Clinical trial NCT02201251
Conditions: Epilepsy
Keywords: Epilepsy Topiramate Levetiracetam Pediatric
Sponsor: Janssen Research & Development, LLC
Start date: 2014-10-06; Completion date: 2020-04-30
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety of topiramate monotherapy compared with levetiracetam another standard antiepileptic drug (AED), as monotherapy for new-onset or recent-onset epilepsy (seizure disorder) on pediatric growth and maturation, bone mineralization, and kidney stone formation in children aged 2 to 15 years.

Detailed description:
This is a randomized (study medication assigned to participants by chance), open-label, multi-centric (conducted in more than one center) and 2-arm flexible-dose monotherapy study of topiramate compared with 1 another AED (levetiracetam) in pediatric participants with epilepsy. The total study duration will be up to of 1 year and 2 months per participant. The study consists of 3 parts: Screening (that is, up to 35 days before study commences on Day 1); Treatment (1 year) and post-treatment (30 days). Safety will primarily be evaluated by percentage of participants with kidney stones and change from baseline in bone mineral density at Month 12.

Arms: arm 1: Topiramate weight based dosing for participants 2 to less than (\<) 10 years of age not to exceed 350 mg/day (milligram per day), as tolerated; not to exceed 400 mg/day in participants 10-15 years of age, as tolerated. arm 2: Levetiracetam weight based dosing for all participants 2-15 years of age, not to exceed 60 milligram per kilogram per day (mg/kg/day), as tolerated. The maximum recommended daily dosage is 3,000 milligram (mg).
Interventions: intervention 1: Topiramate intervention 2: Levetiracetam
Intervention descriptions: intervention 1: Topiramate weight based dosing for participants 2 to \<10 years of age not to exceed 350 mg/day, as tolerated; not to exceed 400 mg/day in participants 10-15 years of age, as tolerated. intervention 2: Levetiracetam weight based dosing for all participants 2-15 years of age, not to exceed 60 mg/kg/day, as tolerated. The maximum recommended daily dosage is 3,000 mg.

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 3 November 2017
Janssen Research & Development *
Clinical Protocol
A Randomized, Active-Controlled, Open-Label, Flexible-Dose Study to Assess the Safety 
and Tolerability of Topiramate as Monotherapy Compared with Levetiracetam as 
Monotherapy in Pediatric Subjects with New or Recent-Onset Epilepsy
Protocol TOPMATEPY4067; Phase 3
Amendment INT-6
RWJ-17021-000 (topiramate)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Sciences Ireland UC; or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.  
EudraCT NUMBER: 2012-001552-19
Status:
Approved
Date:
3 November 2017
Prepared by:
Janssen Research & Development, LLC 
EDMS No & Version:
EDMS-ERI-21111756, 14.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02201251


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
2
Approved, Date: 3 November 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 19
TIME AND EVENTS SCHEDULE .............................................................................................................. 25
ABBREVIATIONS ...................................................................................................................................... 29
1.
INTRODUCTION................................................................................................................................ 30
1.1.
COMPARATOR AGENT ................................................................................................................... 36
1.2.
OVERALL RATIONALE FOR THE STUDY...................................................................................... 39
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 40
2.1.
OBJECTIVES .................................................................................................................................... 40
2.2.
HYPOTHESIS.................................................................................................................................... 40
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 40
3.1.
OVERVIEW OF STUDY DESIGN...................................................................................................... 40
3.2.
STUDY DESIGN RATIONALE.......................................................................................................... 44
3.2.1.
Blinding .......................................................................................................................................... 45
3.2.2.
Active Control................................................................................................................................. 45
4.
SUBJECT SELECTION..................................................................................................................... 46
4.1.
INCLUSION CRITERIA ..................................................................................................................... 46
4.2.
EXCLUSION CRITERIA.................................................................................................................... 48
4.3.
PROHIBITIONS AND RESTRICTIONS ............................................................................................ 51
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 52
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 53
7.
TREATMENT COMPLIANCE............................................................................................................ 55
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 55
9.
STUDY EVALUATIONS .................................................................................................................... 57
9.1.
STUDY PROCEDURES .................................................................................................................... 57
9.1.1.
Overview ........................................................................................................................................ 57
9.1.2.
Screening Phase............................................................................................................................ 58
9.1.3.
Open-Label Treatment Phase........................................................................................................ 58


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
3
Approved, Date: 3 November 2017
9.1.4.
Posttreatment Phase (Follow-Up).................................................................................................. 59
9.1.5.
Post-Study Phase (Follow-Up)....................................................................................................... 59
9.2.
PHARMACOKINETICS ..................................................................................................................... 60
9.2.1.
Sample Collection and Handling.................................................................................................... 60
9.2.2.
Analytical Procedures .................................................................................................................... 60
9.2.3.
Pharmacokinetic Parameters......................................................................................................... 60
9.3.
SAFETY EVALUATIONS .................................................................................................................. 60
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 71
10.1. COMPLETION ................................................................................................................................... 71
10.2. WITHDRAWAL FROM THE STUDY................................................................................................. 71
11.
STATISTICAL METHODS................................................................................................................. 72
11.1. SUBJECT INFORMATION................................................................................................................ 72
11.2. SAMPLE SIZE DETERMINATION.................................................................................................... 72
11.3. PHARMACOKINETIC ANALYSES................................................................................................... 73
11.4. SAFETY ANALYSES ........................................................................................................................ 73
11.5. DATA MONITORING COMMITTEE.................................................................................................. 76
12.
ADVERSE EVENT REPORTING ...................................................................................................... 76
12.1. DEFINITIONS .................................................................................................................................... 76
12.1.1. Adverse Event Definitions and Classifications............................................................................... 76
12.1.2. Attribution Definitions ..................................................................................................................... 78
12.1.3. Severity Criteria.............................................................................................................................. 78
12.2. SPECIAL REPORTING SITUATIONS .............................................................................................. 78
12.3. PROCEDURES.................................................................................................................................. 79
12.3.1. All Adverse Events......................................................................................................................... 79
12.3.2. Serious Adverse Events................................................................................................................. 80
12.3.3. Pregnancy ...................................................................................................................................... 81
12.4. CONTACTING SPONSOR REGARDING SAFETY.......................................................................... 81
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 81
13.1. PROCEDURES.................................................................................................................................. 81
13.2. CONTACTING SPONSOR REGARDING PRODUCT QUALITY..................................................... 82
14.
STUDY DRUG INFORMATION......................................................................................................... 82
14.1. PHYSICAL DESCRIPTION OF STUDY DRUGS.............................................................................. 82
14.2. PACKAGING ..................................................................................................................................... 83
14.3. LABELING......................................................................................................................................... 83
14.4. PREPARATION, HANDLING, AND STORAGE............................................................................... 83


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
4
Approved, Date: 3 November 2017
14.5. DRUG ACCOUNTABILITY ............................................................................................................... 83
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 84
16.
ETHICAL ASPECTS ......................................................................................................................... 85
16.1. STUDY-SPECIFIC DESIGN CONSIDERATIONS ............................................................................ 85
16.2. REGULATORY ETHICS COMPLIANCE .......................................................................................... 87
16.2.1. Investigator Responsibilities .......................................................................................................... 87
16.2.2. Independent Ethics Committee or Institutional Review Board....................................................... 87
16.2.3. Informed Consent........................................................................................................................... 89
16.2.4. Privacy of Personal Data................................................................................................................ 90
16.2.5. Country Selection........................................................................................................................... 91
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 91
17.1. PROTOCOL AMENDMENTS............................................................................................................ 91
17.2. REGULATORY DOCUMENTATION................................................................................................. 91
17.2.1. Regulatory Approval/Notification.................................................................................................... 91
17.2.2. Required Prestudy Documentation................................................................................................ 92
17.3. SUBJECT IDENTIFICATION, ENROLLMENT, AND SCREENING LOGS...................................... 92
17.4. SOURCE DOCUMENTATION........................................................................................................... 93
17.5. CASE REPORT FORM COMPLETION ............................................................................................ 94
17.6. DATA QUALITY ASSURANCE/QUALITY CONTROL..................................................................... 94
17.7. RECORD RETENTION...................................................................................................................... 95
17.8. MONITORING.................................................................................................................................... 95
17.9. STUDY COMPLETION/TERMINATION............................................................................................ 96
17.9.1. Study Completion........................................................................................................................... 96
17.9.2. Study Termination.......................................................................................................................... 96
17.10.
ON-SITE AUDITS....................................................................................................................... 97
17.11.
USE OF INFORMATION AND PUBLICATION ......................................................................... 97
REFERENCES............................................................................................................................................ 99
ATTACHMENTS....................................................................................................................................... 102
INVESTIGATOR AGREEMENT ............................................................................................................... 126
LAST PAGE.............................................................................................................................................. 126


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
5
Approved, Date: 3 November 2017
LIST OF ATTACHMENTS
Attachment 1: 
Habitual Activity Estimation Scale ............................................................................ 102
Attachment 2: 
Titration Schedules for Topiramate and Levetiracetam ........................................... 109
Attachment 3: 
Pharmacokinetic Collection and Handling Procedure .............................................. 112
Attachment 4: 
Labeling Instructions for Pharmacokinetic Samples ................................................ 114
Attachment 5: 
Shipment of Pharmacokinetic Samples.................................................................... 115
Attachment 6: 
CBCL-Preschool....................................................................................................... 116
Attachment 7: 
CBCL School Age..................................................................................................... 118
Attachment 8: 
Columbia Suicide Severity Scale: Baseline Version ................................................ 120
Attachment 9: 
Columbia Suicide Severity Scale: Since Last Visit Version ..................................... 123
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Topiramate Monotherapy Target Total Daily Maintenance Dosing for Subjects 2 to 
<10 Years of Age ...................................................................................................................... 54
Table 2:  
Volume of Blood to be Collected From Each Subject (mL) ...................................................... 57
FIGURES
Figure 1: 
Study Diagram .......................................................................................................................... 44


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
6
Approved, Date: 3 November 2017
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
21 November 2013
Amendment INT-1
11 March 2014
Amendment INT-2
23 April 2014
Amendment INT-3
15 October 2014
Amendment INT-4
Amendment INT-5
10 July 2015
24 August 2017
Amendment INT-6
3 November 2017
Amendments are listed beginning with the most recent amendment.
Amendment INT-6 (03 November 2017)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall objective of this amendment is to include minor changes and 
corrections for consistency within the protocol, and to align the protocol with the sponsor’s current protocol 
template.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that tapering off of treatment after study completion or at early withdrawal is not 
mandatory linked to the use of study drug but is also possible with commercially available product.
6. Dosage and 
Administration; 9.1.1. 
Overview
The term “study drug” was replaced by the generic drug name “topiramate or 
levetiracetam” to allow the use of commercially available drug for tapering off.
Rationale: To clarify that the decision regarding subects’ eligibility to participate in the optional Post Study 
Follow-up phase is based on local dual energy x-ray absorptiometry (DEXA) scan results (change in Z-score of -
0.5 or greater). This is because the central DEXA scan results are available only with delay, and the decision 
should be made on the day of the regular M12 visit.
3.1 Overview of 
Study Design; 9.1.1. 
Overview
The statement “… based on local DEXA scan results …” was added.
Rationale: Changes were made to align the protocol text per the sponsor’s current protocol template.
17.11. Use of 
Information and 
Publication
Outdated text regarding Authorship of publications resulting from this study was 
updated to reflect changes to the International Committee of Medical Journal Editors 
(ICMJE) Recommendations.
Rationale: Minor errors were noted.
Throughout the 
protocol
Abbreviations were updated per the sponsor’s style guide


