries, and cell phones onto the scale; should remove their coats and shoes 
before being weighed, and should empty their pockets of any heavy items.
A physical exam will be performed at Screening (V1) and Week 12 (Visit 6). Items included
will be:

General appearance – including height (at Screening only);

Skin – Examination for the presence of rash;

HEENT – Examination of extraocular movements, pupillary response, determination 
of nystagmus, and visual field examination by confrontation;

Lungs and Cardiovascular – Auscultation of lung fields, determination of BP, cardiac 
rhythm and rate auscultation for the presence of murmurs, gallops, or rubs;

Neurologic – Including mental status, station and gait, cranial nerves, motor and 
sensory function, reflexes, and coordination;

Abdominal – Palpation and auscultation performed.


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Additional physical assessment will be made as necessary to evaluate symptoms or adverse 
experiences at the discretion of the investigator.  Any clinically significant negative changes
on the physical examination from the entry examination should be recorded as an adverse 
event and/or based on the clinical judgment of the PI.
7.4. Electrocardiogram (ECG)
A 12-lead ECG (singlet) will be performed at Screening (Visit 1).  ECG should be performed 
after the subject has rested quietly for at least 10 minutes in a supine position.  ECG tracing 
will be evaluated by the investigator in a real time for the safety monitoring of the subjects.  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.
7.5. Assessment of Suicidal Ideation and Behavior
Three tools are being used to assess for suicidal ideation and behavior during the study; the 
Sheehan-Suicidality Tracking Scale (S-STS), the Columbia-Suicidality Severity Rating Scale 
(C-SSRS) and the Suicidal Behaviors Questionnaire – Revised (SBQ-R). Subjects
randomized prior to Amendment 4 will only complete the S-STS.
7.5.1. Sheehan-Suicidality Tracking Scale (S-STS)
The Sheehan-Suicidality Tracking Scale (S-STS) is an 8-item prospective rating scale that 
tracks treatment-emergent suicidal ideation and behaviors. This scale was adapted from the 
Suicidality Module of the Mini International Neuropsychiatric Interview (MINI) Structured 
Diagnostic Interview for DSM-IV.  Items 1a, 2-6, 7a, and 8 are scored on a 5-point Likert 
scale (ranging from 0= not at all to 4=extremely).  Items 1, 1b, and 7 require yes or no 
responses.  This scale can be administered either by a clinician (ie, MD or a PhD level 
clinical Psychologist) or patient through self-report.  The baseline Lifetime Assessment will 
be completed at Screening and the “Since Last Visit” version will be completed at Baseline
(Visit 2), Randomization (Visit 3), Week 1 (Visit 4), Week 6 (Visit 5), Week 12 (Visit 6), 
Week 15 (Visit 7) and ET. 
Subjects randomized prior to Amendment 4 will complete the S-STS and not the C-SSRS or 
SBQ-R. Subjects enrolled/randomized after implementation of Amendment 4 will not 
complete the S-STS but will instead complete the C-SSRS and SBQ-R.
7.5.2. Columbia-Suicidality Severity Rating Scale (C-SSRS)
The Columbia-Suicidality Severity Rating Scale (C-SSRS) is a semi-structured interview 
developed in the National Institute of Mental Health Treatment of Adolescent Suicide 
Attempters Study to assess severity and track suicidal events through any treatment.14 The 
C-SSRS is being used in the current study to provide a summary measure of suicidal risks. 
This scale is to be completed by a trained clinician. Training materials on the scale will be 
provided to investigator sites by Pfizer. The Lifetime version is completed during the first 
visit and the Since Last Visit version will be completed at subsequent visits.


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7.5.3. Suicide Behaviors Questionnaire – Revised (SBQ-R)
The SBQ-R is a 4-item; self-report questionnaire that assesses behaviors associated with 
suicidality.  The SBQ-R will be completed at Screening (V1) following implementation of 
Amendment 4. Subjects screened under Amendment 3 but continue under Amendment 4 
should complete the SBQ-R at the baseline or randomization visit.
7.5.4. Patient Health Questionnaire-8 (PHQ) 
The PHQ-8 is a self-administered version of the PRIME-MD diagnostic instrument for 
common mental disorders.  The PHQ-9 is the depression module, which scores each of the 9 
DSM-IV criteria as 0 (not at all) to 3 (nearly every day).15  The PHQ-8, a validated subset of 
the PHQ-9, which comprises the first 8 items of the measure, will be completed by subjects 
at Screening (Visit 1). 
The score is the sum of items 1-8. A total score 15 indicates significant depression and 
requires mental health risk assessment.16
When scoring the PHQ-8, if more than one response is given on an item and two consecutive 
numbers are checked, score the higher (more distress) number; however, if the numbers are 
not consecutive, do not score the item. If more than 1 item is missing, the PHQ-8 should be 
reported as Not Done.
7.5.5. Assessment of Suicidal Ideation and Behavior During Screening
The Investigator will review the results of the STS (Lifetime), C-SSRS (Lifetime), SBQ-R, 
PHQ-8 and medical history.  The following criteria would indicate a potential risk:

Positive subject’s responses (score 1) on any of these S-STS questions:

1a (To what extent did you plan or intend to hurt yourself?), 

1b (Did you intend to die as a result of this accident?), 

both 3 and 4 (How seriously did you ever want to harm yourself or to hurt or to 
injure yourself? and Did you think about suicide?), 

5 (How seriously did you ever plan for a suicide?), 

6 (How seriously did you ever take active steps to prepare for a suicide attempt in 
which you expected or intended to die?),  

8 (How seriously did you ever attempt suicide?).

Suicidal ideation associated with actual intent and/or method and/or plan in the past 
year based on C-SSRS assessment (ie, ‘yes’ response to C-SSRS items 4 (Active 
suicidal ideation with some intent to act, without specific plan) or 5 (Active suicidal 
ideation with specific plan and intent)). 


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
Any previous history of suicidal behaviors reported or documented within the past 
10 years.

For events that occurred within the past 10 years, an answer of “yes” to any of the 
suicidal behavior items of the C-SSRS.

SBQ-R total score 8. 

Clinically significant depression: PHQ-8 total score 15.

The presence of any current major psychiatric disorder that is not explicitly permitted 
in the inclusion/exclusion criteria.

In the investigator’s judgment a risk assessment or exclusion is required.
If any of these criteria are met and the subject is being considered for study participation, a 
risk assessment must be completed to determine whether it is appropriate for the subject to be 
enrolled. 
Risk assessments should be done by a qualified mental health professional (MHP).  A
qualified MHP is a clinically-qualified MHP with appropriate training in the assessment of 
suicide risk, according to local clinical practice standards and regulations, who would 
normally evaluate the risk for suicidal ideation or behavior in a patient. In the United States, 
in addition to psychiatrists (board certified or board eligible), clinically qualified MHPs 
include the following: (1) Psy.D. or Ph.D. level Clinical Psychologists, (2) licensed Master’s 
level Clinical Social Workers (LCSW), or (3) licensed Psychiatric Nurse Practitioners (PNP), 
who have specific training and experience in the assessment and management of acutely 
suicidal patients.
The MHP may be a member of study site team.  If an MHP is not available within the study 
team, the Investigator should make the necessary referral.
The Investigator must obtain and review the risk assessment prior to the subject continuing in 
the study.  A written copy of the risk assessment should be included in the subject’s clinical 
record (source documentation).
7.5.6. Assessment of Suicidal Behavior and Ideation During the Clinical Trial
Beginning with Visit 2, if there are any positive response:

On the S-STS (Since Last Visit version) items 1a, 1b, both 3 and 4, 5, 6, or 8;
or

On items 4, 5, or on any behavioral question of the C-SSRS (Since Last Visit 
version).


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A risk assessment should be done by a qualified MHP to determine whether it is safe for the 
subject to continue to participate in the trial. 
Suicidal risk should be managed appropriately by the Investigator together with a qualified
MHP (or the Investigator alone if the Investigator is a qualified MHP).  In addition, the 
Investigator should consult with the Pfizer medical monitor to determine whether the subject 
can continue the trial. 
A narrative should be prepared for subjects who have undergone any post-baseline risk 
assessment, using relevant information from the STS, C-SSRS and risk assessment.  
7.6. Patient Assessment of Seizure Frequency 
Global change of seizure frequency will be rated as increased, no change or decreased by 
patient at Visit 6 (Week 12) or Early Termination (ET).
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  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 SAEs, 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.  SAEs 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 SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.


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
AEs (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of investigational product through the subject’s last
visit.
8.3. Definition of an Adverse Event
An AE 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 AEs 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;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.


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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, 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 medication 
error CRF, which is a specific version of the AE page, and on the 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 is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE 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 or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;


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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Lack of efficacy should be reported as an AE when it is associated with an SAE.
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 AE 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.
8.6.1. 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 the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level 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 values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 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 level increased from baseline by an amount of at least 1 × ULN or
if the value reaches 3 × ULN (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 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 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 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 SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  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, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;


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
Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE 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 examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These 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 AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  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.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  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 SAEs, listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (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 
AE; 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 an SAE 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 SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also Section 6.4 Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  


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When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding, and occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
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 AE.
For all SAEs, 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 SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE 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, vaccines and/or 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. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.


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8.14.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
9.1. Sample Size Determination
The study will be powered to show non-inferiority of pregabalin with respect to placebo on 
the mean deviation score from the Humphrey threshold test, a secondary endpoint.
Non-inferiority from placebo will be declared with respect to mean deviation if the lower 
bound of the 95% 2-sided confidence interval of the difference in mean deviation scores 
between pregabalin and placebo is greater than -2.0 decibels (dB). Assuming the mean 
deviation scores to be equal and assuming estimated common standard deviation of 1.3 dB, 
then the proposed sample size of 187 subjects will provide greater than 85% power to show 
non-inferiority of pregabalin to placebo. 
The estimated common standard deviation of 1.3 dB, from the 15 March 2019 dataset 
prepared for the annual Internal Review Committee (IRC) blinded review (refer to 
Section 9.6), was used to re-estimate the sample size for the secondary endpoints. Previously, 
at the time of study design, a common standard deviation of 5.6 dB had been used for the 
sample size determination based on literature.12 Table 1 below used common standard 
deviation (1.3) and the number of enrolled subjects (n=187) to estimate the study power.
Table 1.
Study 1096 Sample Size and Power for the Secondary Endpoint
Total Number of 
enrolled subjects
Common Standard 
Deviation
Non-inferiority Margin
Power
187
1.3
-2.0
>99.9%
For the primary endpoint, the proposed sample size will provide >99.9% power to show 
non-inferiority of pregabalin to placebo with respect to the proportion of subjects with a 
repeated decrease in the same 5 visual field points, with non-inferiority declared if the upper 
bound of the 95% confidence interval for the difference between pregabalin and placebo does 
not exceed 10% and assuming a proportion of subjects meeting primary endpoint definition 
of 1% for both groups. Table 2 below provided the estimated power for the primary 
endpoint.
Table 2.
Study 1096 Sample Size and Power for the Primary Endpoint
Total Number of 
enrolled subjects
Proportion of Subjects 
Meeting Primary 
Endpoint Definition
Non-inferiority Margin
Power
187
1%
10%
>99.9%
9.2. Efficacy Analysis
Not Applicable.


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9.3. Analysis of Other Endpoints
Not Applicable.
9.4. Safety Analysis
9.4.1. Analysis of Primary Endpoint

Definition: The primary endpoint is the proportion of subjects with a decrease in the 
threshold value from baseline to termination in five or more points (in either eye) at 
the p<.05 level repeated in the same five points on subsequent computerized 
automated perimetry testing (Humphrey 24-2 SITA standard).

Baseline: Baseline is determined from the last VFTs prior to receiving investigational 
product.  A point will be considered abnormal at baseline only if it was abnormal 
(<0.05) at both baseline tests.

Termination: Termination is the VFT done at Week 12 (including a repeat test if 
applicable).  For subjects who did not complete the study, the last available test(s) 
after Day 1 will be used.  Data will not be imputed for subjects who do not have any 
VFTs after baseline; rather, such subjects will be treated as missing values.

Comparison: The difference in proportions between pregabalin and placebo will be 
compared using a 2-sided 95% confidence interval (CI). Non-inferiority will be 
demonstrated if the upper CI bound is less than 0.10 (10%).

Populations: The intent-to-treat (ITT) population is defined as all subjects 
randomized to treatment who received at least one dose of investigational product.  
The Per Protocol population is a subset of the ITT population, and excludes subjects 
who had a decrease in at least 5 points at termination but did not return for a repeat 
test.  The Per Protocol population may also exclude subjects with major protocol 
violations; the list of subjects excluded will be determined prior to breaking the blind.  
The primary analysis will be performed on the Per Protocol population, the 
expectation is that the Per Protocol subset will be close in the number of subjects to 
the number of subjects randomized.  A supplementary analysis of the primary 
parameter will be performed using the ITT population.
9.4.2. Analysis of Secondary Endpoints
9.4.3. Mean Deviation
Change in mean deviation from baseline to termination will be computed for each subject.  
Baseline mean deviation will be the average of the two mean deviations from the Baseline 
visit, and termination mean deviation will be the mean deviation at the Week 12 visit (or the 
last available after Day 1 for subjects who terminate early).  If a repeat test was done at 
termination, the mean deviation from the repeat test will be used.  For each subject, the worst 
eye (ie, the eye with the greatest decrease in mean deviation) will be used in the analysis.  
Change in mean deviation will be analyzed for the ITT population using analysis of 
covariance (ANCOVA), with treatment and center in the model and the baseline mean
deviation as the covariate.  Least squares means will be obtained from the model and a 


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2-sided 95% confidence interval will be constructed on the difference in least squares means 
between pregabalin and placebo.  Non-inferiority with respect to mean deviation will be 
demonstrated if the lower bound of the CI is greater than –2.0 dB.
9.4.4. Visual Acuity
Visual acuity (best-corrected, measured using ETDRS charts) is expressed in terms of 
number of letters correctly identified.  Change in visual acuity from baseline to termination 
will be computed for each subject.  Baseline will be defined as the last visual acuity 
assessment prior to receiving investigational product, and termination will be the visual 
acuity assessment at the Week 12 visit (or the last available after Day 1 for subjects who 
terminate early).  If acuity was assessed at a repeat visit at termination, the acuity from the 
repeat test will be used. For each subject, the worst eye (ie, the eye with the greatest 
decrease in visual acuity) will be used in the analysis.  Change in visual acuity will be 
analyzed for the ITT population using ANCOVA, with treatment and center in the model and 
the baseline acuity as the covariate.
9.4.5. Other Safety Measurements
Other safety parameters, including adverse events, physical examination results, vital signs, 
body weight, clinical laboratory results, and subject assessment of seizure frequency as 
compared to before taking investigational product, and C-SSRS/S-STS, will be summarized 
by treatment group, but not analyzed inferentially.
9.5. Interim Analysis
N/A.
9.6. Data Monitoring Committee
This study will use an Internal Review Committee (IRC).  
The IRC will be responsible for ongoing monitoring of safety of subjects in the study 
according to the Charter.  The recommendations made by the IRC to alter the conduct of the 
study will be forwarded to the clinical lead or delegate 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
Pfizer or its agent will conduct periodic monitoring visits during trial conduct to ensure that 
the protocol and Global Clinical Practices are being followed.  The monitors may review 
source documents to confirm that the data recorded on CRFs are 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.  This verification 
may also occur after study completion.