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
7
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Protocol amendment 
table, Amendment 
INT-5
(24 August 2017)
The 24-hour urine collection was moved from Baseline/W1 visit to Screening period. 
This change in timing of urine collection was made in the synopsis (safety evaluations), 
but, it was not captured in amendment table of Amendment INT-5.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
8
Approved, Date: 3 November 2017
Amendment INT-5 (24 August 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does impact the scientific 
value of the trial.
The overall reason for the amendment: The overall objective of this amendment is to improve a 
slower-than-expected study enrollment. At the current rate of subject randomization, the previously agreed-upon 
milestone for the study completion will not be met. Two major revisions, which should lead to a higher enrollment 
rate without impacting the overall study objectives and data analysis, will be implemented in this amendment: 

The inclusion criterion # 2 will be expanded to allow a higher number of seizures within a longer period 
prior to subject enrollment – from “up to 2 seizures within the last 3 months” to “up to 10 seizures within 
the last 5 months” – and

An optional use of local laboratory evaluations as basis for randomization (in addition to the mandatory 
central laboratory evaluation), although the central laboratory evaluation results will be used for 
change-from-baseline analyses. The optional use of a local lab for the evaluation of 25-hydroxy-vitamin 
D, 1,25-dihydroxy-vitamin D, Parathyroid hormone (intact) and IGF-1 might significantly reduce the 
duration of the screening period and consequently might increase the enrollment rate. Investigators have 
objected that a screening period of up to 28 days before initiating a drug treatment for new-onset, pediatric 
seizure disorder is not a reasonable waiting period for the subjects, their parents, and treating/referring 
physicians. It is expected that a shorter minimum screening period will improve the enrollment rate.
In addition, minor changes were included to specify the use of local DEXA scan results for deciding about the 
subject’s eligibility to participate in the optional Follow-Up phase, and a clarification that the screening period 
should start no more than 35 days before baseline, instead of “28 ± 7 days”, and may be as short as possible if all 
appropriate screening assessments will have been completed.
Applicable Section(s)
Description of Change(s)
Rationale: The expansion of inclusion criterion #2 increases the number of eligible study participants and might 
lead to an increased enrollment rate without hazarding the study objectives. By allowing subjects to have at least 
1 seizure, but no more than 10 seizures in 5 months (that is, a seizure frequency of approximately no greater than 
2 seizure episodes per month), the loss of prospective subjects will be reduced, while the expected efficacy of 
monotherapy, using either of the two study drugs, would not be adversely affected. Moreover, this revision is 
expected not to change the treatment that each patient would otherwise receive if the patient were to receive 
treatment outside of the study.
Synopsis, Study Population;
3.1 Overview of Study Design;
4.1 Inclusion Criteria,
Criterion #2
Inclusion criterion #2 was revised to specify that subjects should have at least 1, 
but no more than 10, unprovoked seizures during the 5 months prior to 
screening.
Rationale: To reduce the duration of the screening period and, in consequence, a potential reduction of the time 
before the study drug treatment can be initiated.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
9
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Time and Events Schedule, 
footnote “ k”;
9.1.1 Study Procedures, 
Overview, Table 2, footnote “a”, 
footnote “c”;
9.3 Safety Evaluations, Clinical 
Laboratory Tests
An optional use of a local laboratory is allowed at screening for the decision 
regarding subject randomization for the following parameters:
25-hydroxy-vitamin D;
1,25-dihydroxy-vitamin D;
Parathyroid hormone 
(intact); and IGF-1.
To reduce the duration of the screening phase, one or more of these laboratory 
parameters may be evaluated at the local laboratory, at the discretion of the 
investigator. In such instance, the local laboratory instructions should be 
followed and local reference ranges should be applied. The local laboratory 
results should be used for decision regarding randomization. The central 
laboratory evaluation results will still be obtained and will be used for change-
from-baseline analyses. The additional use of a local laboratory might lead to an 
increase in blood volume to be drawn from the subject at screening.
Rationale: To ensure that the initial 24-hour urine collection will be completed before initiation of study drug 
therapy and the 24-hour urine collection at Month-12 during study drug therapy.
Time and Events Schedule, 
footnote “m”;
9.3 Safety Evaluations, Clinical 
Laboratory Tests
The 24-hour urine collection was moved from Baseline/W1 visit to Screening 
period. It should be ensured that the initial 24-hour urine collection is completed 
before study drug therapy is initiated. Additionally, it is clarified that the 
24-hour urine collection at Month 12 should be completed before the Month-12 
visit as this evaluation should be obtained during study-drug therapy. 
Rationale: To clarify that tapering off of treatment after study completion or at early withdrawal is not mandatory 
linked to the use of study drug but is also possible with commercially available product.
3.1 Overview of Study Design, 
Posttreatment Phase;
9.1.4 Posttreatment Phase 
(Follow Up)
The term “study drug” was replaced by the generic drug name “topiramate or 
levetiracetam” to allow the use of commercially available drug for tapering off.
Rationale: To clarify that the screening phase is any period up to 35 days. The previous Time and Event Schedule 
described a screening phase of 21 to 35 days (28 ±7days). A screening phase of less than 21 days is desirable and 
this is reflected in the updated Time and Event Schedule.
Time and Events Schedule
Synopsis, Overview of Design;
3.1 Overview of Study Design;
9.1.1 Overview;
9.1.2 Screening Phase
The screening phase with study day -28 including a study day window of 
±7days was changed to study day ≤-28 including a study day window of -
7 days (ie, day -35).
Rationale: To clarify that the decision regarding subects’ eligibility to participate in the optional Post Study Follow-
up phase is based on local DEXA scan results (change in Z-score of -0.5 or greater). This is because the central 
DEXA scan results are available only with delay, and the decision should be made on the day of the regular M12 
visit.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
10
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Synopsis, Overview of Study 
Design; Time and Events 
Schedule, footnote “b”;
3.1 Overview of Study Design, 
Post Study Phase (Follow Up);
Figure 1: Study Diagram, 
footnote “a”;
9.1.5 Post Study Phase (Follow 
Up).
The statement “… based on local DEXA scan results …” was added.
Amendment INT-4 (10 July 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to respond to health authority 
feedback requesting a more specific definition of age at which to conduct Tanner staging. Also the eligibility 
criterion for vitamin D level at screening was revised, and text was clarified for other study eligibility criteria and 
procedures.
Applicable Section(s)
Description of Change(s)
Rationale: Systematically conducting Tanner staging at a sufficiently early age ensures that all children who may be 
exhibiting pubertal changes earlier than expected will be identified. This change was requested by the US health 
authority.
Synopsis, Safety Evaluations; 
Time and Events Schedule 
footnote "n"; 
Sec. 9.3. Safety Evaluations,
Physical Examination 
Text was added to clarify that Tanner staging is to be conducted uniformly in 
subjects of age 8 years and above.
Rationale: To ensure consistency of seizure counting for determination of study eligibility.
Sec. 4.1., Inclusion Criteria
Inclusion criterion #2 was revised to specify that unprovoked seizure clustering
that occurs within a 24 hour period is to be considered as a single unprovoked 
seizure. This is in accordance with International League Against Epilepsy (ILAE) 
clinical definitions.16
Rationale: To ensure correct units are applied to the collection of WBC and neutrophil counts for determination of 
study eligibility.
Sec. 4.2., Exclusion Criteria
Exclusion criterion #17 was corrected to show the units for WBC count and 
neutrophil count to be per μL.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
11
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Rationale: The threshold of clinical concern for 25-hydroxy-vitamin D is the deficiency threshold (<12ng/mL 
[<30 nmol/L]).19,42
Sec. 4.2., Exclusion Criteria
Exclusion criterion #17 was revised to define the threshold of clinical concern 
for 25-hydroxy-vitamin D.
Rationale: To clarify that the 7-day window allowed for scheduling study visits applies to all visits. 
Time and Events Schedule
A row was added to depict that the “± 7day” window applies to all study visits.
Rationale: To ensure that source data is collected correctly and, with regard to height, to clarify the blinded manner
in which it is to be obtained.
Sec. 5., Treatment Allocation 
and Blinding; 
Sec 9.3., Safety Evaluations,
Physical Examination; 
Sec. 17.4., Source 
Documentation
Text was edited to state that the specified parameters would be recorded in 
source documents first and then entered into the CRF, and text was added to 
clarify how how height measurements is to be obtained so as to remain blinded.
Rationale: To clarify that venous ammonia is to be analyzed by the central laboratory in countries where local 
testing is not available.
Sec. 9.1.1., Table 2, footnote 
"b"; Sec. 9.3., Safety 
Evaluations, Clinical 
Laboratory Tests
The clinical laboratory tests will be performed by the central laboratory, except 
venous ammonia, which will be evaluated locally (except in select countries 
where local testing is not possible, in which case the central laboratory will also 
evaluate venous ammonia).
Rationale: To clarify and maintain consistency within the protocol regarding the timing and volume of blood 
collection for venous ammonia.
Sec. 9.1.1., Table 2
Table 2 (Volume of Blood to be Collected From Each Subject (mL)) was revised
to reflect a blood draw volume of 1.2 mL for venous ammonia at Month 1 for a 
corresponding total blood volume of 7.2 mL collected during the study. 
Accordingly, also in Table 2, total blood volumes were revised at Month 1 and 
during the study to 4.7 mL and 45.8 mL, respectively.
Text in Sec. 9.1.1. was revised to reflect a total blood volume of 44.7 mL 
collected during the study. For adolescent girls who require serum pregnancy 
test at screening, text was revised to reflect a total blood volume of 45.8 mL 
collected during the study.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
12
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Rationale: To clarify and maintain consistency within the protocol regarding the timing of serum biochemical 
assessments of bone metabolism and DEXA scans.
Sec. 9.3., Safety Evaluations, 
Bone Mineralization
Text was revised to reflect that serum biochemical assessments of bone 
metabolism are to be obtained at screening, Month 6 and Month 12/early 
withdrawal, and DEXA scans are to be obtained at baseline, Month 6 and 
Month 12/early withdrawal.
Rationale: To clarify that C-SSRS is to be administered for subjects 6 to 15 years of age.
Time and Events Schedule, 
footnote “x”; Sec. 9.3., Safety 
Evaluations, Suicidality
Text was revised in Sec. 9.3 to state that C-SSRS will be administered for 
subjects 6 to 15 years of age and a footnote was added to the Time and Events 
Schedule to clarify the ages for which to administer C-SSRS.
Rationale: Concern that, in certain countries, the current protocol language would disagree with local product 
handling instructions on the study drug label.
Sec. 14.4., Preparation, 
Handling and Storage
Revised language to delete specific storage parameters and add "All study drug 
should be stored and handled per the labelled storage conditions."
Rationale: To clarify that ECG data would not be transmitted directly to the sponsor's database from a central 
laboratory.
Sec. 17.6, Data Quality 
Assurance/Quality Control and 
Sec. 17.11., Use of Information 
and Publication
Text was revised to remove that ECG data would be transmitted directly to the 
sponsor's database from a central laboratory.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-3 (15 October 2014)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to change the phase of the study 
from Phase 4 to Phase 3, due to investigational monotherapy dosing for study medications in some countries, and to 
add a subspecialty referral for clinically important reductions in bone mineral density Z-score.
Applicable Section(s)
Description of Change(s)
Rationale: Since topiramate and levetiracetam are not approved in all pediatric age groups as monotherapy in all 
countries in which the study is being conducted, the study is being changed from Phase 4 to Phase 3.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
13
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Title page
Phase of the study changed from Phase 4 to Phase 3.
Rationale: For subjects with a clinically relevant drop in bone mineral density Z-score, a consultation may be 
recommended at the discretion of the investigator to assess the subject and guide potential management of the case.
Sec. 9.3, Safety 
Evaluations, Bone 
Mineralization
Language added for the investigator to make an appropriate referral (ie, subspecialty 
consult) for further evaluation of subjects who develop treatment-emergent clinically 
significant bone mineral density Z-scores (at 6 month or 12 month measurement).
Rationale: To provide consistent interpretation of all renal ultrasound results (ie, screening, 6- and 12-month 
results) in all patients across sites, central rather than local readings will be performed.
Time and Events Schedule; 
Sec. 9.3, Safety 
Evaluations, Renal Stone 
Evaluation
Text changed to indicate that renal ultrasounds will be read and interpreted centrally 
rather than locally (local reading at the screening visit is acceptable to determine 
eligibility for study enrollment), and that both the technician administering the text 
and the central and local readers are blinded to study drug treatment.
Rationale: Clarified that subjects will not be discontinued from the study for exceeding currently labeled, 
maximum recommended doses if higher doses are required for optimal clinical effect, as judged by the investigator. 
In the event a subject takes a higher-than-recommended dose, their data collected while receiving higher doses may 
be analyzed separately. Higher doses could possibly confound safety evaluations including DEXA scans, laboratory 
tests (eg, bicarbonate), and renal ultrasounds (eg, increased nephrolithiasis). 
Synopsis; 
Section 6, Dosage and 
Administration
Added language that subjects will not be discontinued from the study if 
recommended maximum doses of study medication are exceeded. For any subject 
that exceeds the maximum recommended daily dose, data collected subsequent to the 
use of higher doses may be analyzed in a secondary analysis for each safety outcome 
of interest. 
Rationale: Evaluation of concomitant medications at screening visit is needed to determine if subjects meet 
inclusion/ exclusion criteria regarding whether they are treatment naïve or have previous treatment with AEDs.
Time and Events Schedule
Added evaluation of concomitant medications at screening visit.
Rationale: To provide flexibility in the Data Monitoring Committee (DMC) meeting frequency according to the 
needs of the study.
Sec. 11.5 Data Monitoring 
Committee
Change DMC meetings from minimally on a quarterly basis to minimally on a 
semiannual basis.
Rationale: Updated versions of Habitual Activity Estimation Scale (HAES) and Child Behavior Checklist (CBCL) 
scales added to protocol.
Attachment 1
Replaced HAES with updated version available from vendor. 
Attachments 6 and 7
Replaced CBCL-Preschool and CBCL-School Age with updated versions (scales 
were edited to meet the needs of this study - revised to remove irrelevant sections and 
open-ended questions).


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
14
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
15
Approved, Date: 3 November 2017
Amendment INT-2 (23 April 2014)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to revise the blood draw volume 
to accommodate a larger volume required for 1,25-dihydroxy-vitamin D; HIV and hepatitis serology at screening 
have been removed to keep blood volume at a minimum.
Applicable Section(s)
Description of Change(s)
Rationale: Blood draw volume revised to accommodate a larger volume required for 1,25-dihydroxy-vitamin D; 
HIV and hepatitis serology at screening have been removed to keep blood volume at a minimum.
Time and Events Schedule;
4.2. Exclusion Criteria;
9.3. Safety Evaluations
HIV and hepatitis serology at screening removed.
9.1.1. Overview
Blood volume revised.
Rationale: Added description of visual field defects reported with topiramate.
1. Introduction, Safety 
Issues of Clinical Concern, 
Vision Abnormalities
Added description of visual field defects reported with topiramate.
Rationale: Study procedures clarified.
Time and Events Schedule;
3.1. Overview of Study 
Design, Screening Phase;
9.1.3. Open-Label 
Treatment Phase;
9.3. Safety Evaluations
Parents of each subject will record the description, rather than the type, of seizure in 
the seizure diary.
3.2.Study Design Rationale
Description of approved uses for levetiracetam revised for consistency with 
Section 1.1, Comparator Agent.
5. Treatment Allocation 
and Blinding;
15. Study-Specific 
Materials
Interactive system will be web-based (IWRS), rather than IVRS.
9.1.1. Overview
Clarification added that higher blood volume will be required for adolescent girls who 
require serum pregnancy test at screening.
9.1.1. Overview;
9.3. Safety Evaluations
Clarification added that venous ammonia will be evaluated locally.
9.1.3. Open-Label 
Treatment Phase
Deleted statement that investigator or study personnel will describe the different types 
of seizures to be recorded in the seizure diary; this is no longer applicable with the 
current setup of the diary.
15. Study-Specific 
Materials
Worksheet for NEPSY II and other scales added.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
16
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
16.2.3. Informed Consent
Language added that assent will be obtained from subjects typically 7 years and older, 
for consistency with language later in the section.
16.2.5. Country Selection
Clarification that the study will only be conducted in those countries where 
topiramate and levetiracetam are commercially available for the treatment of 
epilepsy.
17.4. Source 
Documentation
Added C-SSRS to assessments that will be recorded separately from the CRF and be 
considered source data.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
17
Approved, Date: 3 November 2017
Amendment INT-1 (11 March 2014)
The overall reason for the amendment: The overall reason for the amendment is to clarify exclusion and 
withdrawal criteria for subjects with a history of or significant risk of suicidal or violent behavior.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify exclusion and withdrawal criteria for subjects with a history of or significant risk of suicidal 
or violent behavior.
4.2. Exclusion Criteria
Added exclusion criterion for subjects with a history of any suicidal behavior 
(attempt, interrupted, aborted, or preparatory) in the past 6 months prior to the 
screening visit.
10.2. Withdrawal From the 
Study
Added withdrawal criterion if the investigator believes the subject to be at significant 
risk of suicidal or violent behavior.
Rationale: Study procedures clarified.
Synopsis Overview of 
Study Design;
Time and Events Schedule;
3.1. Overview of Study 
Design;
3.2.1. Blinding;
5. Treatment Allocation 
and Blinding;
9.3. Safety Evaluations;
16.1. Study-Specific 
Design Considerations
Renal ultrasound will be obtained under blinded conditions after randomization; 
screening ultrasound will not be blinded.
Synopsis Dosage and 
Administration; 
6. Dosage and 
Administration
Maximum recommended daily dosage for levetiracetam added, for consistency with 
approved labeling.
Synopsis Safety 
Evaluations;
Time and Events Schedule;
Renal ultrasound changed from baseline to screening, for consistency with 
Section 9.3, Safety Evaluations, to ensure results are available prior to randomization.
Synopsis Safety 
Evaluations;
Time and Events Schedule;
9.3. Safety Evaluations
BMI will not be obtained by the site, but will be calculated during statistical analysis.
Time and Events Schedule
Clarification added that seizure counts will be recorded in the seizure diary (in 
addition to the date and type of seizure)
9.3. Safety Evaluations
Statement added that for all evaluations, if possible, the same individual should 
evaluate the subject at all visits.
Statement regarding shipment of ammonia samples deleted, since testing will be done 
locally.
“Bone Age Scan” changed to “Bone Age Radiograph” for accuracy; clarification 
added that this will be obtained in the nondominant hand/wrist.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
18
Approved, Date: 3 November 2017
Applicable Section(s)
Description of Change(s)
Number of questions for CBCL-Preschool and CBCL-School Age revised to 
99 questions and 112 questions, respectively, for consistency with Attachments 6 and 
7.
Clarification added for who can administer the Columbia Suicide Severity Rating 
Scale (C-SSRS), and that subjects themselves will respond if cooperative, in all 
subjects 6 years of age and older. 
9.3. Safety Evaluations;
11.4. Safety Analyses
Reference to vital signs obtained in a seated position deleted, since orthostatic vital 
signs will be measured supine then standing.
15. Study-Specific 
Materials
Added “refrigerated centrifuge, if not available locally”.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
19
Approved, Date: 3 November 2017
SYNOPSIS
A Randomized, Active-Controlled, Open-Label, Flexible-Dose Study to Assess the Safety and 
Tolerability of Topiramate as Monotherapy Compared With Levetiracetam as Monotherapy in Pediatric 
Subjects With New or Recent-Onset Epilepsy
TOPAMAX® (topiramate) (2,3:4,5-Di-O-isopropylidene-ß-D-fructopyranose sulfamate) is a structurally 
unique compound that is effective and well tolerated as an anticonvulsant after oral administration in 
animals and humans. Topiramate is approved as adjunctive treatment in adults and in pediatric patients 
(2 to 16 years of age) with partial-onset seizures (POS), primary generalized tonic-clonic seizures
(PGTCS), or seizures associated with Lennox-Gastaut syndrome. It is also approved for monotherapy 
treatment in adult and pediatric patients down to 2 years of age with newly or recently diagnosed POS or 
PGTCS, and for the prophylaxis of migraine in adults and adolescents 12 years of age and older.
The effects of topiramate on growth, bone mineralization, and kidney stone formation have not been fully 
and systematically evaluated or well characterized in pediatric populations. This study will systematically 
assess the long-term safety of topiramate monotherapy compared with levetiracetam monotherapy;
specific emphasis will be on metabolic acidosis related to topiramate therapy and its association with 
nephrolithiasis, bone mineral density (BMD) abnormalities, and delayed growth in children (2 to 15 years 
of age). Levetiracetam is an appropriate comparator because of its established efficacy for target seizure 
types, relatively low toxicity, and lack of significant known risk of kidney stones or possible deleterious 
effects on bone or growth.
EudraCT NUMBER: 2012-001552-19
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to evaluate the effects of topiramate monotherapy compared with levetiracetam, 
another standard antiepileptic drug (AED), as monotherapy for new-onset or recent-onset epilepsy on 
pediatric growth and maturation, bone mineralization, and kidney stone formation in children 2 to 
15 years of age.
Secondary Objective
Overall safety will be assessed.
Hypothesis
The study will test the hypothesis that flexible dosages of topiramate monotherapy have the same effect as 
flexible dosages of levetiracetam monotherapy on pediatric growth, bone mineralization, and kidney stone 
formation in children 2 to 15 years of age with new-onset or recent-onset epilepsy, versus the alternative 
hypothesis that the effect of topiramate is different from that of levetiracetam.
OVERVIEW OF STUDY DESIGN
This is a 1-year, active-controlled, randomized, outpatient, multicenter, open-label, 2-arm flexible-dose 
monotherapy study of topiramate compared with 1 other AED (levetiracetam) in pediatric subjects with 
epilepsy. Subjects will be required to have newly or recently diagnosed epilepsy characterized by POS
with or without secondary generalized tonic-clonic seizures or PGTCS.
The study will include the following 3 phases: a screening phase of up to 35 days, an open-label treatment 
phase of 1 year's duration, and a posttreatment phase of 30 days’ duration. There may be an optional 
post-study follow-up phase to obtain dual energy x-ray absorptiometry (DEXA) measurements in a 
subgroup of subjects who experience a clinically important reduction (change in Z-score of -0.5 or 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
20
Approved, Date: 3 November 2017
greater) in BMD, based on local DEXA scan results, after 1 year of treatment with topiramate, to 
determine whether a decrease in BMD after or during 1 year of treatment with topiramate is reversible. 
These subjects will have a repeat DEXA scan 6 months after discontinuation of study drug.
To minimize any bias in measurement, after randomization 3 of the safety assessments will be obtained in 
a blinded fashion, including the DEXA scan, renal ultrasound, and height.
An external, independent Data Monitoring Committee will be commissioned for this study and will 
evaluate safety data periodically throughout the study. 
SUBJECT POPULATION
Approximately 282 male and female subjects, 2 to 15 years of age with newly or recently diagnosed 
epilepsy, will be randomly assigned to either the topiramate or levetiracetam arm, in a 1:1 ratio. The 
randomization will be balanced using randomly permuted blocks and will be stratified by country and age 
group (2 to 5 years of age, 6 to 9 years of age, 10 to 12 years of age, and 13 to 15 years of age). The 
enrollment will be monitored throughout the study to ensure that subjects are enrolled for each integer 
year in each treatment group.
Subjects will be required to have newly or recently diagnosed epilepsy characterized by POS with or 
without secondary generalization or PGTCS. The epilepsy diagnosis must be within the previous 2 years 
before screening and the subject must have at least 1, but not more than 10, unprovoked seizures during 
the 5 months prior to screening. Subjects must have evidence of appropriate physical development (height 
and weight), including weight and height values within the 5th to 95th percentile for chronological age at 
study entry. Previous AED exposure is limited to no more than 31 days immediately preceding study 
enrollment or to a total of 6 months of previous AED exposure in the past if the AED has been 
discontinued for at least 1 year prior to study enrollment. If the subject is currently treated with an AED, 
inadequacy of current epilepsy treatment must be documented.
Subjects must not have nephrocalcinosis, renal stones of any type, hydronephrosis, a history of long bone 
fractures, indwelling hardware, or abnormalities of the skeleton or spine. Subjects must not have 
congenital glaucoma, known ocular deficits, or clinically relevant abnormalities on renal ultrasound or 
DEXA scans. Subjects must not have a known history of disturbances of autonomic function, inborn 
errors of metabolism, mitochondrial dysfunction, or prior evidence of hyperammonemia. Subjects must 
not have any clinically significant abnormality in laboratory tests at screening, including a bicarbonate 
level <20 mEq/L, have a diagnosis of metabolic acidosis, or be on alkali therapy. 
Caregivers of the subjects must be able to accurately maintain the subject take-home record and seizure 
diary.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned to receive unblinded, flexible dosages of topiramate or levetiracetam 
as follows:

Topiramate: weight-based dosing for subjects 2 to <10 years of age, not to exceed 350 mg/day, as 
tolerated; dosage for subjects 10 to 15 years of age not to exceed 400 mg/day, as tolerated

Levetiracetam: weight-based dosing for all subjects 2 to 15 years of age, not to exceed 60 mg/kg/day, 
as tolerated. The maximum recommended daily dosage is 3,000 mg (1,500 mg BID).
Subjects will receive study drug in a twice-a-day regimen. After randomization, subjects will be titrated 
as tolerated to the maximum recommended dosage for optimal clinical effect over 6 to 8 weeks and will 
be maintained on that dosage through the open-label treatment phase, with the option for dosage
adjustment as required for optimal clinical effect. Changes to this schedule will be based on a risk-benefit 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
21
Approved, Date: 3 November 2017
assessment of the subject’s clinical condition by the investigator. All study drugs will be provided in 
child-resistant packaging during the study.
Subjects are recommended not to exceed maximum recommended maintenance dosages; however,
subjects will not be discontinued from the study if higher dosages are required for optimal clinical effect 
as judged by the investigator. Data collected while on dosages that exceed maximal recommendations 
may be analyzed separately, as appropriate.
Only AED monotherapy will be used for both treatment groups. However, subjects will not be 
discontinued from the study if 1 or more concomitant AEDs are added after initiating treatment with 
study drug. Data will be collected prior to the use of the concomitant AED(s) for the primary analysis. 
Data subsequently collected while on the concomitant AED(s) will be analyzed in a secondary analysis 
for each safety outcome of interest.
PHARMACOKINETIC EVALUATIONS
Blood samples (1 mL per sample) for the determination of plasma topiramate and levetiracetam 
concentrations will be obtained during clinic visits according to the Time and Events schedule. If 
possible, blood samples for pharmacokinetic (PK) evaluations should be trough samples (ie, taken 
immediately before the morning dose) and coincide with samples drawn for clinical laboratory tests.
During each PK assessment, the dosing regimen, dose administered, time and date of dose administration, 
time of sample collection, and concomitant medications will be recorded in the case report form.
Pharmacokinetic parameters will not be estimated. Topiramate and levetiracetam plasma concentration 
data will be summarized.
SAFETY EVALUATIONS
Safety evaluations will include:

12-lead electrocardiogram (screening only)

Vital signs (including orthostatic vital signs), body weight, and height (all visits except Month 2)

Neurologic and physical examinations (all visits except Month 2)

Physical activity evaluation (screening)

Clinical laboratory tests (screening, Month 1, Month 3, Month 6, Month 9, and Month 12/early 
withdrawal)

Pregnancy testing (for girls of childbearing potential; serum at screening only; urine at all other visits)

24-hour urine collection (Screening, Month 6, and Month 12/early withdrawal)

Adverse event monitoring, concomitant medication monitoring (throughout)

Suicidality, as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS; all visits except 
screening)

DEXA scan (baseline, Month 6, and Month 12/early withdrawal)

Renal ultrasound, biochemical bone markers (screening, Month 6, and Month 12/early withdrawal)

Bone age, as determined by hand/wrist x-ray (baseline and Month 12/early withdrawal)

Tanner staging of subjects of age 8 years and above (baseline, Month 6, and Month 12 or early 
withdrawal)

Seizure counts recorded by parent/guardian in take-home seizure diary (all visits beginning at 
baseline)


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
22
Approved, Date: 3 November 2017

Cognitive, developmental, and behavioral assessments, conducted as follows:

Cogstate Battery (2 practice sessions, 1 at screening and 1 at baseline prior to the baseline 
assessment; assessed at baseline, Month 6, and Month 12/early withdrawal):
o
For subjects 6 to 15 years of age, the Detection Test, Identification Test, One Card 
Learning Test, One Back Test, and Groton Maze Learning Test will be administered.
o
For cooperative subjects 4 to 5 years of age, the Detection Test and the Identification Test 
will be administered.

Language function test (Animal Fluency NEPSY-II (A Developmental NEuroPSYchological 
Assessment); 1 practice session at screening; assessed at baseline, Month 6, and Month 
12/early withdrawal for subjects 6 to 15 years of age) 

Vineland Adaptive Behavior Scale (to be completed by a parent or guardian for subjects 2 to 
5 years of age, assessed at baseline, Month 3, Month 6, and Month 12/early withdrawal)

Child Behavior Checklist (CBCL; assessed at baseline, Month 3, Month 6, and 
Month 12/early withdrawal) - Parent version (Achenbach System of Empirically Based 
Assessment)
o
Preschool version – subjects 2 to 5 years of age
o
School-age version - subjects 6 to 15 years of age
Note: For subjects who turn 6 years of age during the study, the Vineland Adaptive Behavior 
Scale and the preschool version of the CBCL will continue to be administered throughout the 
study.
STATISTICAL METHODS
Sample Size Determination
A total of 282 randomized subjects, 141 in each treatment group, will be enrolled in the study. The 
sample size takes into account a 1-year dropout rate of 29%, which is a conservative estimate based on 
the dropout rates was observed in a previous monotherapy study in the 6- to 15-year-old age group, Study 
TOPMAT-EPMN-106, including a dropout rate of 22% in the study overall (both double-blind and open-
label phases) and a dropout rate of 35% for the double-blind phase. The sample size was estimated in 
order to achieve a sufficient precision for the estimates of the treatment effect on the key endpoints. The 
precision of the confidence interval (CI) estimates for the key safety parameters are shown below:

Annual change in BMD (L1-L4) Z-score: In the Bone Mineral Density in Childhood Study (BMDCS), 
mean annual change in BMD (L1-L4) Z-score in 6- to 15-year-old healthy subjects was, as expected, 
minimal (0.01-0.07). The standard deviation (SD) varied from 0.3 to 0.48 across sex and age groups. 
Assuming an SD of 0.4, with 100 completed subjects per group, the 95% CI for the treatment 
difference will have a precision of 0.12.

Annual change in height Z-score in the 2- to 9-year-old age group: In the monotherapy epilepsy study 
TOPMAT-EPMN-106, the observed change from baseline in mean height Z-score at 1 year among the 
2- to 9-year-old subjects treated with topiramate 400 mg/day was -0.18, with an SD of 0.28. Assuming 
that 53% of the subjects will be recruited in the 2 to 9-year-old age group, ie, 53 completed subjects 
per treatment group, the 95% CI for the treatment difference will have a precision of 0.11.

Incidence of kidney stone formation: In the studies TOPMAT-PEP-3001 and TOPMAT-PEP-1002 in 
infants (1 month to 2 years of age), a 7% incidence of kidney stones was observed during the 1-year 
topiramate adjunctive treatment period. A sample size of 100 completed subjects per treatment group 
will provide a 95% CI (Wilson score CI) for the treatment difference with a width of 0.12, assuming 
that the incidence of kidney stone formation is 7% and near zero in the topiramate group and the 
levetiracetam group, respectively.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
23
Approved, Date: 3 November 2017

Change in weight Z-score in the 2- to 15-year-old age group: In the monotherapy epilepsy study 
TOPMAT-EPMN-106, a -0.59 decrease from baseline in weight Z-score, with an SD of 0.43, was 
observed after 1 year of treatment with topiramate 400 mg/day. Assuming an SD of 0.43, a sample 
size of 100 completed subjects per treatment group will provide a 95% CI with a precision of 0.12.
Safety Analyses
The key safety endpoints will include:

Percentage of subjects with kidney stones 

Change from baseline in weight Z-score over time

The following height analyses will be conducted for prepubertal subjects 2 to 9 years of age, subjects 
10 to 15 years of age, and subjects 2 to 15 years of age:

Height at 1 year postbaseline

Height change from baseline over time

Height Z-score at 1 year postbaseline

Change from baseline in height Z-score over time

Height velocity at 1 year postbaseline

Height velocity Z-score at 1 year postbaseline

Percentage of outlier subjects with height Z-score decrease of >0.5, >1.0, and >2.0 over time

The following BMD and bone mineral content (BMC) endpoints:

BMD and BMC over time

BMD and BMC change from baseline over time

Z-score for BMD and BMC over time

Change from baseline in Z-score for BMD and BMC over time

Percent change from baseline in BMD and BMC over time

Percentage of outlier subjects with BMD Z-score decrease of >0.5, >1.0, and >2.0 over time

Change from baseline in biochemical markers of bone mineralization including: serum levels of 
calcium, phosphorus, alkaline phosphatase, 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, 
insulin-like growth factor 1 (IGF-1), and parathyroid hormone.