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During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), 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.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
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 Case Report Form (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 trial.
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.
It is the investigator's responsibility to ensure completion and to review and approve all 
CRFs.  CRFs must be signed by the investigator or by an authorized staff member.  These 
signatures serve to attest that the information contained on the CRFs is true.  At all times, the 
investigator has final personal responsibility for the accuracy and authenticity of all clinical 
and laboratory data entered on the CRFs.  Subject source documents are the physician's 
subject records maintained at the trial site.  In most cases, the source documents will be the 
hospital's or the physician's chart.  In cases where the source documents are the hospital or 
the physician's chart, the information collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, Pfizer and 
the investigator must prospectively document which items will be recorded in the source 
documents and for which items the CRF will stand as the source document.


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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 forms, copies of all CRFs, serious adverse event forms, source documents, and 
detailed records of treatment disposition.  The records should be retained by the investigator 
according to ICH, local regulations, or as specified in the Clinical Study Agreement, 
whichever is longer.
If the investigator relocates, retires, or for any reason withdraws from the trial, Pfizer should 
be prospectively notified.  The trial records must be transferred to an acceptable designee, 
such as another investigator, another institution, or to Pfizer.  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 trial protocol, 
protocol amendments, informed consent forms, and other relevant documents, 
eg, 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 within 5 working 
days after the implementation.
12.2. Ethical Conduct of the Trial
The trial will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice guidelines, 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.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subject 
personal data.
The informed consent form must be agreed to by Pfizer and the IRB/IEC and must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements.


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The investigator must ensure that each trial subject, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the trial and possible risks 
associated with participation.  The investigator, or a person designated by the investigator, 
will obtain written informed consent from each subject or the subject's legally acceptable 
representative before any trial-specific activity is performed.  The informed consent form 
used in this trial, and any changes made during the course of the trial, must be prospectively 
approved by both the IRB/IEC and Pfizer before use.  The investigator will retain the original 
of each subject's signed consent form.
12.4. 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 all Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit.
13.2. End of Trial in a Member State of European Union
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 Study 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.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of 
Pfizer.  If a trial is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects within 
72 hours.  As directed by Pfizer, all trial materials must be collected and all CRFs completed 
to the greatest extent possible.


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15. PUBLICATION OF TRIAL 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), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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 study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 


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publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication 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, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the
principal investigator will reference that primary publication.  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, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the 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 (CSA)
between Pfizer and the institution.  In this section entitled PUBLICATION OF TRIAL 
RESULTS, the defined terms shall have the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Lyrica USPI, Pfizer Inc, December 2013.
2.
Lyrica SPC, Pfizer Inc, 
http://emc.medicines.org.uk/medicine/14651/SPC/Lyrica+Capsules/.
3.
Jung MJ, Palfreyman MG. Vigabatrin mechanisms of action. In: Levy RH, Mattson RH, 
Meldrum BS, eds. New York: Raven Press, Ltd, 1195:903-13.
4.
Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated 
with vigabatrin. Br Medical J 1997; 314:180-1.
5.
Krauss GL, Johnson MA, Miller NR. Vigabatrin-associated retinal cone system 
dysfunction. Neurology 1998; 50:614-8.
6.
Baulac M, Nordmann YL. Severe visual-field constriction and side-effects of 
GABA-mimetic antiepileptic agents. The Lancet 1998; 352:546.
7.
Wilson EA, Brodie MJ. Severe persistent visual field constriction associated with 
vigabatrin: chronic refractory epilepsy may have role in causing these unusual 
symptoms. Br Medical J 1997; 314:1693.
8.
Wong ICK, Mawer GE, Sander JW. Severe persistent visual field constriction 
associated with vigabatrin: reaction might be dose dependent. Br Medical J 1997; 
314:1693-4.
9.
Blackwell N, Hayllar, Kelly G. Severe persistent visual field constriction associated 
with vigabatrin: patients taking vigabatrin should have regular field testing. Br Medical 
J 1997; 314:1694.
10.
Harding GFA. Severe persistent visual field constriction associated with vigabatrin: four 
possible explanations exist. Br Medical J 1997;314:1694.
11.
Beck RW. Vigabatrin-associated retinal cone system dysfunction. Neurology 1998; 
51:1778-9.
12.
Musch DC, Gillespie BW, Motyka BM et al; Converting to SITA-Standard from Full-
Threshold Visual Field Testing in the Follow-Up Phase of a Clinical Trial. Invest
Ophthalmol Vis Sci 2005; 46: 2755-2759.
13.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  
Nephron 1976;16:31-41.
14.
Kelly Posner, PhD, Glenn A. Melvin, PhD, Barbara Stanley, PhD, Maria A. Oquendo, 
MD, and Madelyn Gould, PhD, MPH. Factors in the Assessment of Suicidality in 
Youth. CNS Spectr. 2007;12(2):156-162.


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15.
Kroenke, K, Spitzer, R.LThe PHQ-9. A new depression diagnostic and severity 
measure. Psychiatric Annals .2002; 32 (9): 1-7.
16.
Instruction Manual – Instructions for Patient Health Questionnaire (PHQ) and GAD-7 
Measures. http://www.phqscreeners.com/.


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Appendix 1. Abbreviations/Definitions
AED
Anti-Epileptic drug
IRB
Institutional Review Board
ALT
Alanine Aminotransferase
ITT
Intent-to-treat
ANCOVA
Analysis of Covariance
kg
Kilogram
AST
Aspartate Aminotransferase
lb
Pound
BID
Twice daily
MD
Mean deviation
BMI
Body mass index
mg
Milligram
BP
Blood pressure
MHRA
Mental Health Risk Assessment
BUN
Blood Urea Nitrogen
MRI
Magnetic Resonance Imaging
CI
Confidence interval
PGB
Pregabalin
CLcr
Creatinine clearance
PHQ
Patient health Questionnaire
CNS
Central Nervous System
Placebo
Inert compound identical to 
investigational drug
CRF
Case Report Form
RBC
Red Blood Cell
CSA
Clinical Study Agreement
SAP
Statistical Analysis Plan
C-SSRS
Columbia-Suicide Severity Rating Scale
SBQ-R
Suicidal Behaviors Questionnaire-
Revised
CT
Computerized Tomography
SITA
Swedish Interactive Threshold 
Algorithm
CTA
Clinical Trial Agreement
S-STS
Sheehan-Suicidality Tracking Scale
D
Diopters
ULN
Upper Limit of Normal
dB
Decibels
US
United States
ECG
Electrocardiogram
VFT
Visual Field Test
EDP
Exposure During Pregnancy
VNS
Vagus Nerve Stimulator 
EEG
Electroencephalogram
WBC
White Blood Cell
EIU
Exposure in Utero
ET
Early Termination in the study
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
HR
Heart rate
IB
Investigator Brochure
ICH
International Conference on Harmonization 
of technical requirements for registration of 
pharmaceuticals for human use


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Appendix 2. Special Notes about Visual Field Testing
Even though the Humphrey Field Analyzer is programmed with highly refined testing and 
analysis methods, the technician continues to play a central role.  Without proper 
management and instruction, the results of perimetric examinations are often of poor quality.
Only central reader trained, certified perimetrists will administer VFT in this study.  
Confirmation of perimetrist qualified to perform VFT will be documented.
Important Instructions for the perimetrist
The chair height and instrument height should be adjusted for subject comfort. 
It is particularly important to tell the subject what to expect during the test.  At the beginning 
of the test you should explain/show to your subject:

The task;

What the stimulus will look like, where it might appear;

How long the test will last;

When blinks are allowed;

How to sit;

How to pause the test;

That more than half of the stimuli shown in a threshold test will be too dim to be seen 
and that the stimuli that are seen are likely to be barely visible.
The perimetrist must be available to monitor the entire test to ensure the subject 
remains in the proper position.
Intercede a test
During the test, the perimetrist may pause the procedure if he/she detects obvious artifact(s).  
The test may be resumed after a 5–10 minute break.  Investigators/perimetrist can 
repeat/reschedule sessions for another time when subjects have poor compliance that 
interferes with visual field testing. 
Timing of the test
It is recommended that all the visual field testing be performed in the morning (or when the 
subject is most alert), and it is recommended that the subject withholds the morning dose of 
the investigational product until the ophthalmic tests are completed to reduce any potential 
CNS effects - that may occur (eg, somnolence) with pregabalin which may interfere with 


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testing. If the subject has taken the morning study dose of medication, testing should be 
performed when the subject is least probably affected by any potential CNS events that may 
occur to ensure the subject is optimally alert during the test.
Common artifacts 
Common false patterns may be caused by:

Lack of previous perimetric experience;

Droopy eye lid – place a surgical tape between eye lid and eye brow;

Misaligned correction lenses;

Subject anxiety – counsel subject prior to testing.
Role of Central Reader/Reading Center  
It is the responsibility of central reader/reading center to ensure VFTs are collected properly 
and accurately.  The central reader /reading center is responsible for: 
Training 

All investigators and staff who will perform study procedures will receive extensive 
training. Refresher training may be offered periodically throughout the study as 
needed;

Completion of training and approval of perimetrist will be documented;

Investigator and staff will not perform the tests until they have been certified by 
central reader.
During the study, the center reader performs the following:

Confirms VFT outcomes and decides if a repeat is necessary.  This result will be 
communicated to the site within 72 hours of receiving test results;

Review VFT conduct and quality control on a monthly basis.  Communicate results 
with the sponsor. Implement improvement measurements as necessary;

Tabulated (post-processed) data will be electronically transferred to Pfizer from the 
Central Reader for storage and data analysis as specified in Statistical Analysis Plan 
(SAP).


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Appendix 3. Clinical Protocol Amendment 1
Current Amendment:
Amendment No.
1
Date
17 October 2006
Country (ies)
All
Site(s)
All
SUMMARY
Reason(s) for Amendment
The protocol section(s) that have been amended and the details of the changes are 
summarized in the following sections.
Protocol Section(s) Amended
The protocol sections that were amended are detailed below.  The format is as follows:

The “change from” section represents the current text in the protocol.  Bolded text is 
used to indicate the addition of information to the current text, and strike-out of text 
(eg, text) is used to show the deletion of information from the current text.

The “change to” section represents the revised text, with the revisions shown in the 
“change from” section in normal text.


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1. Summary and Section 3, Trial Design
Change From
A total of 284 subjects will participate in the study, 142 randomized to pregabalin, 142 to 
placebo.  Approximately 1015 centers will be selected that have the capability to perform the 
comprehensive visual field testing.
Change To
A total of 284 subjects will participate in the study, 142 randomized to pregabalin, 142 to 
placebo.  Approximately 15 centers will be selected that have the capability to perform the 
comprehensive visual field testing.
2. Section 4.1, Inclusion Criteria
Change From
6.  Be 18 to 65 years old and weigh ≥ 50kg (110 lb) with BMI 18 - 32;
Change To
6.  Be 18 to 65 years old;
3. Section 6.1, Week –1 (Screening)
Change From
At the Screening visit (one week up to 21 days prior to Baseline), subjects will be eligible 
for the study after verification of the inclusion/exclusion criteria and the study has been 
explained to them.  The following procedures will be completed at the screening visit:
Change To
At the Screening visit (up to 21 days prior to Baseline), subjects will be eligible for the study 
after verification of the inclusion/exclusion criteria and the study has been explained to them.  
The following procedures will be completed at the screening visit:


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Appendix 4. Clinical Protocol Amendment 2
Current Amendment: 2
Amendment No.
2
Date
12 August 2009
Country (ies)
Site(s)
Previous Amendments:
Amendment No.
1
Date
17 October 2006
Country (ies)
All
Site(s)
All
SUMMARY
Reason(s) for Amendment
The rational is “add to reflect current internal SOP”.
The protocol section(s) that have been amended and the details of the changes are 
summarized in the following sections.
Protocol Section(s) Amended
The protocol sections that were amended are detailed below.  The format is as follows:

The “change from” section represents the current text in the protocol.  Bolded text is 
used to indicate the addition of information to the current text, and strike-out of text 
(eg, text) is used to show the deletion of information from the current text.

The “change to” section represents the revised text, with the revisions shown in the 
“change from” section in normal text.
Section <Insert section number> , <Insert section title> , Page 
<Insert page number as appropriate> 
Change From
Change To


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1. Section ABBREVIATIONS/DEFINITIONS
Change From
AED
Anti-Epileptic drug
lb
Pound
ALT
Alanine Aminotransferase
MD
Mean deviation
ANCOBVA
Analysis of Ccovariance
Mg
Milligram
AST
Aspartate Aminotransferase
MRI
Magnetic Resonance Imaging
BID
Twice daily
PGB
Pregabalin
BMI
Body mass index
Placebo
Inert compound identical to 
investigational drug
BP
Blood pressure
RBC
Red Blood Cell
BUN
Blood Urea Nitrogen
SAP
Statistical Analysis Plan
CI
Confidence interval
SITA
Swedish Interactive Threshold
Algorithm
CLcr
Creatinine clearance
S-STS
Sheehan-Suicidality Tracking Scale
CNS
Central Nervous System
ULN
Upper Limit of Normal
CRF
Case Report Form
VFT
Visual Field Test
CT
Computerized Tomography
VNS
Vagus Nerve Stimulator 
D
Diopters
WBC
White Blood Cell
dB
Decibels
ECG
Electrocardiogram
EEG
Electroencephalogram
EIU
Exposure in Utero
ET
Early Termination in the study
ETDRS
Early Treatment Diabetic 
Retinopathy Study
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
HR
Heart rate
ICH
International Conference on 
Harmonization of technical 
requirements for registration of 
pharmaceuticals for human use
IEC
Independent Ethics Committee
IOP
Intra Ocular Pressure
IRB
Institutional Review Board
ITT
Intent-to-treat
kg
Kilogram


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Change To
AED
Anti-Epileptic drug
lb
Pound
ALT
Alanine Aminotransferase
MD
Mean deviation
ANCOVA
Analysis of Covariance
Mg
Milligram
AST
Aspartate Aminotransferase
MRI
Magnetic Resonance Imaging
BID
Twice daily
PGB
Pregabalin
BMI
Body mass index
Placebo
Inert compound identical to 
investigational drug
BP
Blood pressure
RBC
Red Blood Cell
BUN
Blood Urea Nitrogen
SAP
Statistical Analysis Plan
CI
Confidence interval
SITA
Swedish Interactive Threshold 
Algorithm
CLcr
Creatinine clearance
S-STS
Sheehan-Suicidality Tracking Scale
CNS
Central Nervous System
ULN
Upper Limit of Normal
CRF
Case Report Form
VFT
Visual Field Test
CT
Computerized Tomography
VNS
Vagus Nerve Stimulator 
D
Diopters
WBC
White Blood Cell
dB
Decibels
ECG
Electrocardiogram
EEG
Electroencephalogram
EIU
Exposure in Utero
ET
Early Termination in the study
ETDRS
Early Treatment Diabetic 
Retinopathy Study
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
HR
Heart rate
ICH
International Conference on 
Harmonization of technical 
requirements for registration of 
pharmaceuticals for human use
IEC
Independent Ethics Committee
IOP
Intra Ocular Pressure
IRB
Institutional Review Board
ITT
Intent-to-treat
kg
Kilogram


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2. Section SUMMARY, Trial Design
Change From
This is a Phase IV, multicenter, randomized controlled trial to further characterize visual 
fields in subjects with partial epilepsy dosed for with pregabalin or placebo. Pregabalin will 
be dosed at eoomg/day for 11 weeks after one week initiation with 150 mg/day, followed by 
one week tapering of 150 mg/day. Total treatment period will be 13 weeks. 13 weeks, 
including a 1 week up titration and 1 week down titration from the target dose of 
pregabalin 300mg/day versus placebo.  Comprehensive ophthalmologic testing will be 
done at pre-treatment baseline to exclude those with pre-existing eye disease.
A total of 284 subjects will participate in the study, 142 randomized to pregabalin and 142 to 
placebo.  Approximately 15 60 centers will be selected that have the capability to perform the 
comprehensive visual field testing.
Placebo
PGB 75mg
BID
Study Week
- 1
Study Week
2-12 
Screening
Treatment
Follow-up
Study Week
1
PGB 150 mg
BID
PGB 75 mg
BID
Study Week
15
Study Week
13 
Change To
This is a Phase IV, multicenter, randomized controlled trial to further characterize visual 
fields in subjects with partial epilepsy dosed for 13 weeks, including a 1 week up titration 
and 1 week down titration from the target dose of pregabalin 300mg/day versus placebo.  
Comprehensive ophthalmologic testing will be done at pre-treatment baseline to exclude 
those with pre-existing eye disease.
Study Week
-1 -3 ~ -1
Study Week
1
Study Week
2 - 12
Study Week
13
Study Week
1514 - 15