Change from baseline in serum and urine laboratory tests, eg, bicarbonate, ammonia, renal function 
tests, and liver function tests 

Change from baseline in bone age
Longitudinal endpoints will be analyzed using a mixed-model repeated measures (MMRM) analysis. The 
MMRM model will include treatment group, age group, visit, treatment-by-visit interaction, baseline 
measure, and baseline-by-visit interaction. An unstructured covariance will be used. Other appropriate 
covariance structures will be explored as needed. Confidence intervals with 95% confidence for the 
estimated treatment differences will be provided at each time point as appropriate. For proportion 
endpoints, 95% confidence intervals will be provided for the treatment difference. Each of the endpoints 
will also be summarized by age group.
Seizure counts and cognitive, developmental, and behavioral assessments will be summarized by 
treatment group and age group. The incidence of suicide-related thoughts and behaviors as determined by 
the C-SSRS will be summarized by treatment group and age group.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
24
Approved, Date: 3 November 2017
In addition to the above endpoints, other safety-related endpoints may be included in the analyses if 
deemed necessary.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
25
Approved, Date: 3 November 2017
TIME AND EVENTS SCHEDULE
Phase
Screening
Open-Label Treatmenta
Posttreatmentb
End-of-
Study/Early 
Withdrawal
Follow-up 
Telephone 
Contact
Week (W)/Month (M)
Baseline/
W1
M1
M2
M3
M6
M9
M12
M13
Study Day
≤-28
1c
30
60
90
180
270
360
390d
Study Day Window
-7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
Visite
1
2
3
4
5
6
7
8
NA
Screening/Administrative 
Informed consent and assent
X
Inclusion/exclusion criteria
X
X
Medical/seizure history
X
X
Physical activity evaluationf
X
Prestudy AED and other therapyg
X
Randomization
X
Study Drug
Dispense study drug
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
Pharmacokinetics
Blood sample collection for 
quantitation of study drugh
X
X
X
X
Safety
Physical examination
X
X
X
X
X
X
X
Neurologic examination
X
X
X
X
X
X
X
12-lead ECG
X
Height/weighti
X
X
X
X
X
X
X
Vital signs (temperature, HR, RR, 
BP)j
X
X
X
X
X
X
X
Clinical laboratory testsk
X
X
X
X
X
X
Pregnancy testl
X
X
X
X
X
X
X
X
24-hour urine collectionm
X
X
X
Tanner stagingn
X
X
X


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
26
Approved, Date: 3 November 2017
Phase
Screening
Open-Label Treatmenta
Posttreatmentb
End-of-
Study/Early 
Withdrawal
Follow-up 
Telephone 
Contact
Week (W)/Month (M)
Baseline/
W1
M1
M2
M3
M6
M9
M12
M13
Study Day
≤-28
1c
30
60
90
180
270
360
390d
Study Day Window
-7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
Visite
1
2
3
4
5
6
7
8
NA
Renal ultrasoundo
X
X
X
Biochemical bone markersp
X
X
X
DEXA scanb,q
X
X
X
Bone age x-rayr
X
X
Dispense seizure diary and take-
home records
X
X
X
X
X
X
Review seizure diary and take-
home record
X
X
X
X
X
X
Cogstate Batteryt
X
X
X
X
Animal Fluency Test NEPSY-IIu
X
X
X
X
Vineland Adaptive Behavior 
Scalev
X
X
X
X
CBCL–Parent Versionw
X
X
X
X
C-SSRSx
X
X
X
X
X
X
X
Ongoing Review
Concomitant therapy
X
X
X
X
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
X
X
X
X
Footnotes appear on the following page.
a Includes a titration period of approximately 6 to 8 weeks, followed by a maintenance period.
b There may be an optional post-study follow-up phase to obtain DEXA measurements in a subgroup of subjects who experience a clinically important reduction
(change in Z-score of -0.5 or greater) in BMD, based on local DEXA scan results, after 1 year of treatment with topiramate; these subjects will have a repeat DEXA 
scan 6 months after discontinuation of study drug.
c The Day 1 visit will serve as the baseline visit. All procedures on Day 1 (except dispensing of study drug) should be completed before randomization.
d The site will contact the subject via telephone at Month 13, to collect data on adverse events and concomitant medications.
e Window for all visits will be ±7 days.
f Adequacy of physical activity will be assessed with the Habitual Activity Estimation Scale.
g Investigator will document inadequacy of any epilepsy treatment that the subject is receiving at the time of screening. Information regarding AED use and other 
medications within 2 years prior to the study will also be collected.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
27
Approved, Date: 3 November 2017
h If possible, blood samples for determination of plasma topiramate and levetiracetam concentrations should be trough samples (taken immediately before the
morning dose) and should coincide with samples drawn for clinical laboratory tests.
i Subjects will be weighed in examination gowns or in lightweight clothing and without shoes. 
Height will be assessed using a wall-mounted stadiometer. 
All study site personnel measuring height will be blinded to treatment to avoid/minimize bias. 
j Orthostatic vital signs will be obtained for all subjects pending cooperation of subjects. A set of 3 measurements will be obtained at baseline only at intervals of 
10 minutes. Thereafter, only 1 orthostatic vital sign measurement will be taken at all subsequent visits. The method for obtaining orthostatic vital signs will be as 
follows: subject will be supine for 5 minutes prior to measurement, and standing for 2 minutes prior to measurement.
k Clinical laboratory tests (nonfasting) include serum chemistry, hematology, venous ammonia and urinalysis. Insulin-like growth factor 1, 1,25-dihydroxy-vitamin D, 
25-hydroxy-vitamin D, and parathyroid hormone will be measured at screening and at Months 6 and 12/early withdrawal. The laboratory tests for 
25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, Parathyroid hormone (intact) and IGF-1 at screening will be evaluated centrally, but additional evaluation at a 
local laboratory is allowed in order to reduce the duration of the screening phase.
l Serum pregnancy test at screening; urine pregnancy test at all other visits.
m A 24-hour urine collection will be analyzed for pH, calcium, citrate, phosphorus, and creatinine levels. Collection instructions and storage conditions will be 
specified in the laboratory manual. A 14-day window on either side of the scheduled Month 6 visit will be allowed for 24-hour urine collection. The collection at 
Month 12 should be completed before the Month–12 visit as this evaluation should be obtained while the subject is still receiving study–drug therapy.
n Tanner staging of subjects of age 8 years and above will be conducted by a qualified pediatric endocrinologist or by a physician trained in the method.
o Renal ultrasound will be obtained under blinded conditions after randomization and will be read/interpreted centrally (local reading at the screening visit is 
acceptable to determine eligibility for randomization). Both the technicians administering the renal ultrasound scans and the local and central readers will be blinded 
to the study treatment group. 
p Biochemical bone markers will include serum calcium, phosphorus, parathyroid hormone [intact], 25-hydroxy-vitamin D, and 1,25-dihydroxy-vitamin D.
q DEXA measurements will include posterior-anterior spine (lumbar) and total body less head areal BMD and BMC. Short-term precision testing will be performed 
for DEXA measurements according to standard protocols. The same DEXA machine will be used at each site for all subjects and all measurements; only clinical 
sites using recent-generation Hologic or General Electric Lunar systems will participate in the study; the GE/Lunar systems will only be used for subjects ≥5 years 
of age. If possible, the same technician should acquire all scans for any particular subject.
Both the technicians administering the DEXA scans and the central reader will be blinded to the treatment group.
For each time point, up to 3 scan attempts will be performed all on the same day (with repositioning between each scan), with the goal of obtaining 2 complete, 
movement-free scans of both the spine and whole body at screening.
r A hand/wrist x-ray (in the nondominant hand/wrist) will be used to determine bone age.
s Subjects will be given a take-home record, to capture data on study drug administration, concomitant medications, and items of general health, and a seizure diary 
with instructions to record seizure counts and the date and description of each seizure.
t The computerized Cogstate Battery will be administered by non-expert (non-psychologist) study site personnel trained in the Cogstate administration method, with 
2 practice sessions, 1 at screening and 1 at baseline prior to the baseline assessment. For subjects 6 to 15 years of age, the Detection Test, Identification Test, One
Card Learning Test, One Back Test, and Groton Maze Learning Test will be administered. For cooperative subjects 4 to 5 years of age, the Detection Test and 
Identification Test will be administered.
u The Animal Fluency Test NEPSY-II will be administered for subjects 6 to 15 years of age, with 1 practice session at screening.
v The Vineland Adaptive Behavior Checklist will be completed by a parent or guardian for subjects 2 to 5 years of age.
w The CBCL-Parent version will be used for all subjects. For subjects 2 to 5 years of age, the preschool version will be administered. For subjects 6 to 15 years of age, 
the school-age version will be administered.
x The C-SSRS will be administered for subjects 6 to 15 years of age and will not be administered for subjects 2 to 5 years of age.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
28
Approved, Date: 3 November 2017
AED=antiepileptic drug; BMC=bone mineral content; BMD=bone mineral density; BP=blood pressure; CBCL=Child Behavior Checklist; C-SSRS=Columbia Suicide 
Severity Rating Scale; DEXA=dual energy x-ray absorptiometry; ECG=electrocardiogram; HR=heart rate; IGF-1=insulin-like growth factor 1; NEPSY =A 
Developmental NEuroPSYchological Assessment; RR=respiratory rate.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
29
Approved, Date: 3 November 2017
ABBREVIATIONS
AED
antiepileptic drug
ALT
alanine aminotransferase
ASEBA
Achenbach System of Empirically Based Assessment
AST
aspartate aminotransferase
BID
twice a day
BMC
bone mineral content
BMD
bone mineral density
BMDCS
Bone Mineral Density in Childhood Study
BMI
body mass index
CBCL
Child Behavior Checklist 
CDC
Centers for Disease Control
CRF
case report form 
C-SSRS
Columbia Suicide Severity Rating Scale
DEXA
dual energy x-ray absorptiometry
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form 
eDC
electronic data capture
EEG
electroencephalogram
GABA
γ-aminobutyrate
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
HAES
Habitual Activity Estimation Scale
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IGF-1
insulin-like growth factor 1
IRB
Institutional Review Board
IWRS
interactive web-based response system
JME
juvenile myoclonic epilepsy
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-model repeated measures
NEPSY
A Developmental NEuroPSYchological Assessment
NSAIDs
nonsteroidal anti-inflammatory drugs
PGTCS
primary generalized tonic-clonic seizures
PK
pharmacokinetic(s)
POS
partial-onset seizures
PQC
product quality complaint
ULN
upper limit of normal
WBC
white blood cell