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A total of 284 subjects will participate in the study, 142 randomized to pregabalin and 142 to 
placebo.  Approximately 60 centers will be selected that have the capability to perform the 
comprehensive visual field testing.
Placebo
PGB 75mg
BID
Study Week
- 1
Study Week
2-12 
Screening
Treatment
Follow-up
Study Week
1
PGB 150 mg
BID
PGB 75 mg
BID
Study Week
15
Study Week
13 
3. Section, Schedule of Activities
Change From
Schedule of Activities
Protocol Activity
Wk -1
(Screening) 
Wk 0
(Baseline)
Wk 0 
RandRandomizat
ion
Wk 1
Wk 
6
Wk 12
(Or 
TermET)
Week 
15
w-Up)
Visit Numbern
1
2
3m
4
5
6
7
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
X
History/Diagnosis/Demograph
ics
X
Physical Examination
X
X
Concomitant Medication 
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
Vital Signs (Sitting BP/HR)
X
X
X
X
X
ECG (Singlet)
X
EEG
Xa
CT or MRI
Xb
Clinical
1) Hematologyc
X
X
Laboratory
2) Chemistry d
X
X
Study Week
-3 ~ -1
Study Week
1
Study Week
2 - 12
Study Week
13
Study Week
14 - 15


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3) Urinalysise
X
X
Urine Pregnancy Testf
X
X
Urine Drug Screen
X
1) External Eye 
Exam
X
X
Xg
2) ETDRS 
Acuity
X
X
X
X
Xg
Ophthalmic 3) Intraocular 
Pressure
X
Examination 4) Dilated 
Funduscopic
X
5) VFT (24-2 
SITA)
Xh, 1
Xh, 1
Xh
Xh
Xg,h
Patient assessment of seizure 
frequency
X
Sheehan-Suicidality Tracking 
Scale
X
X
X
X
X
X
X
Patient Health 
Questionnaire–8 (PHQ-8)
X
Adverse Events Report
                    X------------------------------------------------------------------------X
Study Medication Dispensing
X i,j,k
Xk
Xk
Xj
a Subjects who have not had a test within 2 years. See inclusion criteria #1
b Subjects who have not had a test within 3 years. See inclusion criteria #4
c Hemoglobin, hematocrit, RBC count, WBC count, platelet count
d Electrolytes (Na, K, Ca, Cl, bicarbonate), creatinine, BUN, glucose, AST, ALT, alkaline phosphatases, 
bilirubin, CK, uric acid, albumin, total protein
e Specific gravity, PH, Glucose (qual), Protein (qual), Blood (qual), Ketones, Nitrite and Microscopy if urine 
dipstick is positive for blood or protein
f Childbearing potential female subjects only
g Subjects who have had visual findings on Week 12 and subsequently confirmed
h A repeat may be necessary upon the confirmation from central reader
i Recommend subject to take first dose on in the evening
j Titration/tapering dose
k Treatment dose
l Conduct 2 tests
m Usually occur between the 3rd – 7th day after Baseline (Visit 2) when the verification of VFT is 
available
n Screening procedures can be completed within 21 days prior to Baseline; Study Visit 4 – 7 have a +/- 3 
days window.


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Change To
Schedule of Activities
Protocol Activity
Screening 
Baseline Wk 0 
Randomization
Wk 1 Wk 6
Wk 12
(Or ET)
Week 
15
(Follow
-Up)
Visit Numbern
1
2
3m
4
5
6
7
Informed Consent
X
Inclusion/Exclusion 
Criteria
X
X
X
History/Diagnosis/Demogr
aphics
X
Physical Examination
X
X
Concomitant Medication 
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
Vital Signs (Sitting 
BP/HR)
X
X
X
X
X
ECG (Singlet)
X
EEG
Xa
CT or MRI
Xb
Clinical
1) 
Hematologyc
X
X
Laboratory
2) Chemistry d
X
X
3) Urinalysise
X
X
Urine Pregnancy Testf
X
X
Urine Drug Screen
X
1) External 
Eye Exam
X
X
Xg
2) ETDRS 
Acuity
X
X
X
X
Xg
Ophthalmic 3) Intraocular 
Pressure
X
Examination 4) Dilated 
Funduscopic
X
5) VFT (24-2 
SITA)
Xh, 1
Xh, 1
Xh
Xh
Xg,h
Patient assessment of 
seizure frequency
X
Sheehan-Suicidality 
Tracking Scale
X
X
X
X
X
X
X
Patient Health 
Questionnaire–8 (PHQ-8)
X
Adverse Events Report
X------------------------------------------------------------------------X
Study Medication 
Dispensing
X i,j
Xk
Xk
Xj


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a Subjects who have not had a test within 2 years. See inclusion criteria 1.
b Subjects who have not had a test within 3 years. See inclusion criteria 4.
c Hemoglobin, hematocrit, RBC count, WBC count, platelet count.
d Electrolytes (Na, K, Ca, Cl, bicarbonate), creatinine, BUN, glucose, AST, ALT, alkaline phosphatases, 
bilirubin, CK, uric acid, albumin, total protein.
e Specific gravity, PH, Glucose (qual), Protein (qual), Blood (qual), Ketones, Nitrite and Microscopy if urine 
dipstick is positive for blood or protein.
f Childbearing potential female subjects only.
g Subjects who have had visual findings on Week 12 and subsequently confirmed.
h A repeat may be necessary upon the confirmation from central reader.
i Recommend subject to take first dose in the evening.
j Titration/tapering dose.
k Treatment dose.
l Conduct 2 tests.
m Usually occur between the 3rd – 7th day after Baseline (Visit 2) when the verification of VFT is available.
n Screening procedures can be completed within 21 days prior to Baseline; Study Visit 4 – 7 have a +/- 3 
days window.
4. Section 1. INTRODUCTION, 1.1. Background, 1st and 3rd paragraphs
Change From
Pregabalin (Lyrica) has been approved in over 50 110 countries to date for varying 
neuropathic pain indications and for adjunctive treatment of patients with partial seizures and 
for generalized anxiety disorder.  Lyrica is was approved in the United States in 
December 2004 for management of neuropathic pain associated with diabetic peripheral 
neuropathy or postherpetic neuralgia, and in June 2005 for the adjunctive treatment of adult 
patients with partial onset seizures, and for management of fibromyalgia.1.  Lyrica iswas
approved in the European Union countries in July 2004 for the treatment of peripheral 
neuropathic pain, and as adjunctive treatment of partial seizures with or without secondary 
generalization, and in March 2006 for the treatment of generalized anxiety disorder. 2
Formal visual field testing was conducted in over 2400 patients treated with pregabalin for 
neuropathic pain, chronic pain syndromes, intractable epilepsy, or generalized anxiety 
disorder in randomized controlled clinical trials of up to 3 months in duration and in over 
3600 patients in open-label trials of up to 4 years in duration.  Ophthalmologic assessments 
were included in the program due to concerns expressed at the time on emerging reports of 
visual field disturbances with the anticonvulsant vigabatrin, a gamma-aminobutyric acid 
(GABA)-transaminase inhibitor.13-9  11  The mechanism of the visual field defects with 
vigabatrin is unknown but was considered as possibly related to its GABA mechanism.  As a 
structural derivative of GABA, regulatory agencies considered similarity of pregabalin to 
vigabatrin as possible.  Subsequently, it became clearer that the mechanism of action of 
pregabalin was not related to GABA-transaminase inhibition or to a GABA related 
mechanism.  While the mechanism of action of pregabalin is not completely understood, 
results in animal models indicate that binding to the alpha-2-delta subunit of voltage-gated 
calcium channels may be involved in the activity of pregabalin.


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Change To
Pregabalin (Lyrica) has been approved in over 110 countries to date for varying neuropathic 
pain indications and for adjunctive treatment of patients with partial seizures and for
generalized anxiety disorder.  Lyrica is approved in the United States for management of 
neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia, for 
the adjunctive treatment of adult patients with partial onset seizures, and for management of 
fibromyalgia.1  Lyrica is approved in European Union countries for the treatment of 
peripheral neuropathic pain, adjunctive treatment of partial seizures with or without 
secondary generalization, and for the treatment of generalized anxiety disorder. 2
Formal visual field testing was conducted in over 2400 patients treated with pregabalin for 
neuropathic pain, chronic pain syndromes, intractable epilepsy, or generalized anxiety 
disorder in randomized controlled clinical trials of up to 3 months in duration and in over 
3600 patients in open-label trials of up to 4 years in duration.  Ophthalmologic assessments 
were included in the program due to concerns expressed at the time on emerging reports of 
visual field disturbances with the anticonvulsant vigabatrin, a gamma-aminobutyric acid 
(GABA)-transaminase inhibitor.3-11  The mechanism of the visual field defects with 
vigabatrin is unknown but was considered as possibly related to its GABA mechanism.  As a 
structural derivative of GABA, regulatory agencies considered similarity of pregabalin to 
vigabatrin as possible.  Subsequently, it became clearer that the mechanism of action of 
pregabalin was not related to GABA-transaminase inhibition or to a GABA related 
mechanism.  While the mechanism of action of pregabalin is not completely understood, 
results in animal models indicate that binding to the alpha-2-delta subunit of voltage-gated 
calcium channels may be involved in the activity of pregabalin.
5. Section 2. TRIAL OBJECTIVES AND ENDPOINTS, Title
Change From
2. TRIAL OBJECTIVES AND ENDPOINTS
Change To
2. TRIAL OBJECTIVES AND ENDPOINTS
6. Section 2. TRIAL OBJECTIVES AND ENDPOINTS, 2.1. Objective, title and 
section
Change From
2.1 Objective
To monitor evaluate visual fields in subjects with partial epilepsy receiving 12 weeks 
treatment of pregabalin compared to or placebo for 12 weeks under highly controlled 
conditions.


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Change To
2.1 Objective
To evaluate visual fields in subjects with partial epilepsy receiving 12 weeks treatment of 
pregabalin compared to placebo.
7. Section 2. TRIAL OBJECTIVES AND ENDPOINTS, 2.2. Endpoints, Title and 
section
Addition
2.2 Endpoints
Primary endpoint: 
The proportion of subjects with a decrease in the threshold value from baseline to week 
12 for any five points (in either eye) at the p<.05 level repeated in the same five points 
on subsequent computerized automated perimetry testing (Humphrey 24-2 SITA 
standard).
Secondary endpoints:
Change in mean deviation score from baseline to week 12 from the Humphrey 
threshold test.
Change in visual acuity from Baseline to Week 12 expressed by number identified in 
ETDRS visual acuity assessment.
8. Section 3. TRIAL DESIGN, 2nd paragraph
Change From
A central reader will assure the quality of all visual field test results with pre-specified 
criteria.  Any field failing this quality assurance either due to poor subject compliance or due 
to failure to follow testing protocol will be repeated within one week.  A total of 284 subjects 
will participate in the study, 142 randomized to pregabalin, 142 to placebo.  Approximately 
15 60 centers will be selected that have the capability to perform the comprehensive testing.
Change To
A central reader will assure the quality of all visual field test results with pre-specified 
criteria.  Any field failing this quality assurance either due to poor subject compliance or due 
to failure to follow testing protocol will be repeated within one week.  A total of 284 subjects 
will participate in the study, 142 randomized to pregabalin, 142 to placebo.  Approximately
60 centers will be selected that have the capability to perform the comprehensive testing.


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9. Section 4. SUBJECT SELECTION, 4.1. Inclusion Criteria, 1st number
Change From
1. Diagnosis of epilepsy with partial seizures (as defined in the International League
Against Epilepsy Classification of Seizures).  Diagnosis must be established by subject’s 
medical history (eg, seizures), family history, and the results of electroencephalogram 
testing done within 2 years prior to baseline (if none available, must be taken during 
Screening)baseline).  Results must be consistent with the diagnosis of focal-onset 
epilepsy;
Change To
1. Diagnosis of epilepsy with partial seizures (as defined in the International League 
Against Epilepsy Classification of Seizures).  Diagnosis must be established by subject’s 
medical history (eg, seizures), family history, and the results of electroencephalogram 
testing done within 2 years prior to baseline (if none available, must be taken during 
Screening).  Results must be consistent with the diagnosis of focal-onset epilepsy;
10. Section 4. SUBJECT SELECTION, 4.2. Exclusion Criteria, 6th, 12th and 18th
numbers
Change From
6. Refractive error in either eye exceeding +/-5 D (sphere) or +/-2.5 D (cylinder);
12. Prior or current pregabalin treatmentSubject with a history of intolerability to 
pregabalin, or with a history of insufficient response (based on investigator’s clinical 
judgment) to pregabalin in the treatment of partial seizure, or subjects with current 
pregabalin treatment; 
18. Have a significant psychiatric disorder, or recurrent episodes of severe depression 
(any pharmacologic treatment or hospitalization for the illness within 1 year prior to 
Screening), or subjects with serious suicidal risk per criteria described in the section 
7.5.1 of the protocol.  Subjects with mild, chronic depression without recent 
hospitalization who are being maintained on a stable dose of a single antidepressant are 
acceptable;
Change To
6. Refractive error in either eye exceeding +/-5 D (sphere) or +/-2.5 D (cylinder);
12. Subject with a history of intolerability to pregabalin, or with a history of insufficient 
response (based on investigator’s clinical judgment) to pregabalin in the treatment of 
partial seizure, or subjects with current pregabalin treatment; 


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18. Have a significant psychiatric disorder, recurrent episodes of severe depression (any 
pharmacologic treatment or hospitalization for the illness within 1 year prior to 
Screening), or subjects with serious suicidal risk per criteria described in the section
7.5.1 of the protocol.  Subjects with mild, chronic depression without recent 
hospitalization who are being maintained on a stable dose of a single antidepressant are 
acceptable;
11. Section 5. TRIAL TREATMENTS, 5.1. Prohibited/Allowable Medications or 
Precautions
Change From
Apart from the background antiepileptics, aAdministration of pCNS-active 
compoundssychotropic compounds is prohibited during the trial, with the exception of a 
single antidepressant.  Concurrent treatment with other investigational agents or devices is 
not allowed during the study.  The prior or current use of vigabatrin is prohibited in this trial.
Change To
Apart from the background antiepileptics, administration of psychotropic compounds is 
prohibited during the trial, with the exception of a single antidepressant.  Concurrent 
treatment with other investigational agents or devices is not allowed during the study.  The 
prior or current use of vigabatrin is prohibited in this trial.
12. Section 5. TRIAL TREATMENTS, 5.2. Allocation to Treatment
Change From
Following the 1-week Bbaseline visit and after confirmation of the validity of the VFTs from 
the central reader, subjects will be randomized to receive either pregabalin or placebo.  
Subjects will be randomly assigned to treatment regimens in a 1:1 ratio according to a 
computer-generated random code.  Each subject will receive the lowest randomization 
number available at the site.
Change To
Following the Baseline visit and after confirmation of the validity of the VFTs from the 
central reader, subjects will be randomized to receive either pregabalin or placebo.  Subjects 
will be randomly assigned to treatment regimens in a 1:1 ratio according to a 
computer-generated random code.  Each subject will receive the lowest randomization 
number available at the site.


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13. Section 6. TRIAL PROCEDURES, 6.1. Screening, Title and 15th, 16th bullets and 3rd
number
Change From
6.1. Week –1 (Screening)

Sheehan-Suicidality Tracking Scale (S-STS) Appendix 2;

Patient Health Questionnaire – 8 (PHQ – 8) Appendix 3;
3. Intraocular pressure by calibrated Goldmann, Perkins, or Tonopen® tonometry as 
long as one is used consistently throughout the study.
Change To
6.1. Screening 

Sheehan-Suicidality Tracking Scale (S-STS) Appendix 2;

Patient Health Questionnaire – 8 (PHQ – 8) Appendix 3;
3. Intraocular pressure by calibrated Goldmann, Perkins, or Tonopen® tonometry as long 
as one is used consistently throughout the study.
14. Section 6. TRIAL PROCEDURES, 6.2.1. Baseline, Title and last bullet
Change From
6.2.1.Week 0 (Baseline)

Sheehan-Suicidality Tracking Scale (S-STS) Appendix 2;
Change To
6.2.1. Baseline 

Sheehan-Suicidality Tracking Scale (S-STS) Appendix 2;
15. Section 6. TRIAL PROCEDURES, 6.2.2, Randomization Visit, 1st paragraph and 5th
bullet
Change From
At this visit, subjects will be randomized after verification that they continue to meet the 
inclusion/exclusion criteria.  This visit occurs after the central reader confirms the validity of 
the VFTs, ie usually between 3 and 7 days after the Baseline visit.


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
Sheehan-Suicidality Tracking Scale (S-STS) Appendix 2;
Change To
At this visit, subjects will be randomized after verification that they continue to meet the 
inclusion/exclusion criteria.  This visit occurs after the central reader confirms the validity of 
the VFTs, ie usually between 3 and 7 days after the Baseline visit.

Sheehan-Suicidality Tracking Scale (S-STS) Appendix 2;
16. Section 6. TRIAL PROCEDURES, 6.2.3. Week 1 Visit, last bullet
Addition

Sheehan -Suicidality Tracking Scale (S-STS) Appendix 2;
17. Section 6. TRIAL PROCEDURES, 6.2.4. Procedures during the Study Drug 
Treatment Period (Weeks 6 and 12)
Change From
Subjects will have the following assessments performed at 6 and 12 weeks following 
randomization (or at Early Terminationendpoint if subject does not complete 12 weeks of 
study).
Change To
Subjects will have the following assessments performed at 6 and 12 weeks following 
randomization (or at Early Termination if subject does not complete 12 weeks of study).
18. Section 6. TRIAL PROCEDURES, 6.2.4.1. The Following Will be Performed at 
Weeks 6 and 12 Visits, 8th bullet
Addition

Sheehan-Suicidality Tracking Scale, Appendix 2;
19. Section 6. TRIAL PROCEDURES, 6.2.4.2. The Following Additional Assessments 
Will be Performed on Week 12 Only, 6th bullet and last paragraph
Change From

Patient assessment of seizure frequency.
If the subject withdraws early, all Week 12 activities are to be conducted.


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Change To

Patient assessment of seizure frequency
Section 6. TRIAL PROCEDURES, 6.3. Follow-up Visit, Title and 4th bullet
Change From
6.3. Follow-up Visit (Week 15 Visit) Week 15 (Follow-up) Visit

Sheehan Suicidality Tracking Scale, Appendix 2.
Change To
6.3. Follow-up Visit (Week 15 Visit)

Sheehan Suicidality Tracking Scale, Appendix 2.
20. Section 6. TRIAL PROCEDURES, 6.4. Subject Withdrawal, last bullet
Addition

Sheehan Suicidality Tracking Scale, Appendix 2.
21. Section 7. ASSESSMENTS, 7.1.1. External Eye Examinations, 2nd paragraph
Change From
The external eye examination will be conducted at the Week –1 (Screening (Visit 1) ) and 
Week 12 (Visit 6) vvisits, and at the Week 15 (Follow-up, Visit 7) visits if deemed 
necessary.
Change To
The external eye examination will be conducted at the Screening (Visit 1) and Week 12 
(Visit 6) visits, and at the Week 15 (Follow-up, Visit 7) visits if deemed necessary.
22. Section 7. ASSESSMENTS, 7.1.2. Direct and Indirect Funduscopy, 1st and 2nd
paragraphs
Change From
At BaselineScreening visit, direct and indirect funduscopy will be used to look at retinal 
morphology (dilated eyes).  Indirect funduscopy will be performed using a biomicroscope 
(slit lamp) and a Volk 90 diopter lens allowing evaluation of maculae and optic nerve. A 20 
or 28 diopter lens can be used to evaluate the the peripheral fundus and providing an 
overall view of the pigment epithelium. Direct funduscopy may be performed using a 
manual ophthalmoscope and will examine the macular ocular disc vessels, looking especially 
for edema and alterations of the macular reflex.  Results will be collected on the case report 
form (CRF).


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Funduscopy will be conducted at Week –1 (Screening) visit.
Change To
At Screening visit, direct and indirect funduscopy will be used to look at retinal morphology 
(dilated eyes).  Indirect funduscopy will be performed using a biomicroscope (slit lamp) and 
a Volk 90 diopter lens allowing evaluation of maculae and optic nerve. A 20 or 28 diopter 
lens can be used to evaluate the the peripheral fundus and providing an overall view of the 
pigment epithelium.  Direct funduscopy may be performed using a manual ophthalmoscope 
and will examine the macular ocular disc vessels, looking especially for edema and 
alterations of the macular reflex.  Results will be collected on the case report form (CRF).
Funduscopy will be conducted at Screening visit.
23. Section 7. ASSESSMENTS, 7.1.3. Visual Acuity, 4th paragraph
Change From
Visual acuity will be measured at Week –1 (Screening (Visit 1)), Week 0 (Baseline (Visit 
2)), Week 6 (Visit 5) , and Week 12(Visit 6) visits visits, and at Week 15 (Follow-up, Visit 
7) visits if deemed necessary.
Change To
Visual acuity will be measured at Screening (Visit 1), Baseline (Visit 2), Week 6 (Visit 5), 
and Week 12 (Visit 6) visits, and at Week 15 (Follow-up, Visit 7) visit if deemed necessary.
24. Section 7. ASSESSMENTS, 7.1.4. Visual Field Test, 1st- 3rd and last paragraphs
Change From
All investigators will receive extensive training at the investigator’s meeting and periodically 
throughout the study to improve the reliability of measurements by monitoring subject 
compliance and recognizing artifact in visual field examination.  Investigators can 
repeat/reschedule sessions when subjects have poor compliance or any difficulties which 
interferes with visual field testing.
Prior to performing the computerized automated perimetry (Humphrey 24-2 SITA), pupil 
size will be measured and recorded and must be 3 mm or greater for VFT, otherwise the 
pupil must be dilated.  Visual fields will be measured using the Humphrey 24-2 SITA and 
analyzed using STATPAC according to the guidelines.  A detailed guideline is provided in
the Appendix 1 of this document.  Because visual field results are strongly affected by 
experience, visual field tests will be repeated on two occasions at Screening and at Baseline 
visits. 
All automated perimetry results (in computer disc form) will be read by a central reader 
within three seven days of the examination.  If the central reader assesses the visual field 
exam to be of poor quality, the exam will be repeated within one week.  The repeat test will 
be performed only on the eye whose test was considered to give a poor result. 


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VFT will be conducted at the Week –1 (Screening(Visit 1)), Week 0 (Baseline(Visit 2)), 
Week 6(Visit 5), and Week 12(Visit 6) vvisits as well as at the Week 15 (follow-up, Visit 7)) 
visit if deemed necessary.
Change To
All investigators will receive extensive training at the investigator’s meeting and periodically 
throughout the study to improve the reliability of measurements by monitoring subject 
compliance and recognizing artifact in visual field examination.  Investigators can
repeat/reschedule sessions when subjects have poor compliance or any difficulties which 
interferes with visual field testing.
Prior to performing the computerized automated perimetry (Humphrey 24-2 SITA), pupil 
size will be measured and recorded and must be 3 mm or greater for VFT, otherwise the 
pupil must be dilated.  Visual fields will be measured using the Humphrey 24-2 SITA and 
analyzed using STATPAC according to the guidelines.  A detailed guideline is provided in 
the Appendix 1 of this document.  Because visual field results are strongly affected by 
experience, visual field tests will be repeated on two occasions at Screening and at Baseline 
visits. 
All automated perimetry results (in computer disc form) will be read by a central reader 
within seven days of the examination.  If the central reader assesses the visual field exam to 
be of poor quality, the exam will be repeated within one week.  The repeat test will be 
performed only on the eye whose test was considered to give a poor result. 
VFT will be conducted at the Screening (Visit 1), Baseline(Visit 2), Week 6 (Visit 5), and 
Week 12 (Visit 6) visits as well as at the Week 15 (follow-up, Visit 7) visit if deemed 
necessary.
25. Section 7. ASSESSMENTS, 7.2. Clinical Laboratory Tests, 7.3. Vital Sign, Body 
Weight and Physical Examination, 7.4. Electrocardiogram (ECG, 7.5. Suicidality 
Assessment, 7.5.1. Sheehan-Suicidality Tracking Scale (S-STS), 7.5.2 Patient Health 
Questionnaire-8 (PHQ), 7.5.3. Suicidality Assessments, and 7.6. Patient Assessment 
of Seizure Frequency
Additions
7.2. Clinical Laboratory Tests
Laboratory
The following safety laboratory tests will be performed at the Screening (Visit 1) and 
Week 12 (Visit 6).


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Safety Laboratory
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC Count
Platelet Count
WBC Count
Creatinine
BUN
Glucose
Ca++
Na+, K+, Cl-
Total CO2
(Bicarbonate)
AST, ALT
Total Bilirubin
Alkaline 
phosphatase
Uric acid
Albumin
Total protein
Creatine 
phosphokinase
PH
Color
Clarity
Specific gravity
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrates
Microscopyb
Urine Pregnancy 
testa
Urine drug testingc 
(amphetamines, 
antidepressants, 
barbiturates, 
benzodiazepines, 
canabinoids, cocaine, 
methadone, 
methaqualone, 
opiates, 
phenothiazines, 
propoxyphene and 
alcohol)
a
Childbearing potential females only
b
Only if urine dipstick is positive for blood or protein
c
Only at Screening
Results of the urine drug tests at screening (V1) must be negative for the subject to 
receive trial medication on Day 1.  

Safety laboratory tests from Screening must have no clinically significant 
findings, as judged by the investigator, in order for a subject to receive trial 
medication on Day 1.

CLcr will be estimated from creatinine at screening to determine 
eligibility using the equations that follow.12  
Creatinine
Serum
72
(kg)
Weight
Body
age)
(140
CLcr
Male




0.85
Creatinine
Serum
72
(kg)
Weight
Body
age)
(140
Female









CLcr
In order to use SI units for creatinine (µmol/L), use the following formulas:
Creatinine
Serum
(kg)
Weight
Body
age)
(140
CLcr
Male



x   1.23 
(mL/min)


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Creatinine
Serum
(kg)
Weight
Body
age)
(140
1.23








Female
CLcr
(mL/min)
0.85

7.3. Vital Sign, Body Weight and Physical Examination
Vital signs (sitting heart rate and blood pressure) will be obtained at Screening (Visit 1), 
Baseline (Visit 2), Week 1 (Visit 4), Week 6 (Visit 5), Week 12 (Visit 6) and Early 
Termination (ET).  BP will be measured with the subject’s arm supported at the level of 
the heart, and recorded to the nearest mm Hg.  The same arm (preferably the dominant 
arm) will be used throughout the trial. BP and heart rate will be measured after at 
least 5 minutes in sitting position.  When done manually, heart rate will be measured in 
the brachial/radial artery for at least 30 seconds.  The use of automated devices for 
measuring BP and heart rate are also acceptable.
Body weight will be collected at Screening (Visit 1), Baseline (Visit 2), Week 1 (Visit 4), 
Week 6 (Visit 5), Week 12 (Visit 6), Week 15 (Visit 7) and Early Termination (ET).  Any 
negative changes from the screening examination will be recorded as adverse events.
To reduce measurement variability of body weight, subjects should be weighed on the 
same scale at each visit that body weight is assessed; should not carry extraneous items 
such as purses, blackberries, and cell phones onto the scale; should remove their coats 
and shoes before being weighed, and should empty their pockets of any heavy items.
A physical exam will be performed at Screening (V1) and Week 12 (Visit 6). Items 
included will be:

General appearance – including height (at Screening only);

Skin – Examination for the presence of rash;

HEENT – Examination of extraocular movements, pupillary response, 
determination of nystagmus, and visual field examination by confrontation;

Lungs and Cardiovascular – Auscultation of lung fields, determination of BP, 
cardiac rhythm and rate auscultation for the presence of murmurs, gallops, or 
rubs;

Neurologic – Including mental status, station and gait, cranial nerves, motor and 
sensory function, reflexes, and coordination;

Abdominal – Palpation and auscultation performed.
Additional physical assessment will be made as necessary to evaluate symptoms or 
adverse experiences at the discretion of the investigator.


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7.4. Electrocardiogram (ECG)
A 12-lead ECG (singlet) will be performed at Screening (Visit 1).  ECG should be 
performed after the subject has rested quietly for at least 10 minutes in a supine 
position.  ECG tracing will be evaluated by the investigator in a real time for the safety 
monitoring of the subjects.  In some cases, it may be appropriate to repeat abnormal 
ECGs to rule out improper lead placement as contributing to the ECG abnormality.  It 
is important that leads are placed in the same positions each time in order to achieve 
precise ECG recordings.
7.5. Suicidality Assessment 
7.5.1. Sheehan-Suicidality Tracking Scale (S-STS)
The Sheehan-Suicidality Tracking Scale (S-STS, see Appendix 3) is an 8-item 
prospective rating scale that tracks treatment-emergent suicidal ideation and 
behaviors.12  This scale was adapted from the Suicidality Module of the Mini 
International Neuropsychiatric Interview (MINI) Structured Diagnostic Interview for 
DSM-IV.  Items 1a, 2-6, 7a, and 8 are scored on a 5-point Likert scale (ranging from 0= 
not at all to 4=extremely).  Items 1, 1b, and 7 require yes or no responses.  This scale 
can be administered either by a clinician or patient through self-report.  In this study, 
the scale will be completed by the patient (self-report). The Baseline-Lifetime 
Assessment will be completed at Screening and the “Since Last Visit” version will be 
completed at Baseline(Visit 2) , Randomization(Visit 3), Week 1 (Visit 4), Week 6
(Visit 5), Week 12 (Visit 6), Week 15 (Visit 7) and ET. 
7.5.2. Patient Health Questionnaire-8 (PHQ), Appendix 3.
The PHQ-8 (See Appendix 3) is a self-administered version of the PRIME-MD 
diagnostic instrument for common mental disorders.  The PHQ-9 is the depression 
module, which scores each of the 9 DSM-IV criteria as 0 (not at all) to 3 (nearly every 
day).15  The PHQ-8, a validated subset of the PHQ-9, which comprises the first 8 items 
of the measure, will be completed by subjects at Screening (Visit 1). 
7.5.3. Suicidality Assessments 
During Screening
A risk assessment should be done by a qualified mental health professional (MHP: a 
psychiatrist or licensed PhD level clinical psychologist) to assess whether it is safe for 
the subject to participate in the trial if at least one of the following three conditions are 
met:

Subject’s responses on the S-STS items 1a, 1b, 3 and 4, 5, 6, or 8 is positive 
(score 1);
or


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
Subject’s Total PHQ- 8 score 15;
or

Presence of any current major psychiatric disorder that is not explicitly 
permitted in the inclusion/exclusion criteria.
A written copy of the risk assessment should be included in the subject’s clinical record 
(source documentation).
During the Clinical Trial:
At the Baseline and post-baseline visits, if there are any positive response on the S-STS 
(since last visit version) items 1a, 1b, 3, 4, 5, 6, or 8, a risk assessment should be done by 
a qualified MHP to determine whether it is safe for the subject to continue to 
participate in the trial. Subjects who have a positive response on S-STS items 1a, 1b, 3 
and 4, 5, 6, or 8 on more than one occasion during a trial must have their potential 
suicidality managed appropriately by the PI together with a qualified MHP (or the PI 
alone if the PI is a qualified MHP). In addition, the PI should consult with the Pfizer 
medical monitor to determine whether the subject can continue the trial.  
7.6. Patient Assessment of Seizure Frequency 
Global change of seizure frequency will be rated as increased, no change or decreased 
by patient at Visit 6 (Week 12) or Early Termination (ET).
26. Section 8. ADVERSE EVENT REPORTING, 8.1. Adverse Events, 2nd paragraph, 
last sentence
Addition
The pregabalin Core Data Sheet (CDS) is the Single Safety Reference Document for this 
study and will be used in determining expected versus unexpected adverse events.
27. Section 8. ADVERSE EVENT REPORTING, 8.2. Reporting Period, 2nd paragraph
Change From

Adverse events (serious and non-serious) should be recorded on the CRF beginning 
with the Week -1 Screening Visit through the last subject visit.
Change To

Adverse events (serious and non-serious) should be recorded on the CRF beginning 
with the Screening Visit through the last subject visit.