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
30
Approved, Date: 3 November 2017
1.
INTRODUCTION
TOPAMAX® (topiramate) (2,3:4,5-Di-O-isopropylidene-ß-D-fructopyranose sulfamate) is a 
structurally unique compound that is effective and well tolerated as an anticonvulsant after oral 
administration in animals and humans. Topiramate is approved as adjunctive treatment in adults 
and in pediatric patients (2 to 16 years of age) with partial-onset seizures (POS), primary 
generalized tonic-clonic seizures (PGTCS), or seizures associated with Lennox-Gastaut 
syndrome. It is also approved for monotherapy treatment in adult and pediatric patients down to 
2 years of age with newly or recently diagnosed POS or PGTCS, and for the prophylaxis of 
migraine in adults and adolescents 12 years of age and older.
Background information on nonclinical and clinical studies with topiramate is provided below.
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of topiramate, refer to the latest version of the Investigator's Brochure for topiramate.33
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
Nonclinical Studies
Pharmacologic Profile
Pharmacologic effects that may contribute to the anticonvulsant activity of topiramate include 
inhibition of some voltage-activated sodium channels; potentiation of the ability of 
γ-aminobutyrate (GABA) to activate some GABAA receptors; inhibition of the kainate or 
∝-amino-3-hydroxy-5-methylisoxazole-4-propionic 
acid
subtype 
but 
not 
the 
N-
methyl-D-aspartate subtype of glutamate receptors; and a modest negative modulatory effect on 
L-type and R-type voltage-activated calcium channels. Some studies suggest topiramate has an 
activating effect on some types of potassium channels, but this may be secondary to effects on 
calcium channels. These pharmacodynamic properties are observed at therapeutically relevant 
concentrations (1 to 100 μM) and may have a common molecular mechanism that affects the 
phosphorylation state of these complex membrane proteins. Topiramate also inhibits some 
carbonic anhydrase isozymes, particularly carbonic anhydrase-II and carbonic anhydrase-IV 
(Ki ∼1 μM). The possible role of carbonic anhydrase inhibitory activity in the AED efficacy of 
topiramate is not definitively established, but there is clear evidence that carbonic anhydrase 
inhibition causes or contributes to metabolic acidosis and nephrolithiasis.33
Toxicology
Acute and long-term oral exposure to topiramate is generally well tolerated. Topiramate is 
teratogenic in animals, does not affect the fertility of male or female rats, and exhibits no 
genotoxic potential.33


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
31
Approved, Date: 3 November 2017
In juvenile rats, findings were similar to those in adults, with no unique toxicities and no effect 
on memory and learning, mating and fertility, or hysterotomy parameters (numbers of corpora 
lutea, implantations, conceptuses or implantation losses). Males had decreased serum inorganic 
phosphate levels, and both males and females had increased urine inorganic phosphate levels at 
dosages of 300 mg/kg/day. There were no effects on mean long bone (tibia) growth; global left 
femoral bone mineral density (BMD) was minimally lower in juvenile rats given 300 mg/kg/day 
compared with controls. Lower (around -20%) mean total height (thickness) of the growth plate 
and mean height of the proliferative or hypertrophic zones taken separately were observed in 
males given 300 mg/kg/day in comparison with controls. Individual values were below or within 
the lower part of the control range. However, there was an opposite trend in females given the 
same dosage, where marginally higher (+3%) mean total height was noted. Individual values in 
females were within the control range.28
Pharmacokinetic Profile
In studies evaluating the pharmacokinetic (PK) profile and metabolism of topiramate in animals, 
oral doses of topiramate were rapidly and almost completely absorbed, rapidly distributed to the 
tissues, poorly bound to plasma protein, and eliminated primarily via the kidneys. The metabolic 
pathways for topiramate are qualitatively similar in the mouse, rat, rabbit, dog, and human.33
Clinical Studies
Human Pharmacokinetics
Topiramate exhibits linear PK, with no evidence of auto-induction or inhibition of metabolism. It 
is rapidly absorbed and not extensively metabolized. Its absolute bioavailability is 81% to 95% 
and its metabolism is not affected significantly by food. The major elimination route of 
unchanged topiramate and its metabolites is renal.
The PK of topiramate were evaluated in pediatric subjects with epilepsy (4 to 17 years of age) 
receiving 1 or 2 other AEDs.32 Pharmacokinetic profiles were obtained after 1 week, at dosages 
of 1, 3, and 9 mg/kg/day. The PK of topiramate were linear, with clearance independent of 
dosage and steady-state plasma concentrations increasing in proportion to dosage. Pediatric 
subjects (4 to 17 years of age) had a 50% higher clearance, and consequently a shorter 
elimination half-life, compared with adults. Consequently, the plasma concentration for the same 
milligram-per-kilogram dosage may be lower in pediatric subjects than in adults. As in adults, 
hepatic enzyme-inducing AEDs decreased the steady-state plasma concentrations of topiramate.
In a separate study, unchanged topiramate and 6 metabolites were quantified from the urine of 
children with infantile spasms who were between the ages of 9 and 43 months and receiving 
topiramate dosages of 7 to 10 mg/kg/day.14 The relative amounts of topiramate and its 
metabolites found in the urine of subjects with infantile spasms were similar to those observed in 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
32
Approved, Date: 3 November 2017
adults.14 Both infants and adults receiving topiramate adjunctive to hepatic enzyme-inducing 
AEDs had a higher proportion of metabolites than of parent topiramate in the urine. Two 
metabolites, topiramate-N-glucuronide and hydroxytopiramate sulfate, were identified in trace 
amounts (≤8%) in infants but were not detected in adults. The results of this study indicate that 
topiramate does not appear to be metabolized significantly differently in infants or young 
children compared with adults.
Efficacy/Safety Studies
Clinical studies have shown that topiramate is effective as an adjunctive treatment in adults and 
in pediatric subjects (2 to 16 years of age) with POS or PGTCS, and in pediatric subjects 
(≥2 years of age) with seizures associated with Lennox-Gastaut syndrome. In the controlled 
adjunctive therapy studies, which included pediatric subjects, target topiramate dosages were 
based on weight and ranged from approximately 5 to 9 mg/kg/day, administered in 2 divided 
doses. Topiramate was superior to placebo with regard to percent reduction in average monthly 
seizure rate, percentage of treatment responders, and global assessments made by investigators 
and subjects. Dosages above 400 mg/day (600, 800, or 1,000 mg/day) have not been shown to 
improve responses in dose-response studies in adults with POS.33
Topiramate has also been shown to be effective as monotherapy in adult and pediatric subjects
with refractory epilepsy or newly or recently diagnosed epilepsy. In monotherapy studies, 
topiramate was administered at dosages ranging from 25 to 400 mg/day in children (≥6 years of 
age) and 50 to 500 mg/day in adults (≥16 years of age), and was effective in reducing the number 
of seizures experienced.7,8,9 In particular, comparison of Kaplan-Meier survival curves for time 
to first seizure (primary efficacy endpoint) in the double-blind monotherapy study 
TOPMAT-EPMN-106 (n=487; age ranging from 6 to 83 years) favored a higher dosage of 
topiramate over a lower dosage (400 mg/day vs. 50 mg/day; p=0.0002 [log-rank test]). The 
separation between the groups in favor of the high-dosage group occurred early in the titration 
phase and was statistically significant as early as 2 weeks after randomization (p=0.046), when, 
by following the weekly titration schedule, subjects in the high-dosage group achieved a 
maximum topiramate dosage of 100 mg/day. The high-dosage group was also superior to the 
low-dosage group with respect to proportion of subjects remaining seizure-free, based on the 
Kaplan-Meier estimates, for at least 6 months (82.9% vs. 71.4%; p=0.005) and for at least 1 year 
(75.7% vs. 58.8%; p=0.001). The treatment effects, with respect to time to first seizure, were 
consistent across subgroups defined by age, sex, geographic region, baseline body weight, 
baseline seizure type, time since diagnosis, and baseline AED use.33


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
33
Approved, Date: 3 November 2017
Pharmacokinetic-pharmacodynamic modeling and simulation bridging was used to identify and 
validate the efficacious monotherapy dosing regimen for topiramate in children 2 to <10 years of 
age with newly diagnosed epilepsy.17
Topiramate appears to be well tolerated; neuropsychiatric events of mild or moderate severity are 
the most common treatment-emergent adverse events across subject populations. In general, 
there were no noteworthy changes in clinical laboratory analytes other than the expected 
decreases in serum bicarbonate/CO2 levels in topiramate clinical studies. Metabolic acidosis, 
considered to be possibly related to the carbonic anhydrase-inhibiting effect of topiramate, has 
been reported less frequently in adults compared with children but was most common in infants
(1 to 24 months of age). In adolescents with migraine, there was no clinically significant effect 
on serum CO2. Overall, the incidence of adverse events and abnormal laboratory findings are not 
notably different for pediatric and adult subjects. 
Several issues of special interest have emerged during the development of topiramate, including 
effects on liver function; metabolic acidosis; effects on growth and maturation; vision 
abnormalities (acute myopia and secondary 
angle-closure glaucoma); oligohidrosis, 
hyperthermia, and secondary rash; hyperammonemia and encephalopathy, and kidney stones. 
These are discussed in brief below, and are described in further detail in the Investigator’s 
Brochure. 
Safety Issues of Clinical Concern
Effects on Liver Function
Comprehensive review of clinical study and postmarketing data revealed no evidence of direct or 
cumulative hepatotoxicity by topiramate. Across study populations (adjunctive epilepsy, 
monotherapy epilepsy, and migraine), hepatic event rates and laboratory liver function test (LFT) 
values for topiramate-treated subjects were similar to those of placebo-treated subjects and, 
generally, better than those of subjects treated with comparator medications (carbamazepine, 
valproate, and lithium). Spontaneously reported hepatic events are very rare (<1/10,000 
patient-years). Based collectively on clinical study and postmarketing data, the majority of 
hepatic events are transient and mild to moderate in severity. Moreover, hepatic adverse events 
that were considered serious, led to discontinuation, or involved markedly abnormal LFT values 
often were confounded by concomitant medications or intercurrent illness.33
Metabolic Acidosis
Hyperchloremic, non-anion gap, metabolic acidosis (ie, decreased serum bicarbonate below the 
normal reference range in the absence of chronic respiratory alkalosis) is associated with 
topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the 
inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
34
Approved, Date: 3 November 2017
observed with the use of topiramate in placebo-controlled clinical studies and in the 
post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in 
treatment, although cases can occur at any time during treatment. Bicarbonate decreases are 
usually mild to moderate (average decrease of 4 mEq/L at daily dosages of 400 mg/day in adults 
and at approximately 6 mg/kg/day in children); rarely, subjects can experience severe decreases, 
to values 10 mEq/L.33
Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, 
nonspecific symptoms such as fatigue and anorexia, or more severe sequelae, including cardiac 
arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for 
nephrolithiasis or nephrocalcinosis, and may also result in osteopenia or osteoporosis, with an 
increased risk for fractures. Chronic metabolic acidosis in pediatric subjects may also reduce 
growth rates. A reduction in growth rate may eventually decrease the maximum height achieved. 
The effect of topiramate on growth and bone-related sequelae has not been systematically 
investigated.
Growth and Maturation
Reports have suggested that certain AEDs may adversely affect growth and maturation in some 
children. Body weight was evaluated among pediatric subjects 6 to 15 years of age in clinical 
studies with topiramate monotherapy, and in 1 of these studies (study TOPMAT-EPMN-106) 
body mass index (BMI) was evaluated according to Centers for Disease Control (CDC) criteria. 
Among 
pediatric 
subjects 
administered 
topiramate 
monotherapy
in 
studies 
TOPMAT-EPMN-104, TOPMAT-EPMN-105, and TOPMAT-EPMN-106, mean body weight 
increased in the double-blind treatment phase; most subjects experienced an increase or no 
change in body weight. Of those with weight loss, most exhibited decreases of 1% to 9%. 
Adverse events of weight loss were reported in 21% of pediatric subjects but none was serious or 
treatment-limiting. 
In 
the 
open-label 
extension 
of 
monotherapy 
treatment 
studies
TOPMAT-EPMN-104 and TOPMAT-EPMN-106, mean body weight of pediatric subjects also 
increased. 
During the double-blind phase of study TOPMAT-EPMN-106, mean BMI decreases were 
observed for approximately half of the pediatric subjects in the topiramate 50-/400-mg/day group 
and topiramate 400-/400-mg/day group, with most of the remaining subjects showing no change 
in BMI. Larger BMI decreases followed 400 mg/day topiramate than followed 50 mg/day. Based 
on CDC criteria, topiramate treatment rarely resulted in underweight BMI among pediatric 
subjects with normal BMI values at baseline. Mean BMI decreases (-1.3 kg/m2) were observed at 
6 months among pediatric subjects whose dosage increased from 50 to 400 mg/day during this 
study's open-label extension.39