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28. Section 8. ADVERSE EVENT REPORTING, 8.6. Hospitalization, 1st paragraph
Change From
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization areprolongation of hospitalization is 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).
Change To
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization is 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).
29. Section 9. DATA ANALYSIS/STATISTICAL METHODS, 9.4.5. Other Safety 
Measurements
Change From
Other safety parameters, including adverse events, physical examination results, vital signs, 
body weight, clinical laboratory results, and subject assessment of seizure frequency as 
compared to before taking study medication, and Sheehan Sucidality Tracking Scale 
(S-STS), Appendix 2 will be summarized by treatment group, but not analyzed inferentially.
Change To
Other safety parameters, including adverse events, physical examination results, vital signs, 
body weight, clinical laboratory results, and subject assessment of seizure frequency as 
compared to before taking study medication, and Sheehan Sucidality Tracking Scale (S-STS) 
Appendix 2, will be summarized by treatment group, but not analyzed inferentially.
30. Section 12. ETHICS, 12.4. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP
Addition
12.4. 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.  


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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.
31. Section 13. DEFINITION OF END OF TRIAL, 13.1. End of Trial in all 
Participating Countries, 13.2. End of Trial in a Member State of European Union
Additions
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit.
13.2. End of Trial in a Member State of European Union
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 Study 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.
32. Section 15. PUBLICATION OF TRIAL RESULTS, 15.1. Communication of Results 
by Pfizer, 15.2. Publications by Investigators
Additions
15.1 Communication of results by Pfizer:
Pfizer fulfils its commitment to publicly disclose the results of studies through posting 
the results of this study on ClinicalStudyResults.org.  Pfizer posts the results of studies 
that fall into either of the following categories:

Studies that Pfizer registered on www.clinicaltrials.gov, (ClinicalTrials.gov) 
regardless of the reason for registration; OR

All other studies for which the results have scientific or medical importance as 
determined by Pfizer.

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:


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
For studies involving products already approved in any country and for studies 
that do not involve a Pfizer product, Pfizer posts results within one year after 
study completion, defined as 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 one year after the first 
regulatory approval of the product;

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year after such discontinuation.
Pfizer's posting on ClinicalStudyResults.org includes the following elements:

Protocol title, study phase, and indication;

A link to approved product labeling, if applicable;

The synopsis of study results;

Citations of known study publications;

Legal disclaimer.
The study results synopsis posted on ClinicalStudyResults.org (called the PhRMA 
website synopsis) uses the format established by the ICH-E3 Clinical Study Report 
(CSR) Synopsis. Study results will be posted to ClinicalStudyResults.org within one 
year of last subject last visit.  For all studies subject to the FDA Amendments Act Title 
VIII and the state of Maine disclosure legislation, Pfizer also posts data in the basic 
results database on clinicaltrials.gov within 1 year of the primary outcome completion 
date.
Pfizer posts citations only for publications that are accessible in recognized (searchable) 
publication databases. Single-centre results publications for a multi-centre study are 
generally not posted because they may not accurately reflect the results of the study.
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. 


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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.
33. Section 16. REFERENCES, numbers 1, 2, 13, 14
Additions, then references renumbered 
1. Lyrica USPI, Pfizer Inc, April 2009
2. Lyrica SPC, Pfizer Inc, 
http://emc.medicines.org.uk/medicine/14651/SPC/Lyrica+Capsules/
13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine.  Nephron 1976;16:31-41.
14. Kroenke, K, Spitzer, R.LThe PHQ-9. A new depression diagnostic and severity 
measure. Psychiatric Annals .2002; 32 (9): 1-7.
34. Section APPENDICES, Appendix 2, Sheehan-Suicidality Tracking Scale (S-STS), 
and Appendix 3, Patient Health Questionnaire (PHQ-8)
Additions
Appendix 2 Sheehan-Suicidality Tracking Scale (S-STS)


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Appendix 3. Patient Health Questionnaire (PHQ-8)

SAP_001.pdf: 
Protocol A0081096
Statistical Analysis Plan
_____________________________________________________________________
PFIZER CONFIDENTIAL
Page 1
PROTOCOL A0081096
PROSPECTIVE RANDOMIZED 12-WEEK CONTROLLED 
STUDY OF VISUAL FIELD CHANGE IN SUBJECTS WITH 
PARTIAL SEIZURES RECEIVING PREGABALIN OR
PLACEBO
STATISTICAL ANALYSIS PLAN 
(SAP)
Version: 
Authors: 
(Clinical Statistics, 
) - Version 1
, Ph.D. (Clinical Statistics, 
) – Version 2
 (Study Statistician, 
) – Version 3
 (Clinical Statistics, 
) – Version 4
 (Clinical Statistics, 
) – Version 5)
Dates: 
24 August 2006 – Version 1
07 July 2008 – Version 2
23 March 2012 – Version 3
10 February 2016 – Version 4
30 September 2020 – Version 5
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
List of Abbreviations Used
AE
Adverse Event
ANCOVA
Analysis of Covariance 
CI
C-SSRS
SBQ-R
MHRA
Confidence Interval
Columbia Suicide Severity Rating Scale
Suicide Behaviors Questionnaire 
Mental Health Risk Assessment
C-CASA
Columbia-Classification Algorithm of Suicide Assessment
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
United States Food and Drug Administration
GABA
Gamma-aminobutyric Acid
IRC
Internal Review Committee
MD
Mean Deviation
MedDRA
The Medical Dictionary for Regulatory Activities
PASS
Post-Authorization Safety Studies
PHQ
Patient Health Questionnaire
PT 
Preferred Term
SPERT
Safety Planning, Evaluation and Reporting Team
S-STS
Sheehan Sucidality Tracking Scale
VFT
Visual Field Test
VA
ETDRS
Visual Acuity
Early Treatment Diabetic Retinopathy Study


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION ...............................................................................................................14
2.1. Study Design ...........................................................................................................15
2.2. Study Objectives .....................................................................................................18
2.3. Statistical Power and Sample Size Considerations .................................................18
3. INTERIM ANALYSES, DATA MONITORING COMMITTEE, FINAL 
ANALYSES AND UNBLINDING....................................................................................19
4. HYPOTHESES AND DECISION RULES.........................................................................19
4.1. Statistical Hypotheses .............................................................................................19
4.2. Statistical Decision Rules........................................................................................19
5. ANALYSIS SETS ...............................................................................................................19
5.1. Full Analysis Set .....................................................................................................19
5.2. ‘PER PROTOCOL’ Analysis Set............................................................................20
5.3. Safety Analysis Set..................................................................................................20
5.4. OTHER ANALYSIS SETS ....................................................................................20
5.5. Treatment Misallocations........................................................................................20
5.6. Protocol Deviations.................................................................................................20
6. ENDPOINTS AND COVARIATES ...................................................................................21
6.1. Efficacy Endpoint(s) ...............................................................................................21
6.2. Safety Endpoints .....................................................................................................21
6.3. Other Endpoints.......................................................................................................22
6.4. Covariates................................................................................................................22
7. HANDLING OF MISSING VALUES ................................................................................23
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................23
8.1. Statistical METHODS.............................................................................................23
8.2. Statistical Analyses .................................................................................................25
8.2.1. Primary Analysis ........................................................................................25
8.2.2. Secondary Analyses....................................................................................25
8.2.3. Other Safety Analyses ................................................................................26


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 4
 
26
8.2.3.2. Suicidal Ideation and Behavior Assessment (S-STS/C-
SSRS) ................................................................................................27
8.2.3.3. Ophthalmologic Assessment (Dilated Funduscopic), 
PHQ-8, SBQ-R, MHRA....................................................................27
8.2.4. Prior and Concomitant Medications...........................................................27
8.2.5. Summary of Safety Analyses......................................................................28
9. REFERENCES ....................................................................................................................29
10. APPENDICES ...................................................................................................................30
10.1. A.1.1 Definition and Use of Visit Windows in Reporting....................................30
10.2. A.1.2 Additional Considerations for Determination of Visual Field 
Deterioration..............................................................................................................31
10.3. A.1.3 Calculation of Visual Acuity Score.............................................................33
34
10.5. A.1.5 Sheehan-Suicidality Tracking Scale (S-STS)..............................................35
10.6. A.1.6- Columbia – Suicide Severity Rating Scale (C-SSRS) ...............................37
LIST OF TABLES
Table 1.
Study 1096 Sample Size and Power for the Secondary Endpoint.............18
Table 2.
Study 1096 Sample Size and Power for the Primary Endpoint ................18
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................30
CCI
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Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 5
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
The statistical analysis plan (Version 2, dated July 07th, 2008) has been amended to 
incorporate the changes in conjunction with the amendment of the study protocol dated 
December 12th, 2011.  
The SAP (Version 3, dated March 23rd, 2012) has been amended to incorporate the changes 
in conjunction with the study protocol dated December 15th, 2015.
The statistical analysis plan (SAP) has been also amended to redefine the visits for the 
analyses of the study endpoints (eg, visual field test, visual acuity, and mean deviation).
Section A.1.3 has been added to define the algorithm for visual acuity scoring. Changes 
made to the previous version have been summarized below:
Version
Date
Author(s)
Summary of Changes/Comments
2
July 
07, 
2008
 
3
March 
23, 
2012
Changes in Section 2 Introduction:
Old: This study is being performed as a Phase IV 
commitment to assess visual fields in subjects taking 
pregabalin as compared to placebo.
To: The purpose of this statistical analysis plan is to
outline the proposed statistical analysis methods for 
protocol A0081096. This analysis plan provides 
additional details concerning the statistical analyses that 
were originally outlined in the study protocol A0081096 
dated December 12th 2012.
Pregabalin (Lyrica®) has been approved in over 
110 countries to date for varying neuropathic pain 
indications and for adjunctive treatment of patients with 
partial seizures and for generalized anxiety disorder.  
Lyrica is approved in the United States for management 
of neuropathic pain associated with diabetic peripheral 
neuropathy or postherpetic neuralgia, for the adjunctive
treatment of adult patients with partial onset seizures, 
and for management of fibromyalgia.  Lyrica is 
approved in European Union countries for the treatment 
of peripheral neuropathic pain, adjunctive treatment of 
partial seizures with or without secondary 
generalization, and for the treatment of generalized 
anxiety disorder.  Since initial market approval of 
Lyrica in 2004 through Jan 31, 2011, it is estimated that 
more than 11,700,000 patient years of exposure will 
have accumulated worldwide.  More detailed 
PPD
PPD


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 6
information, including efficacy results in adults and the 
possible risks associated with administration of 
pregabalin, are summarized in the Core Data Sheet.
Prospectively planned ophthalmologic assessments, 
including visual acuity testing, formal visual field testing 
and dilated funduscopic examination, were performed in 
the pregabalin clinical development program for all of 
the initial indications.
Formal visual field testing was conducted in over 
2400 patients treated with pregabalin for neuropathic 
pain, chronic pain syndromes, intractable epilepsy, or 
generalized anxiety disorder in randomized controlled 
clinical trials of up to 3 months in duration and in over 
3600 patients in open-label trials of up to 4 years in 
duration.  Ophthalmologic assessments were included in 
the program due to concerns expressed at the time on 
emerging reports of visual field disturbances with the 
anticonvulsant vigabatrin, a gamma-aminobutyric acid 
(GABA)-transaminase inhibitor.  The mechanism of the 
visual field defects with vigabatrin is unknown but was 
considered as possibly related to its GABA mechanism.  
As a structural derivative of GABA, regulatory agencies
considered similarity of pregabalin to vigabatrin as 
possible.  Subsequently, it became clearer that the 
mechanism of action of pregabalin was not related to 
GABA-transaminase inhibition or to a GABA related 
mechanism.  While the mechanism of action of 
pregabalin is not completely understood, results in 
animal models indicate that binding to the alpha-2-delta 
subunit of voltage-gated calcium channels may be 
involved in the activity of pregabalin.
In controlled pregabalin studies, a higher proportion of 
patients treated with pregabalin reported blurred vision 
(6%) than did patients treated with placebo (2%), which 
resolved in the majority of patients during treatment.  In 
patients assessed with prospectively planned 
ophthalmologic testing, visual acuity was reduced in 7% 
of patients treated with pregabalin, and 5% of 
placebo-treated patients.  Visual field changes were 
detected in 13% of pregabalin-treated, and 12% of 
placebo-treated patients.  Funduscopic changes were 
observed in 2% of pregabalin-treated and 2% of 
placebo-treated patients.