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
35
Approved, Date: 3 November 2017
Weight, height, and BMI Z-scores decreased from baseline to endpoint in pediatric subjects in 
monotherapy studies. These results indicate that, in general, children continue to grow while 
receiving topiramate monotherapy treatment, although at a rate slower than their normal healthy 
counterparts.33
Vision Abnormalities (Acute Myopia and Secondary Angle-Closure Glaucoma)
A medical condition consisting of sudden worsening of vision and an elevation of fluid pressure 
in the eyes (secondary glaucoma) has been described in clinical studies and post-marketing 
reports in subjects taking topiramate, usually at the beginning of their treatment. In contrast to 
primary narrow-angle glaucoma, which is rare under 40 years of age, secondary angle-closure 
glaucoma associated with topiramate has been reported in pediatric as well as adult subjects. 
Symptoms include acute onset (within 1 month of initiating topiramate therapy) of decreased 
visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber 
shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or 
may not be present. The primary treatment to reverse symptoms is discontinuation of topiramate 
as rapidly as possible according to the judgment of the treating physician.33
Visual field defects have been reported in subjects receiving topiramate independent of elevated 
intraocular pressure. In clinical studies, most of these events were reversible after topiramate 
discontinuation. If visual problems occur at any time during topiramate treatment, consideration 
should be given to discontinuing the drug.
Oligohidrosis, Hyperthermia, and Secondary Rash 
Oligohidrosis (decreased sweating) and hyperthermia, infrequently resulting in hospitalization, 
has been reported in clinical studies and post-marketing reports in association with the use of 
topiramate. These cases were characterized by decreased sweating and an elevation in body 
temperature above normal. Some of the cases were reported after exposure to elevated 
environmental temperatures. The majority of the reports have been in children. Skin erythema 
has been reported secondary to the hyperthermia and oligohidrosis and should be monitored; 
adequate hydration is encouraged. 
Hyperammonemia and Encephalopathy 
In clinical studies and post-marketing reports, concomitant administration of topiramate and 
valproic acid has been associated with hyperammonemia with or without encephalopathy in 
subjects who have tolerated either drug alone. In most cases, symptoms and signs abated with 
discontinuation of either drug. This adverse event is not due to a PK interaction. 
Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical 
studies in adolescents (12-16 years of age) who were treated with topiramate monotherapy for 
migraine prophylaxis and in very young pediatric subjects (1-24 months of age) who were 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
36
Approved, Date: 3 November 2017
treated with adjunctive topiramate for POS. In some subjects, ammonia was markedly increased
(defined in the clinical study report as >50% increase from baseline and absolute value >2x 
upper limit of normal [ULN]). In the adolescent subjects, the incidence of markedly increased 
hyperammonemia was 3% (1 subject), 0%, and 9% (3 subjects) for the placebo, 50 mg/day, and 
100 mg/day groups, respectively.10
The hyperammonemia associated with topiramate treatment occurred with and without 
encephalopathy in placebo-controlled studies, and in an open-label extension study in infants. 
Dose-related hyperammonemia was also observed in the open-label extension study in pediatric 
subjects 1 month to 2 years of age. Clinical symptoms of hyperammonemic encephalopathy may 
include acute alterations in level of consciousness and/or cognitive function with lethargy or 
vomiting. Hyperammonemia with and without encephalopathy has also been observed in 
post-marketing reports in patients who were taking topiramate without concomitant valproic 
acid.38
Kidney Stones
The occurrence of renal calculi (1.5% to 1.9% incidence) was observed in clinical studies and 
post-marketing reports of topiramate in adult and pediatric subjects ≥2 years of age with 
epilepsy. The majority of cases did not require surgical intervention. Kidney stones have also 
been reported in infant subjects during long-term (up to 1 year) topiramate treatment. In an 
open-label extension study (TOPMAT-PEP-1002_3001 OLE) of 284 pediatric subjects 1 to 
24 months old with epilepsy, 7% developed kidney or bladder stones, which were primarily 
asymptomatic and were assessed systematically by renal ultrasound. Topiramate is not approved 
for pediatric patients less than 2 years of age.38
The mechanism is believed to be associated with the carbonic anhydrase inhibitory activity of 
topiramate. Carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) 
can promote stone formation by reducing urinary citrate excretion and by increasing urinary 
pH.33
1.1.
Comparator Agent 
Levetiracetam
Levetiracetam is indicated for use as an adjunctive therapy for POS (adults and children 
≥1 month of age with epilepsy), PGTCS (adults and children ≥6 years of age with idiopathic 
generalized epilepsy), and myoclonic seizures (adults and children ≥12 years of age with juvenile 
myoclonic epilepsy [JME]).24 The safety profile in pediatric subjects with epilepsy is 
summarized below. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
37
Approved, Date: 3 November 2017
Subjects With Partial-Onset Seizures
In pediatric subjects experiencing POS, levetiracetam is associated with somnolence, fatigue, and 
behavioral abnormalities.24
In a double-blind, controlled study in children with epilepsy experiencing POS, 22.8% of 
levetiracetam-treated subjects experienced somnolence, compared with 11.3% of placebo 
subjects. The design of the study prevented accurately assessing dose-response effects. No 
subject discontinued treatment for somnolence. In about 3.0% of levetiracetam-treated subjects 
and in 3.1% of placebo subjects, the dosage was reduced as a result of somnolence.24
Asthenia was reported in 8.9% of levetiracetam-treated subjects, compared with 3.1% of placebo 
subjects. No subject discontinued treatment for asthenia, but asthenia led to a dosage reduction in 
3.0% of levetiracetam-treated subjects compared with 0% of placebo subjects.24
A total of 37.6% of the levetiracetam-treated subjects experienced behavioral symptoms 
(reported as agitation, anxiety, apathy, depersonalization, depression, emotional lability, 
hostility, hyperkinesia, nervousness, neurosis, and personality disorder), compared with 18.6% of 
placebo subjects. Hostility was reported in 11.9% of levetiracetam-treated subjects, compared 
with 6.2% of placebo subjects. Nervousness was reported in 9.9% of levetiracetam-treated 
subjects, compared with 2.1% of placebo subjects. Depression was reported in 3.0% of 
levetiracetam-treated subjects, compared with 1.0% of placebo subjects.24
A total of 3.0% of levetiracetam-treated subjects discontinued treatment due to psychotic and 
nonpsychotic adverse events, compared with 4.1% of placebo subjects. Overall, 10.9% of 
levetiracetam-treated subjects experienced behavioral symptoms associated with discontinuation 
or dosage reduction, compared with 6.2% of placebo subjects.24
Subjects With Myoclonic Seizures
During clinical development, the number of subjects with myoclonic seizures exposed to 
levetiracetam was considerably smaller than the number with partial seizures. Therefore, 
underreporting of certain adverse events was more likely to occur in the myoclonic seizure 
population. In adult and adolescent subjects experiencing myoclonic seizures, levetiracetam is 
associated with somnolence and behavioral abnormalities. It is expected that the events seen in 
POS subjects would occur in patients with JME. In a double-blind, controlled study in adults and 
adolescents with JME experiencing myoclonic seizures, 11.7% of levetiracetam-treated subjects
experienced somnolence compared with 1.7% of placebo subjects. 
In 1.7% of 
levetiracetam-treated subjects and in 0% of placebo subjects, the dosage was reduced as a result 
of somnolence.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
38
Approved, Date: 3 November 2017
Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of 
the levetiracetam-treated JME subjects compared with 0% of placebo subjects. Non-psychotic 
mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of 
levetiracetam-treated JME subjects compared with 3.3% of placebo subjects. A total of 5.0% of 
levetiracetam-treated subjects had a reduction in dosage or discontinued treatment due to 
behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, 
and nervousness), compared with 1.7% of placebo subjects.
In a well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult 
subjects with myoclonic seizures, the most frequently reported adverse events associated with 
the use of adjunctive levetiracetam, not seen at an equivalent frequency among placebo-treated 
subjects, were somnolence, neck pain, and pharyngitis. The different pattern of adverse events, 
as compared with subjects with POS, is likely due to the much smaller number of subjects in the 
JME study.24
Subjects With Primary Generalized Tonic-Clonic Seizures
During clinical development, the number of subjects 4 years of age and older with PGTCS 
exposed to levetiracetam was considerably smaller than the number with POS. As in the POS 
subjects, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait 
disorders and somnolence were also described in the study in PGTCS, but with no difference 
between placebo and levetiracetam treatment groups and no appreciable discontinuations. 
Although it may be expected that drug-related events seen in POS subjects would be seen in 
PGTCS subjects (eg, somnolence and gait disturbance), these events may not have been 
observed because of the smaller sample size.24
Discontinuation or Dosage Reduction in Well-Controlled Clinical Studies
The adverse events most commonly associated (≥3% in subjects receiving levetiracetam) with 
discontinuation or dosage reduction in the well-controlled pediatric POS study were asthenia, 
hostility, and somnolence. The adverse event most commonly associated (≥3% in subjects
receiving levetiracetam) with discontinuation or dosage reduction in the well-controlled pediatric 
JME study was anxiety (2 subjects, 3.3%), but the small study size (a total of 113 subjects 
enrolled with JME) limits the conclusions that can be drawn. The PGTCS study was too small to 
adequately characterize the adverse events leading to discontinuation or dosage reduction.24
Hematologic Abnormalities
Levetiracetam-treated pediatric subjects with POS experienced small, but statistically significant, 
decreases in white blood cell (WBC) and neutrophil counts and increases in lymphocyte counts, 
as compared with placebo. In a well-controlled study, more levetiracetam-treated pediatric 
subjects with POS had a possibly clinically significant abnormally low total WBC value (3.0% 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
39
Approved, Date: 3 November 2017
levetiracetam-treated versus 0% placebo); however, there was no apparent difference between 
treatment groups with respect to neutrophil count. No subject was discontinued secondary to low 
WBC or neutrophil counts. Although there were no obvious hematologic abnormalities observed 
in subjects with JME, the limited number of subjects limits the conclusions that can be drawn.24
Liver Function Test Abnormalities 
There were no meaningful changes in mean LFT values in controlled studies in adult or pediatric 
subjects; LFT abnormalities were similar in drug- and placebo-treated subjects in controlled 
studies (1.4%). No pediatric subjects were discontinued from controlled studies due to LFT 
abnormalities.24
Impaired Renal Function 
Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse 
reactions to this drug may be greater in patients with impaired renal function.24
Post-Marketing Experience With Adjunctive Therapy
The following have been reported in patients receiving marketed levetiracetam worldwide