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 7
This study is a Post-Authorization Safety Studies (PASS).  
It is being conducted as a commitment agreed upon with 
the United States Federal Drug Administration (FDA) 
regulatory agency.
Changes in Section 2.1 Study Design:
Old: This is a Phase IV, multicenter, double-blind, 
randomized controlled trial to measure visual field 
sensitivity in subjects with partial epilepsy dosed with 
pregabalin or placebo.  Pregabalin will be dosed at 
300 mg/day for 11 weeks after one-week initiation with 
150 mg/day, followed by one-week tapering of 
150 mg/day.
To: This is a Phase IV, multicenter, double-blind, 
randomized, placebo-controlled trial to measure visual
field sensitivity in subjects with partial epilepsy dosed 
with pregabalin or placebo.  Pregabalin will be dosed at 
300 mg/day for 11 weeks after one-week initiation with 
150 mg/day, followed by one-week tapering of 
150 mg/day. Total treatment period will be 13 weeks.
Changes in Section 2.2 Study Objectives:
Old: The objective of the study is to monitor visual 
fields in subjects with partial epilepsy receiving 
pregabalin or placebo for 12 weeks under highly 
controlled conditions.
To: The objective of the study is to evaluate visual fields 
in subjects with partial epilepsy receiving 12 weeks 
treatment of pregabalin compared to placebo.
Old: The primary endpoint is the proportion of subjects 
with a decrease in the threshold value from baseline to 
termination for any five points (in either eye) at the 
p<0.05 level repeated in the same five points on 
subsequent computerized automated perimetry testing 
(Humphrey 24-2 SITA standard).
To: The primary endpoint is the proportion of subjects 
with a decrease in the threshold value from baseline to 
termination in any five or more points (in either eye) at 
the p<0.05 level repeated in the same five points on 
subsequent computerized automated perimetry testing 
(Humphrey 24-2 SITA standard). The primary endpoint 


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8
will be analyzed using a non- inferiority analysis.
A new Section 2.3 Statistical Power and Sample Size 
Considerations has been included 
Changes in Section 3 Interim Analyses, Final 
Analyses and Unblinding:
Old: Interim Analyses, Final Analyses and Unblinding
To: Interim Analyses, Data Monitoring Committee, 
Final Analyses, and Unblinding
Old: No interim analyses are planned.
To: No interim analysis has been planned for this study.
This study will use an Internal Review Committee (IRC).
The IRC for this study will be independent of the study 
team and will not be involved in the conduct of the study
otherwise. The Pfizer colleagues comprising the 
independent IRC and their responsibilities will be 
defined in an IRC Charter.  The IRC will be responsible 
for ongoing monitoring of the safety of subjects in the 
study according to the Charter. Communication between 
the IRC and the Study Team will be from the IRC Chair
to the clinical lead or delegate to the Study Team. The 
possible IRC recommendations and the method of 
communicating the IRC recommendations will be stated 
in the Charter. 
Changes in Section 5.1 Full Analysis Set:
Old: The Full Analysis Set (referred to in the protocol as 
the intent-to-treat (ITT) population) is defined as all 
subjects randomized to treatment who received at least 
one dose of study medication.  Since data will not be 
imputed for patients who do not have a baseline or for 
patients who do not have post-baseline data for a 
specific parameter, such patients will not be in the FAS 
for that parameter.
To: The Full Analysis Set (referred to in the protocol as 
the intent-to-treat (ITT) population) is defined as all 
subjects randomized to treatment who received at least 
one dose of study medication.  Since data will not be
imputed for patients who do not have a baseline or for 


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 9
patients who do not have post-baseline data for a 
specific parameter, such patients will not be in the FAS 
for that parameter. Subjects who had a decrease in at 
least 5 points at termination but did not return for a 
repeat test will be included in the ITT set and will be 
assumed to have a confirmed decrease for VFT analysis.
Changes in Section 6.2 Safety Endpoints Second 
Paragraph:
Old: The primary endpoint (proportion of patients with 
deterioration) is determined as follows:
A patient with 5 or more points that are p<0.05 at 
termination (ie, a 1 in the database) that were not 
significant (a 0 in the database) at baseline is required to 
have a repeat test.  If at the repeat test 5 or more of the 
same points are p<0.05, then that patient is considered to 
have deterioration. This comparison is done separately 
for each eye, and a patient is considered to have 
deterioration if this is true for either eye.
To: The primary endpoint (proportion of patients with 
deterioration) is determined as follows: Baseline and all 
other visits for visual field test (VFT) will be based on 
the visits defined by the central reader. There are 2 tests 
performed for the Screening visit, these values will not 
be used for baseline determination. A point will be 
considered abnormal at baseline only if it was abnormal 
(p<0.05) at both baseline tests. A patient with 5 or more 
points that are p<0.05 at termination (ie, a value of 1 in 
the database) that were not significant (a 0 in the 
database) at baseline is required to have a repeat test.  If 
at the repeat test 5 or more of the same points are 
p<0.05, then that patient is considered to have 
deterioration. This assessment is done separately for 
each eye, and a patient is considered to have 
deterioration if this is true for either eye.
Old: Mean Deviation (MD) is a global index of visual 
field depression.  The MD ranges from 0 decibels (dB) 
(no defect) to about -32 dB (end-stage damage). Change 
in mean deviation from baseline to termination will be 
computed for each subject.  Baseline mean deviation 
will be the average of the two mean deviations from the 
Baseline visit, and termination will be the mean 
deviation at the Week 12 visit (or the last available after 


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 10
Day 1 for subjects who terminate early). If a repeat test 
was done at termination, the mean deviation from the 
repeat test will be used.  For each subject, the worst eye 
(ie, the eye with the greatest decrease in mean deviation) 
will be used in the analysis.
To: Mean Deviation (MD) is a global index of visual 
field depression.  The MD ranges from 0 decibels (dB) 
(no defect) to about -32 dB (end-stage damage). Change 
in mean deviation from baseline to termination will be 
computed for each subject.  Baseline and all other visits 
for mean deviation will be based on the visits defined by 
the central reader. Baseline mean deviation will be the 
average of the two mean deviations from the Baseline 
visit, and termination will be the mean deviation at the 
Week 12 visit (or the last available after Day 1 for 
subjects who terminate early).  If a repeat test was done 
at termination, the mean deviation from the repeat test 
will be used.  For each subject, the worst eye (ie, the eye 
with the greatest decrease in mean deviation) will be 
used in the analysis.
Old: Visual Acuity (best corrected) is measured using 
ETDRS charts.  It is expressed in terms of number of 
letters correctly identified.  A patient who identified all 
letters correctly in the 20/20 line and all previous lines 
would have a score of 55 letters (as this is the 11th line, 
and there are 5 letters per line).
To: The best corrected visual acuity (with glasses or 
best possible glasses prescription) will be measured 
using the ETDRS charts.  The letters on chart A are read 
using the right eye and chart B using the left eye.  The 
subject starts at the top of the chart and begins to read 
down the chart.  The subject reads down the chart until 
they reach a row where a minimum of three letters on a 
line cannot be read.  The subject is scored by how many 
letters could be correctly identified.  Details of visual 
acuity scoring have been defined in Section A.1.3.
Old: Other safety parameters, including adverse events, 
physical examination results, vital signs, body weight, 
clinical laboratory results, and subject assessment of 
seizure frequency as compared to before taking study 
medication, will be summarized by treatment group, but 
not analyzed inferentially.


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 11
To: Other safety parameters, including adverse events, 
physical examination results, vital signs, body weight, 
clinical laboratory results, and subject assessment of 
seizure frequency as compared to before taking study 
medication, and Sheehan Suicidality Tracking Scale 
(S-STS) will be summarized by treatment group, but not 
analyzed inferentially.
Changes in Section 6.3 Other Endpoints
Old: There are no other endpoints being reported in this 
study.
To: Screening ophthalmologic assessment (Dilated 
Funduscopic) and self-administered Patient Health 
Questionnaire (PHQ-8) will be summarized by treatment 
group.
Changes in Section 8.2.3 Other Safety Analyses
Old: Other safety parameters, including adverse events, 
physical examination results, vital signs, body weight, 
clinical laboratory results, and subject assessment of 
seizure frequency as compared to before taking study 
medication, will be summarized by treatment group, but 
not analyzed inferentially.
To: Other safety parameters, including adverse events, 
physical examination results, vital signs, body weight, 
clinical laboratory results, and subject assessment of 
seizure frequency as compared to before taking study 
medication, and Sheehan Sucidality Tracking Scale 
(S-STS) will be summarized by treatment group, but not 
analyzed inferentially. Ophthalmologic assessment and 
self-administered Patient Health Questionnaire (PHQ-8) 
completed at the screening visit will be summarized by 
treatment group.
 
A new Section 8.2.3.2 Sheehan Suicidality Tracking
Scale (S-STS) has been included.
A new Section 8.2.3.3 Ophthalmologic Assessment 
(Dilated Funduscopic) and Patient Health 
Questionnaire (PHQ-8) has been included.
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Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 12
A new Section 8.2.4 Concomitant Medication has 
been included.
Changes in Section 8.2.5 Summary of Safety 
Analyses:
Old: Missing data for VFT analyses LOCF.
To: Missing data for VFT analyses Not Applicable.
Changes in Appendix A.1.1 Definition and use of visit 
windows in reporting:
Old: Analyses will be conducted using change from 
baseline to the week 12 visit (or the last visit after Day 1 
for patients who discontinue prior to week 12).  
Week 15 follow up assessments (or the assessments 
conducted approximately 2 weeks after discontinuation 
of treatment, for subjects who discontinue early) will be 
excluded from consideration.  Additional considerations 
for determination of Visual Field Deterioration are given 
in section A.1.2.
To: Analyses will be conducted using change from 
baseline to the week 12 visit (or the last visit after Day 1 
for patients who discontinue prior to week 12).  Week 
15 follow up assessments and for early terminators, the 
assessments conducted approximately 2 weeks after 
discontinuation of treatment will be excluded from 
analysis consideration.  
For VFT and MD, Baseline and all other visits including 
the repeat visits will be based on the visits defined by 
the central reader. Additional considerations for 
determination of Visual Field Deterioration are given in 
Section A.1.2.
For visual acuity the following week assignments will be 
used for the planned visits:
Changes in Appendix A.1.2 Additional 
considerations for determination of Visual Field 
Deterioration:
An eye map has been included in Appendix A.1.2 and 
the example table has been updated with the actual test 
points’ names. 


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 13
Appendix A.1.3 Calculation of Visual Acuity Score
has been included.
 
Appendix A.1.5 Sheehan-Suicidality Tracking Scale 
(S-STS) has been included.
4
Feb 16
,2016
As of protocol amendment, dated December 15, 2015 
the following changes has been incorporated: 
1. The Sheehan Suicidality Tracking Scale has been 
replaced by the Columbia Suicide Severity Rating 
Scale (C-SSRS), For subjects who randomized prior 
to Amendment 4, S-STS will be mapped to
Columbia-Classification Algorithm of Suicide 
Assessment (C-CASA) and for subjects who 
randomized after amendment 4, C-SSRS will be 
mapped to  Columbia-Classification Algorithm of 
Suicide Assessment (C-CASA).
2. SBQ-R has been added at screening. 
3. Core Data Sheet (CDS) has been replaced by 
Investigator’s Brochure (IB).  
4. The schedule of activities and introduction text have
been updated accordingly.
5. To be consistent with new version of the protocol, 
some wording has changed in the introduction 
section of this SAP and other section.
6. Additional SAP amendment not related to protocol 
4th amendment:
•
Mental Health Risk Assessment (MHRA);
•
Added the SAS code for primary endpoint.
5
Sep 
30,
2020
1. Per protocol amendment (amendment 5) and
adjusted the sample size and power of the study
using the observed mean deviation (MD) common 
standard deviation (SD = 1.3) from a 15 March 2019 
dataset prepared for the annual IRC review. 
Common SD changed from 5.6 dB from literature1 at 
the time of design of the study to observed common 
SD 1.3 dB
PPD
PPD
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PFIZER CONFIDENTIAL
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2. INTRODUCTION 
The purpose of this statistical analysis plan is to outline the proposed statistical analysis 
methods for protocol A0081096. This analysis plan provides additional details concerning 
the statistical analyses that were originally outlined in the study protocol A0081096 dated 
December 12th 2012, and the subsequent amendment of the protocol dated December 15, 
2015.
Pregabalin (Lyrica) has been approved in over130 countries to date for varying 
neuropathic pain indications and for adjunctive treatment of patients with partial seizures 
and for generalized anxiety disorder.  Lyrica is approved in the United States for 
management of neuropathic pain associated with diabetic peripheral neuropathy or 
postherpetic neuralgia, for the adjunctive treatment of adult patients with partial onset 
seizures, and for management of fibromyalgia.  Lyrica is approved in European Union 
countries for the treatment of peripheral neuropathic pain, adjunctive treatment of partial 
seizures with or without secondary generalization, and for the treatment of generalized 
anxiety disorder.2  Since initial market approval of Lyrica in 2004 through 2014, it is 
estimated that more than 28.5 million patient years of exposure will have accumulated 
worldwide.  More detailed information, including efficacy results in adults and the possible 
risks associated with administration of pregabalin, can be found in the current Investigator 
Brochure (IB).
Prospectively planned ophthalmologic assessments, including visual acuity testing, formal 
visual field testing and dilated funduscopic examination, were performed in the pregabalin 
clinical development program for all of the initial indications.
Formal visual field testing was conducted in over 2400 patients treated with pregabalin for 
neuropathic pain, chronic pain syndromes, intractable epilepsy, or generalized anxiety 
disorder in randomized controlled clinical trials of up to 3 months in duration and in over
3600 patients in open-label trials of up to 4 years in duration.  Ophthalmologic assessments 
were included in the program due to concerns expressed at the time on emerging reports of 
visual field disturbances with the anticonvulsant vigabatrin, a gamma-aminobutyric acid 
(GABA)-transaminase inhibitor.  The mechanism of the visual field defects with vigabatrin is 
unknown but was considered as possibly related to its GABA mechanism.  As a structural 
derivative of GABA, regulatory agencies considered similarity of pregabalin to vigabatrin as 
possible.  Subsequently, it became clearer that the mechanism of action of pregabalin was 
not related to GABA-transaminase inhibition or to a GABA related mechanism.  While the 
mechanism of action of pregabalin is not completely understood, results in animal models 
indicate that binding to the alpha-2-delta subunit of voltage-gated calcium channels may be 
involved in the activity of pregabalin.
In controlled pregabalin studies, a higher proportion of patients treated with pregabalin 
reported blurred vision (6%) than did patients treated with placebo (2%), which resolved in 
the majority of patients during treatment.  In patients assessed with prospectively planned 
ophthalmologic testing, visual acuity was reduced in 7% of patients treated with pregabalin, 
and 5% of placebo-treated patients.  Visual field changes were detected in 13% of 


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 15
pregabalin-treated, and 12% of placebo-treated patients.  Funduscopic changes were 
observed in 2% of pregabalin-treated and 2% of placebo-treated patients.
This study is a Post-Authorization Safety Studies (PASS).  It is being conducted as a
commitment agreed upon with the United States Federal Drug Administration (FDA) 
regulatory agency.
2.1. Study Design
This is a Phase IV, multicenter, double-blind, randomized, placebo-controlled trial to 
measure visual field sensitivity in subjects with partial epilepsy dosed with pregabalin or 
placebo.  Pregabalin will be dosed at 300 mg/day for 11 weeks after one-week initiation with 
150 mg/day, followed by one-week tapering of 150 mg/day. Total treatment period will be 
13 weeks.
Placebo
PGB 75mg
BID
Study Week
- 1
Study Week
2-12 
Screening
Treatment
Follow-up
Study Week
1
PGB 150 mg
BID
PGB 75 mg
BID
Study Week
15
Study Week
13 


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
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Schedule of Activities 
Protocol Activity
Screening
Baseline
Wk 0 
Randomization
Wk 1
Wk 6
Wk 12
(Or ET)
Week 15
(Follow-Up)
Visit Numbern
1
2
3m
4
5
6
7
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
X
History/Diagnosis/Demographics
X
Physical Examinationp
X
X
Concomitant Medication 
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
Vital Signs (Sitting BP/HR)
X
X
X
X
X
ECG (Singlet)
X
EEG
Xa
CT or MRI
Xb
Clinical
1) Hematologyc
X
X
Laboratory
2) Chemistryd
X
X
3) Urinalysise
X
X
Urine Pregnancy Testf
X
X
Urine Drug Screen
X
1) External Eye 
Exam
X
X
Xg
2) ETDRS Acuity
X
X
X
X
Xg
Ophthalmic 
3) Intraocular 
Pressure
X
Examination
4) Dilated 
Funduscopic
X
5) VFT (24-2 
SITA)
Xh,l
Xh,l
Xh
Xh
Xg,h
Patient assessment of seizure 
frequency
X
Investigational product 
Dispensing
Xi,j
Xk
Xk
Xj
Sheehan-Suicidality Tracking 
Scale (S-STS)o,r
X
X
X
X
X
X
X
Columbia-Suicide Severity 
Rating Scale (C-SSRS)o,r
X
X
X
X
X
X
X
Suicidal Behaviors Questionnaire 
– Revised (SBQ-R)r
X
Patient Health Questionnaire–8 
(PHQ-8)
X
Assessment of need to complete a 
risk assessmentr
X
X
X
X
X
X
X
Adverse Events Report
X------------------------------------------------------------------------X


Protocol A0081096
Statistical Analysis Plan
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a.
Subjects who have not had a test within 2 years.  See inclusion criteria 1.
b.
Subjects who have not had a test within 3 years.  See inclusion criteria 4.
c.
Hemoglobin, hematocrit, RBC count, WBC count, platelet count.
d.
Electrolytes (Na, K, Ca, Cl, bicarbonate), creatinine, BUN, glucose, AST, ALT, alkaline phosphatase, bilirubin, CK, 
uric acid, albumin, total protein.
e.
Specific gravity, PH, Glucose (qualitative), Protein (qualitative), Blood (qualitative), Ketones, Nitrite and 
Microscopy if urine dipstick is positive for blood or protein.
f.
Childbearing potential female subjects only.
g.
Subjects who have had visual findings on Week 12 and subsequently confirmed.
h.
A repeat may be necessary upon the confirmation from central reader.
i.
Recommend subject to take first dose in the evening.
j.
Titration/tapering dose.
k.
Treatment dose.
l.
Conduct 2 tests.
m.
Usually occur between the 3rd – 7th day after Baseline (Visit 2) when the verification of VFT is available.
n.
Screening procedures can be completed within 21 days prior to Baseline; Study Visits 4 – 7 have a ±3 days window.
o.
The “Lifetime” assessment is completed at Screening and the “Since Last Visit” assessment is completed at all other 
visits.
p.
Including neurological exam at screening.
q.
A risk assessment must be performed and documented if the subject meets the criteria detailed in Protocol. 
r.
Subjects screened/randomized under Amendment 3 will continue the S-STS for assessment of suicidal ideation and 
behaviour. Subjects screened/randomized under Amendment 4 will have suicidal ideation and behaviour assessed 
by the C-SSRS and the SBQ-R.


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2.2. Study Objectives
The objective of the study is to evaluate visual fields in subjects with partial epilepsy 
receiving 12 weeks treatment of pregabalin compared to placebo.
2.3. Statistical Power and Sample Size Considerations
The study will be powered to show non-inferiority of pregabalin with respect to placebo on 
the mean deviation score from the Humphrey threshold test, a secondary endpoint.
Non-inferiority from placebo will be declared with respect to mean deviation if the lower 
bound of the 95% 2-sided confidence interval of the difference in mean deviation scores 
between pregabalin and placebo is greater than -2.0 decibels (dB). Assuming the mean 
deviation scores to be equal and assuming estimated common standard deviation of 1.3 dB, 
then the proposed sample size of 187 subjects will provide greater than 85% power to show 
non-inferiority of pregabalin to placebo. 
The estimated common standard deviation of 1.3 dB, from the 15 March 2019 dataset 
prepared for the annual Internal Review Committee (IRC) blinded review (refer to 
Section 9.6), was used to re-estimate the sample size for the secondary endpoints. 
Previously, at the time of study design, a common standard deviation of 5.6 dB had been 
used for the sample size determination based on literature.2 Table 1 below used common 
standard deviation (1.3) and the number of enrolled subjects (n=187) to estimate the study 
power.
Table 1.
Study 1096 Sample Size and Power for the Secondary Endpoint
Total Number of 
enrolled subject
Common Standard 
Deviation
Non-inferiority Margin
Power
187
1.3
-2.0
>99.9%
For the primary endpoint, the proposed sample size will provide >99.9% power to show 
non-inferiority of pregabalin to placebo with respect to the proportion of subjects with a 
repeated decrease in the same 5 visual field points, with non-inferiority declared if the upper 
bound of the 95% confidence interval for the difference between pregabalin and placebo 
does not exceed 10% and assuming a proportion of subjects meeting primary endpoint 
definition of 1% for both groups. Table 2 below provided the estimated power for the 
primary endpoint.
Table 2.
Study 1096 Sample Size and Power for the Primary Endpoint
Total Number of 
enrolled subjects
Proportion of 
Subjects Meeting 
Primary Endpoint 
Definition
Non-inferiority 
Margin
Power
187
1%
10%
>99.9%


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3. INTERIM ANALYSES, DATA MONITORING COMMITTEE, FINAL ANALYSES 
AND UNBLINDING 
No interim analysis has been planned for this study.
This study will use an Internal Review Committee (IRC).
The IRC for this study will be independent of the study team and will not be involved in the 
conduct of the study otherwise. The Pfizer colleagues comprising the independent IRC and 
their responsibilities will be defined in an IRC Charter.  The IRC will be responsible for 
ongoing monitoring of the safety of subjects in the study according to the Charter.
Communication between the IRC and the Study Team will be from the IRC Chair to the 
clinical lead or delegate to the Study Team. The possible IRC recommendations and the 
method of communicating the IRC recommendations will be stated in the Charter.
The final analyses will be performed after requirements for final release of the randomization 
codes have been met, and the official database is released.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The null hypothesis is that the proportion of patients with deterioration in the pregabalin 
group is greater than or equal to 10% higher than in the placebo group.  The alternative 
hypothesis is that the difference in proportions (pregabalin minus placebo) is less than 10%.  
That is:
H0: PGB - PBO ≥10%
Ha: PGB - PBO <10%
In these hypothesis statements π is the parameter for the proportion of patients with 
deterioration in the respective treatment group.
4.2. Statistical Decision Rules
The difference in proportions between pregabalin and placebo will be compared using a 2-
sided 95% confidence interval (CI). Non-inferiority will be demonstrated if the upper CI 
bound is less than 0.10 (10%).
5. ANALYSIS SETS
5.1. Full Analysis Set
The Full Analysis Set (referred to in the protocol as the intent-to-treat (ITT) population) is 
defined as all subjects randomized to treatment who received at least one dose of study 
medication.  


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Since data will not be imputed for patients who do not have a baseline or for patients who do 
not have post-baseline data for a specific parameter, such patients will not appear in the FAS 
analyses for that parameter. Subjects who had a decrease in at least 5 points at termination 
but did not return for a repeat test will be included in the FAS set and will be assumed to 
have a confirmed decrease for VFT analysis. Termination is the VFT performed at Week 12 
or the last available post-treatment VFT for subjects who did not complete the study (per 
Protocol Section 9.4.1). 
5.2. ‘PER PROTOCOL’ Analysis Set 
The primary analysis will be performed on the Per Protocol population.  
The Per Protocol population is a subset of the ITT population, and excludes subjects who 
had a decrease in at least 5 points at termination but did not return for a repeat test.  The 
Per Protocol population may also exclude subjects with major protocol violations; the list of 
subjects excluded will be determined prior to breaking the blind. The expectation is that the 
PP subset will be close in the number of subjects to the to the number of subjects 
randomized.
5.3. Safety Analysis Set
In this study, all parameters to be analyzed are safety parameters. The primary analysis of 
the primary parameter will be performed using the Per Protocol population, with a 
supplementary analysis that uses the ITT population.  All other safety data will be 
summarized using the ITT population.  
5.4. OTHER ANALYSIS SETS
Not applicable.
5.5. Treatment Misallocations 
Subjects who were:

Randomized but not treated are not in the ITT population and will thus be excluded 
from all safety summaries.

Randomized but took incorrect treatment will be reported under the treatment actually 
received for all safety summaries.
5.6. Protocol Deviations
The list of protocol deviations will be compiled prior to database closure.  Subjects who had 
a decrease in at least 5 points at termination (the Week 12 VFT or last available post-
treatment VFT) but did not return for a repeat test will be excluded from the Per Protocol 
population, as will patients with certain protocol deviations (to be determined based on 
clinical judgment prior to breaking the blind.


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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
Not applicable, as this is a safety study without efficacy endpoints.
6.2. Safety Endpoints
Primary Endpoint:
The primary endpoint is the proportion of subjects with a decrease in the threshold value
from baseline to termination in any five or more points (in either eye) at the p<0.05 level 
repeated in the same five points on subsequent computerized automated perimetry testing 
(Humphrey 24-2 SITA standard).
The primary endpoint is derived from the Humphrey 24-2 SITA Standard visual field 
analyzer.  For each eye there are 52 test points. For each test point, the Humphrey analyzer
determines the threshold value for sensitivity to light by the subject.  In addition, for each of 
the 52 points, the test provides probabilities (p<0.05, p<0.02, etc) that a patient with normal
vision of the same age would have the same result, ie, that the measured value at that point 
was at or below the respective percentile of the age-specific empiric distribution at that 
position of the field for normal subjects. For each of the 52 test points for each eye, the data 
received from the Central Reader will contain a 1 if p<0.05 or a 0 otherwise. (see 
Appendix A.1.2).  
The primary endpoint (proportion of patients with deterioration) is determined as follows:
Baseline and all other visits for visual field test (VFT) will be based on the visits defined by 
the central reader. There are 2 tests performed for the Screening visit, these values will not 
be used for baseline determination. A point will be considered abnormal at baseline only if it 
was abnormal (p<0.05) at both baseline tests. A patient with 5 or more points that are 
p<0.05 at termination (ie, a value of 1 in the database) that were not significant (a 0 in the 
database) at baseline is required to have a repeat test.  If at the repeat test 5 or more of the 
same points are p<0.05, then that patient is considered to have deterioration.  This assessment 
is done separately for each eye, and a patient is considered to have deterioration if this is true 
for either eye.
Secondary Endpoints:
Mean Deviation (MD) is a global index of visual field depression.  The MD ranges from 
0 decibels (dB) (no defect) to about -32 dB (end-stage damage). Change in mean deviation 
from baseline to termination will be computed for each subject.  Baseline and all other visits 
for mean deviation will be based on the visits defined by the central reader and study 
treatment dates. Baseline mean deviation will be the average of the two mean deviations 
from the Baseline visit, and termination will be the mean deviation at the Week 12 visit (or 
the last post-treatment values available after Day 1 for subjects who terminate early).  If a 
repeat test was done at termination, the mean deviation from the repeat test will be used.  
For each subject, the worst eye (ie, the eye with the greatest decrease in mean deviation) will 
be used in the analysis.


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The best corrected visual acuity (with glasses or best possible glasses prescription) will be
measured using the Early Treatment Diabetic Retinopathy Study( ETDRS) charts.  The letters on 
chart A are read using the right eye and chart B using the left eye.  The subject starts at the 
top of the chart and begins to read down the chart.  The subject reads down the chart until 
they reach a row where a minimum of three letters on a line cannot be read.  The subject is 
scored by how many letters could be correctly identified.  Details of visual acuity scoring 
have been defined in Appendix A.1.3. Change in visual acuity from baseline to termination 
will be computed for each subject.  Baseline will be defined as the last visual acuity 
assessment prior to receiving study medication, and termination will be the visual acuity 
assessment at the Week 12 visit (or the last post-treatment assessment available after Day 1 
for subjects who terminate early).  If acuity was assessed at a repeat visit at termination, the 
acuity from the repeat test will be used.  For each subject, the worst eye (ie, the eye with the 
greatest decrease in visual acuity) will be used in the analysis.  
Other Safety Endpoints:
Other safety parameters, including adverse events, physical examination results, vital signs, 
body weight, clinical laboratory results, and subject assessment of seizure frequency as
compared to before taking study medication. Sheehan Suicidality Tracking Scale (S-
STS),and Columbia Suicide Severity Scale (C-SSRS) will be summarized by treatment group, 
but not analyzed inferentially. For subjects who randomized prior to Amendment 4, -STS
will be mapped to Columbia-Classification Algorithm of Suicide Assessment (C-CASA) and 
for subjects who randomized after amendment 4, C-SSRS will be mapped to Columbia-
Classification Algorithm of Suicide Assessment (C-CASA) before being analysed.
Any adverse events (AE) occurring following start of treatment should be counted as 
treatment emergent.  Events that occur in a non-treatment period after treatment was initiated 
(for example, washout or follow-up) will be counted as treatment emergent and attributed to 
treatment.
6.3. Other Endpoints 
Screening ophthalmologic assessment (Dilated Funduscopic), SBQ-R and self-administered 
Patient Health Questionnaire (PHQ-8) will be summarized for both treatments combined and
by treatment group.  For subjects who require Mental Health Risk Assessment (MHRA), it 
may be assessed at screening, baseline and post treatment, eg, for those subjects who require 
evaluation.
6.4. Covariates 
The covariate for Mean Deviation is the baseline MD, which is the average of the two mean 
deviations from the Baseline visit.
The covariate for Visual Acuity is the baseline visual acuity, defined as the last visual acuity 
assessment prior to receiving study medication.


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7. HANDLING OF MISSING VALUES
For each endpoint, if the Week 12 test is missing then the last available post-treatment test 
after Day 1 will be used, eg, a last observation carried forward (LOCF) approach will be 
taken.  Data will not be imputed for subjects who do not have any VFTs or visual acuity tests 
after baseline or for subjects who do not have a baseline; rather such subjects will not 
contribute to the analysis of that endpoint.
Subjects who had a decrease in at least 5 points at termination but did not return for a return 
test will be excluded from the Per Protocol set.  In the analysis of the ITT population, such 
patients will be assumed to have a confirmed decrease.  
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical METHODS 
The primary analysis will compare the difference in proportions for the primary endpoint
(based on a 2x2 contingency table combined across centers) using a 2-sided 95% confidence 
interval.  Because it is expected that the proportions will be small for each treatment group, 
unconditional exact methods (StatXact or Proc-StatXact)2 will be used to compute the 
confidence interval. Or the following code may be used.
/***
***  Hypothetic Example of calculated Exact approximation 95% CI 
***  where there are 4 cases of deterioration and all 4 belong to PGB
***/
%macro pairs(x1px2=,nper=);
%do x1=0 %to &x1px2;
  data a;
  x2=&x1px2 -&x1;
  r=0; d=1; w=&nper-&x1; output;
  r=1; d=1; w=&x1; output;
  r=0; d=2; w=&nper - x2; output;
  r=1; d=2; w=x2; output;
  run;
proc freq data=a;


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  tables d*r / norow nocol nopct exact riskdiff(cl=newcombe); 
   exact riskdiff(method=score);
   weight w;
   output out=diffs riskdiff;
run;
data diffs2; set diffs;
keep x1 n1 x2 n2 _rdif2_ xl_rdif2 xu_rdif2;
x1=&x1; n1=&nper; x2=(&x1px2 - &x1); n2=&nper;
run;
proc append base=pairvary data=diffs2; run;
%end;
%mend pairs;
************************************;
%pairs(x1px2=4,nper=142); * where there are 4 cases of deterioration 
                            and all 4 belong to PGB
run;


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Continuous measures (MD, visual acuity) will be analyzed using an ANCOVA main effects 
model, with treatment and study center in the model and the respective baseline score as a 
covariate.  Output from the ANCOVA models will include adjusted (least squares) means 
and standard errors for each treatment group, p-values for the pregabalin versus placebo 
comparison, and 95% confidence intervals on the difference in LS means between pregabalin 
and placebo.
The only time point analyzed is Week 12 (or last observation, for patients who terminate 
early).  Ophthalmologic data collected at Week 6 and follow-up will be summarized 
descriptively but not analyzed inferentially, unless it is used as the termination time point in 
the primary analysis
Centers with fewer than 4 patients will be combined with other centers prior to breaking the 
blind.  Centers with 4 or more patients may be combined with other centers as needed, or 
may be left as separate centers.  The pooling will be done geographically if possible.  These 
pooled centers will be used in place of center in the analyses that include center in the model.
8.2. Statistical Analyses 
8.2.1. Primary Analysis
The primary endpoint will be analyzed using a non- inferiority analysis. The difference in 
proportions between pregabalin and placebo in the per protocol population will be 
compared using a 2-sided 95% confidence interval (CI).  Non-inferiority will be 
demonstrated if the upper CI bound is less than 0.10 (10%).
The primary analysis is based on the Per Protocol set and the primary endpoint proportion of 
patients with visual field deterioration.  A 2-sided 95% confidence interval on the difference 
in proportions between pregabalin and placebo will be constructed using unconditional exact 
methods.  To support interpretation of the primary analysis, an analysis as described above
but based on the ITT population rather than the Per Protocol set, will be performed.  In this 
analysis, patients with a decrease in ≥5 points at termination but no repeat visit will be 
treated as if they did have a repeat visit that confirmed the decrease. 
8.2.2. Secondary Analyses
Mean Deviation
Change in mean deviation from baseline to termination will be computed for each subject.  
Baseline mean deviation will be the average of the two mean deviations from the Baseline 
visit, and termination will be the mean deviation at the Week 12 visit (or the last available 
after Day 1 for subjects who terminate early).  If a repeat test was done at termination, the 
mean deviation from the repeat test will be used. For each subject, the worst eye (ie, the eye 
with the greatest decrease in mean deviation) will be used in the analysis.  Change in mean 
deviation will be analyzed for the ITT population using analysis of covariance (ANCOVA), 
with treatment and center in the model and the baseline mean deviation as the covariate.  
Least squares means will be obtained from the model and a 2-sided 95% confidence interval 
will be constructed on the difference in least squares means between pregabalin and placebo.  


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Non-inferiority with respect to mean deviation will be demonstrated if the lower bound of the 
CI is greater than –2.0 dB.
Visual Acuity
Visual acuity (best-corrected, measured using ETDRS charts) is expressed in terms of 
number of letters correctly identified.  Change in visual acuity from baseline to termination 
will be computed for each subject.  Baseline will be defined as the last visual acuity 
assessment prior to receiving study medication, and termination will be the visual acuity 
assessment at the Week 12 visit (or the last available after Day 1 for subjects who terminate 
early).  If acuity was assessed at a repeat visit at termination, the acuity from the repeat test 
will be used.  For each subject, the worst eye (ie, the eye with the greatest decrease in visual 
acuity) will be used in the analysis.  Change in visual acuity will be analyzed for the ITT 
population using ANCOVA, with treatment and center in the model and the baseline acuity 
as the covariate.
8.2.3. Other Safety Analyses
Other safety parameters, including adverse events, physical examination results, vital signs, 
body weight, clinical laboratory results, subject assessment of seizure frequency as
compared to before taking study medication, and S-STS/C-SSRS will be summarized by 
treatment group, but not analyzed inferentially. Screening ophthalmologic assessment 
(Dilated Funduscopic), SBQ-R and self-administered Patient Health Questionnaire (PHQ-8)
will be summarized for both treatments combined and by treatment group.  Mental Health 
Risk Assessment (MHRA) will be summarized at screening, baseline and post treatment.
 
 
 
 
 
 
 
CCI


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8.2.3.2. Suicidal Ideation and Behavior Assessment (S-STS/C-SSRS)
Both S-STS and C-SSRS will be mapped to Columbia-Classification Algorithm of Suicide 
Assessment (C-CASA) codes described in Appendix A.1.5 and will be summarized 
descriptively by visit using count (percentage) for each C-CASA category. Percentages in a 
given visit will be based on the number of subjects assessed in that visit in the respective 
treatment groups.
The S-STS and C-SSRS data will also be presented in data listing.
8.2.3.3. Ophthalmologic Assessment (Dilated Funduscopic), PHQ-8, SBQ-R, MHRA
The external eye exam and funduscopic examination (normal/abnormal/not done) conducted 
at screening will be summarized descriptively using count (percentage) by treatment group.
The 8-question PHQ will be summarized for each question by its response categories using 
count and percentages. Percentages will be based on the number of subjects who answered 
the question in the respective treatment groups.
Ophthalmologic assessment and PHQ-8 data will also be presented in data listing. 
Summary, using count and percentages, and listing of screening Suicide Behavior 
Questionnaire (SBQ-R) will be provided by treatment group.
Mental Health Risk Assessment (MHRA) will be summarized at screening, baseline and post 
treatment and presented in a data listing
8.2.4. Prior and Concomitant Medications
Prior and concomitant medications will be summarized for each treatment group. All 
medications will also be presented in data listing.


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8.2.5. Summary of Safety Analyses 
Endpoint
Analysis 
Set
Statistical 
Method 
Model/ 
Covariates/ 
Strata
Missing 
Data
Interpretation
Proportion of patients 
with a deterioration in 
visual field threshold
Per 
Protocol
Confidence 
interval on 
difference
Treatment
Not 
Applicable
Primary Analysis. Subjects with a 
decrease in ≥5 points at termination are 
required to have a repeat assessment to 
be part of the analysis. 
Proportion of patients 
with a deterioration in 
visual field threshold
ITT
Confidence 
interval on 
difference
Treatment 
Not 
Applicable
Check for robustness of primary 
analysis. In this analysis, patients with 
a decrease in ≥5 points at termination 
but no repeat assessment will be treated 
as if they did have a repeat visit that 
confirmed the decrease.
Mean Deviation (MD)
ITT
ANCOVA
Treatment, 
Center/
Baseline MD
LOCF
Secondary Analysis
Visual Acuity
ITT
ANCOVA
Treatment, 
Center/
Baseline Acuity
LOCF
Secondary Analysis


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9. REFERENCES 
1.
Musch DC, Gillespie BW, Motyka BM, Nizoil LM, Mills RP, Lichter PR.  Converting 
to SITA-Standard from Full-Threshold  Visual Field Testing in the Follow-Up Phase of 
a Clinical Trial.  Invest Ophthalmol Vis Sci 2005; 46:2755-2759.
2.
StatXact: Statistical Software for Exact Nonparametric Inference.   CYTEL Software 
Corporation.  Cambridge, MA.


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10. APPENDICES
Appendix 1. DATA DERIVATION DETAILS
10.1. A.1.1 Definition and Use of Visit Windows in Reporting
Analyses will be conducted using change from baseline to the week 12 visit (or the last visit 
after Day 1 for patients who discontinue prior to week 12).  Week 15 follow up assessments 
and for early terminators, the assessments conducted approximately 2 weeks after 
discontinuation of treatment will be excluded from analysis consideration.  
For VFT and MD, Baseline and all other visits including the repeat visits will be based on the
visits defined by the central reader in conjunction with the dates when treatment was 
administered. Additional considerations for determination of Visual Field Deterioration are 
given in Appendix A.1.2.
For visual acuity the following week assignments will be used for the planned visits: 
Time (Windowed 
Week)
Range (Days*)
Target 
Day
Baseline
[-99 to 1]
1
Week 6
[2 to 62]
42
Week 12
[63 to 95]
84
Week 15 Follow-up 
≥96
105
LOCF** Week 12 
[2 to 95]
84
*For purposes of windowing, a derived Day will be defined as (Visit Date-First Dose Date) + 1, where Visit 
Date is a follow-up visit that is greater than the baseline visit. Brackets indicate bound value is included in the 
window. In the case of two competing visits that are equally distant to the target day, the first visit will be 
selected as the assigned Week.
**LOCF imputation will be used only if the subject has missing data for Day 84 (Week 12), otherwise the Day 
84 and Last Visit will be the same. If LOCF imputation is employed, then the first derived Day in the window 
closest to the target day will be chosen as the LOCF Week 12 assignment.
If visual acuity was assessed at a repeat visit or if there are multiple assessments at Week 12 
window, then the latest of the assessments which is within the Week 12 window will be 
considered as the visual acuity at termination.


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10.2. A.1.2 Additional Considerations for Determination of Visual Field Deterioration
Visual Field Deterioration:
There are 52 test points for each eye. Below is an eye map for visual field test. 
1
A
B
C
D
E
F
G
H
I
J
2
2D
2E
2F
2G
3
3C
3D
3E
3F
3G
3H
4
4B
4C
4D
4E
4F
4G
4H
4I
5
5A
5B
5C
5D
5E
5F
5G
5H
5I
5J
6
6A
6B
6C
6D
6E
6F
6G
6H
6I
6J
7
7B
7C
7D
7E
7F
7G
7H
7I
8
8C
8D
8E
8F
8G
8H
9
9D
9E
9F
9G
There are 56 points in the above eye map. While testing the left eye, the points 5A, 6A, 5C, 
and 6C are left blank, of these 5C & 6C represent the blind spots, and 5A & 6A represent the 
points near the left ear. Similarly while testing the right eye, the points 5H, 6H, 5J, and 6J
are left blank, of these 5H & 6H represent the blind spots, and 5J & 6J represent the points 
near the right ear.  
Let Ti (where i=1, 2, 3,…, 52) represent the 52 test points for each eye. Each of these test 
points (for each eye and for each visual field test performed) contains a 1 (if abnormal at 
p<0.05) or a 0 otherwise.
Baseline is determined from the 2 tests performed at the baseline visit.  For each eye, the 
baseline value of a test point is 1 only if that point was 1 at both baseline tests.  That is, for a 
specific test point in a specific eye:
Value at 1st Baseline Test
Value at 2nd Baseline Test
Value to be Used as 
Baseline in the Analysis
0
1
0
1
0
0
0
0
0
1
1
1
Termination visual field deterioration is determined as follows:
If 5 or more test points that were 0 at baseline are 1 at termination for:
a.
either eye, then the patient will come in for a repeat visit.  If the repeat visit indicates 
a 1 for at least 5 of the same test points in the same eye, then the patient is considered 
to have visual field deterioration.


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b. both eyes, then the patient will come in for a repeat visit.  If the repeat visit has at 
least one eye with a 1 for at least 5 of the same test points, then the patient is 
considered to have visual field deterioration. 
Programmatically, this would be done as follows: If the following condition: [Ti=0 at 
baseline, Ti=1 at termination and Ti=1 at the repeat test] (where i=1,…, 52 and T represents 
the test points) is true for ≥5 test points (T1, T2,…T52) for either eye, then that patient is 
considered to have visual field deterioration. 
The following table gives some examples for 5 patients. (Assume that the left eye for Patients 
1 and 2 and the right eye for Patients 3 and 5 are not shown because of no test points=1 at 
either baseline or termination.):
Patient/eye
Test points=1 at 
baseline
Test points=1 at 
termination
Test points=1 at 
repeat visit
Met criteria for 
deterioration
1/R
2D, 2E 2F
2D, 2E, 2F, 2G, 3C
Not applicable
No, Repeat test not 
required since 
<5 new points 
= 1 at termination.
2/R
2D
3D, 3E, 3F, 3G, 
3H, 4B, 4C
2D, 4E, 4F, 4G, 
4H, 4I
No. None of the
same test points 
were =1 at both 
termination and 
repeat test.
3/L
3C, 3D, 3E
2D, 2E, 2F, 4D, 
4E, 4F
2E, 2F, 4D, 4E, 4F
Yes. 2E, 2F, 4D, 
4E, 4F are =1 at 
termination and 
repeat visit and 
were not =1 at 
baseline. 
4/R
2D, 2E, 2F, 2G, 
3C, 3D
2D, 3E, 3F, 3G, 
3H, 4B, 4C
3E, 3F, 3G, 3H,  
4C
Yes. 3E, 3F, 3G, 
3H, 4C are =1 at 
termination and 
repeat visit and 
were not =1 at 
baseline.
4/L
2D, 2E, 2F, 2G, 
3C, 3D
2D, 3E, 3F, 4F, 4G, 
4H
4F, 4G, 4H, 4I, 5B, 
5D
No. <5 points 
= 1 at both 
termination and 
repeat tests. 
5/L
3C, 3D, 3E
3G, 3H, 4B, 4C, 
4D
Not done
Yes for ITT 
sensitivity analysis
as the patient had 
5 points=1 at 
termination that 
were 0 at baseline; 
patient excluded 
from primary 
analysis (Per 
Protocol set.) as the 
patient lacks a 
repeat test. 


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In these examples, Patients 3 and 4 are considered to have visual field deterioration and 
Patients 1 and 2 are not.  Note that for Patient 4 only one of the eyes met the criteria on the 
repeat visit, but that was sufficient.  
Confirmation (or lack of confirmation) of deterioration will be done programmatically, as 
specified above.
10.3. A.1.3 Calculation of Visual Acuity Score
The ETDRS chart will be used to measure the best corrected visual acuity (with glasses or 
best possible glasses prescription). For the purpose of calculating the visual acuity scores, 
data will be read starting from the first row and by accumulating the number of letters 
correctly read until the first instance of row where the number of letters read is <3. This 
assumes that the contiguous rows between row 1 and the first instance of row with a score of 
<3 have scores ≥3. If row 1 is non-missing but has a score <3, then data will be read only up 
to row 1 and the visual acuity score will equal the score of row 1. If row 1 is missing or ND 
then visual acuity will also be missing. In all other cases data will be read until the row 
where the score is <3 or ND. Below are some examples of some arbitrary cases for 
calculating the VA scores: 
Dummy
SubjID
ETDRS 
Chart 
Row
Number of letters
Read Correctly 
(Row Score)  
VA Score
101
1
5
Row 1 Score+ Row 2 Score+ Row 3 Score+ Row 4 Score+ Row 
5 Score+ Row 6 Score+ Row 7 Score=
5+5+3+5+3+3+2 = 26
2
5
3
3
4
5
5
3
6
3
7
2
8
9
10
11
12
13
14
102
1
5
Row 1 Score+ Row 2 Score+ Row 3 Score =5+5+3 = 13
2
5
3
3
4
ND
5
3
6
3
7
2
8
9
10
11
12
13
14
103
1
5
Row 1 Score+ Row 2 Score+ Row 3 Score=5+5+3 = 13
2
5


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 34
Dummy
SubjID
ETDRS 
Chart 
Row
Number of letters
Read Correctly 
(Row Score)  
VA Score
3
3
4
0
5
3
6
3
7
2
8
9
10
11
12
13
14
 
 
 
 
 
 
 
 
 
                
                
                
                
CCI


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 35
10.5. A.1.5 Sheehan-Suicidality Tracking Scale (S-STS)
The eight-item S-STS as shown below will be converted to Columbia-Classification 
Algorithm of Suicide Assessment (C-CASA) codes as described in Table 1.
Table 1. Universal S-STS Mapping to C-CASA
C-CASA 
Category
C-CASA 
Category 
Number
Eight-item
S-STS
Completed Suicide
1
Obtain from SAE
Suicide Attempt
2
'Yes' to Item 1b OR
≥1 to Item 1a and 1b is 
missing OR
≥1 to Item 8
Preparatory action toward 
3
≥1 to Item 6


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 36
C-CASA 
Category
C-CASA 
Category 
Number
Eight-item
S-STS
imminent suicidal behavior 
(including interrupted 
attempt or aborted attempt)
Suicidal Ideation
4
≥1 to Item 2 OR
≥1 to Item 3 OR
≥1 to Item 4 OR
≥1 to Item 5
Self-injurious behavior with 
unknown intent
5
n/a
Not enough information, 
fatal
6
n/a
Self-injurious behavior 
without suicidal intent
7
EITHER
≥1 to Item 7a
OR
≥1 to Item 1a AND
''No' to Item 1b
Other (accidental, 
psychiatric, other)
8
n/a
Not enough information, 
non fatal
9
n/a
* Note: C-CASA codes 5, 6, 8, and 9 are not applicable to prospectively collected data.


Protocol A0081096
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 37
10.6. A.1.6- Columbia – Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an interview based rating scale that systematically assesses suicidal ideation 
and suicidal behavior.  Table 2 describes the mapping of C-SSRS to C-CASA categories.
Table 2.
C-SSRS Mapped to C-CASA - Suicidality 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?”