(alphabetical order): abnormal LFT values, choreoathetosis, dyskinesia, erythema multiforme, 
hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow 
suppression identified in some of these cases), Stevens-Johnson syndrome, thrombocytopenia, 
toxic epidermal necrolysis, and weight loss. Alopecia has been reported with levetiracetam use; 
recovery was observed in the majority of cases where levetiracetam was discontinued. 
Levetiracetam Monotherapy
Levetiracetam is not approved as monotherapy for epilepsy; however, investigator-initiated 
studies of children with epilepsy support its use in this indication. These monotherapy studies 
used the same titration and maintenance dosing as pivotal adjunctive studies; overall efficacy and 
safety outcomes were similar in both treatment settings.21,24,29,43
1.2.
Overall Rationale for the Study
Among its various pharmacologic actions, topiramate is a carbonic anhydrase inhibitor and may 
induce metabolic acidosis, and other changes (eg, hypocitraturia, hypercalciuria, and elevated 
urine pH) that may be associated with an increased tendency for kidney stone formation.41
Chronic metabolic acidosis may be associated with abnormal bone mineralization and/or 
homeostasis of vitamin D, calcium, or phosphorus. Childhood is a critical period for bone 
mineralization and growth. The effects of topiramate on growth, bone mineralization, and kidney 
stone formation have not been fully and systematically evaluated or well characterized in 
pediatric populations. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
40
Approved, Date: 3 November 2017
Preclinical juvenile rat studies demonstrated various clinical chemistry and bone findings 
(eg, changes in serum and urinary phosphate, decreased global BMD, decreased growth plate 
thickness) with topiramate treatment that raise concerns about long-term toxicities in pediatric 
patients. 
This study will systematically assess the long-term safety of topiramate monotherapy compared 
with levetiracetam monotherapy; specific emphasis will be on metabolic acidosis related to 
topiramate therapy and its association with nephrolithiasis, BMD abnormalities, and delayed 
growth in children (2 to 15 years of age).
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to evaluate the effects of topiramate monotherapy compared with 
levetiracetam, another standard AED, as monotherapy for new-onset or recent-onset epilepsy on 
pediatric growth and maturation, bone mineralization, and kidney stone formation in children 2 
to 15 years of age.
Secondary Objective
Overall safety will be assessed.
2.2.
Hypothesis
The study will test the hypothesis that flexible dosages of topiramate monotherapy have the same 
effect as flexible dosages of levetiracetam monotherapy on pediatric
growth, bone 
mineralization, and kidney stone formation in children 2 to 15 years of age with new-onset or 
recent-onset epilepsy, versus the alternative hypothesis that the effect of topiramate is different 
from that of levetiracetam.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a 1-year, randomized, active-controlled, outpatient, multicenter, open-label, 2-arm 
flexible-dose monotherapy study of topiramate compared with 1 other AED (levetiracetam) in 
pediatric subjects with epilepsy. Subjects will be required to have newly or recently diagnosed 
epilepsy (within the previous 2 years, with at least 1, but no more than 10, unprovoked seizures 
during the 5 months prior to screening) characterized by POS with or without secondary 
generalization or PGTCS. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
41
Approved, Date: 3 November 2017
Approximately 282 male and female subjects, 2 to 15 years of age, with newly or recently 
diagnosed epilepsy, who meet the inclusion/exclusion criteria will be randomly assigned to either 
the topiramate or levetiracetam arm, in a 1:1 ratio. The randomization will be balanced using 
randomly permuted blocks and will be stratified by country and age group (2 to 5 years of age, 6 
to 9 years of age, 10 to 12 years of age, and 13 to 15 years of age). The enrollment will be 
monitored throughout the study to ensure that subjects are enrolled for each integer year in each 
treatment group.
For each subject, his or her parent(s) (preferably both parents, if available) or a legally 
acceptable representative(s), as required by local regulations, must give written consent 
(permission) according to local requirements after the nature of the study has been fully 
explained and before the performance of any study-related activity. Children (minors) or subjects 
who are unable to comprehend the information provided can be enrolled only after obtaining
consent from parents or a legally acceptable representative. Assent must be obtained from 
children (minors) capable of understanding the nature of the study, typically subjects 7 years of 
age and older, depending on the institutional policies. For the purposes of this study, all 
references to subjects who have provided informed assent/consent refers to the subject (assent as 
applicable) and his or her parent(s) or the subject's legal guardian(s) or legally acceptable 
representative(s) who have provided consent according to this process. Minors who assent to a 
study and later withdraw their assent should not be maintained in the study against their will, 
even if their parents still want them to participate.
The study will include the following 3 phases: a screening phase of up to 28 days, an open-label 
treatment phase of 1 year's duration, and a posttreatment phase of 30 days’ duration. There may 
be an optional post-study follow-up phase to obtain dual energy x-ray absorptiometry (DEXA) 
measurements in a subgroup of subjects who experience a clinically important reduction (change 
in Z-score of -0.5 or greater) in BMD, based on local DEXA scan results, after 1 year of 
treatment with topiramate, to determine whether a decrease in BMD after or during 1 year of 
treatment with topiramate is reversible. These subjects will have a repeat DEXA scan 6 months 
after discontinuation of study drug.
To minimize any bias in measurement, after randomization 3 of the safety assessments will be 
obtained in a blinded fashion, including the DEXA scan, renal ultrasound, and height.
Screening Phase:
Subjects meeting the inclusion/exclusion criteria (see Section 4, Subject Selection) will be eligible 
to enter into the study. They (and/or their parents or legally acceptable representatives) will sign an 
informed consent/assent form as appropriate (see Section 16.2.3, Informed Consent) and enter a 
screening phase of up to 35 days. During the screening phase, subjects will be assessed for study 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
42
Approved, Date: 3 November 2017
qualifications. Subjects (or their parents/guardians) will keep a seizure diary (date of seizure and 
description). Information will be transcribed onto the case report form (CRF). Seizure diaries will 
be maintained with the source documents.
Open-Label Treatment Phase:
Immediately following the Screening Phase, qualified subjects, based on inclusion/exclusion 
criteria, will be randomly assigned to 1 of 2 treatment groups during the open-label treatment 
phase: topiramate (up to 350 mg/day in subjects 2 to <10 years of age, and up to 400 mg/day in 
subjects 10 to 15 years of age) or levetiracetam (up to 60 mg/kg/day). Antiepileptic drug dosages 
may be adjusted for clinical effect (efficacy and safety) during the open-label treatment phase but 
may not exceed these maximum dosages. 
Only AED monotherapy will be used for both treatment groups. However, subjects will not be 
discontinued from the study if 1 or more concomitant AEDs are added after initiating treatment 
with study drug. Data will be collected prior to the use of the concomitant AED(s) for the 
primary analysis. Data subsequently collected while on the concomitant AED(s) will be analyzed 
in a secondary analysis for each safety outcome of interest.
All subjects will enter a 30-day posttreatment phase after completing the open-label treatment 
phase.
The open-label treatment phase has 2 periods, titration and maintenance.
Titration Period
Randomization will take place on Day 1 (Visit 2). The Day 1 visit will serve as the baseline visit. 
All procedures on Day 1 (except dispensing of study drug) should be completed before 
randomization.
Study drug will be titrated as tolerated to the maximum recommended dosage for optimal clinical 
effect over approximately 6 to 8 weeks, based on titration guidelines according to clinical 
response (see Section 6, Dosage and Administration). For all subjects, at any time, up-titration of 
open-label study drug may be slowed down if clinically indicated for tolerability, and may be 
accelerated if clinically indicated for seizure control. 
Subjects will return for a clinic visit at Month 1 and Month 2 for dispensing of study medication. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
43
Approved, Date: 3 November 2017
Maintenance Period
Subjects should be maintained on the dosage achieved at the end of the titration period through 
the remainder of the open-label treatment phase, with the option for dosage adjustment as 
required for optimal clinical effect. Changes to this schedule will be based on a risk-benefit 
assessment of the subject’s clinical condition by the investigator.
Clinic visits will be scheduled at Months 1, 2, 3, 6, 9, and 12/early withdrawal. Extra visits may 
be scheduled at the discretion of the investigator. Blood samples for PK evaluations will be taken 
at Months 1, 3, 6, and 12/early withdrawal.
Posttreatment Phase
Subjects will be contacted by telephone 30 days after the last dose of study drug to monitor 
adverse events and concomitant medications. Subjects who complete the study or discontinue 
early from the study may, at the discretion of the investigator, either continue on commercially 
available topiramate or levetiracetam or taper off topiramate or levetiracetam over a period of up 
to 2 weeks during the posttreatment phase.
Post-Study Follow-up Phase
There may be an optional post-study follow-up phase to obtain DEXA measurements in a 
subgroup of subjects who experience a clinically important reduction (change in Z-score of -0.5 
or greater) in BMD, based on local DEXA scan results, after 1 year of treatment with topiramate, 
to determine whether a decrease in BMD after or during 1 year of treatment with topiramate is 
reversible. These subjects will have a repeat DEXA scan 6 months after discontinuation of study 
drug. During study conduct, the sponsor will assess site/investigator interest for participation in 
this phase to determine if the follow-up phase will be included. An additional consent/assent will 
be required for this phase.
An external, independent Data Monitoring Committee (DMC) will be commissioned for this 
study. See Section 11.5, Data Monitoring Committee, for details.
A diagram of the study design is provided in Figure 1.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
44
Approved, Date: 3 November 2017
Figure 1: 
Study Diagram
Levetiracetam
(n=141)
Topiramate
(n=141)
Open-Label Maintenance Period
(304 to 318 days)
Titration Period
(6-8 weeks;
42-56 days)
Month 3 Visit
Month 6  Visit
Month 9  Visit 
Post-
treatment 
phase 
(30 days)
Month 12  Visit 
Optional DEXA 
follow-up scan
(18 months from 
Randomization)a
Screening 
phase 
(up to 28 
days)
Month 1 Visit
Baseline/
Randomization (Day 1)
Month 13 Telephone Contact
Month 2 Visit
a Optional post-study follow-up phase to obtain DEXA measurements in a subgroup of subjects who experience a 
clinically important reduction (change in Z-score of -0.5 or greater) in BMD , based on local DEXA scan results,
after 1 year of treatment with topiramate; these subjects will have a repeat DEXA scan 6 months after 
discontinuation of study drug.
3.2.
Study Design Rationale
A study population from 2 to 15 years of age is appropriate for this study because this is the 
approved pediatric age group for topiramate monotherapy. Levetiracetam is indicated as 
adjunctive therapy for POS in adults and children ≥1 month of age with epilepsy), PGTCS 
(adults and children ≥6 years of age with idiopathic generalized epilepsy), and myoclonic 
seizures (adults and children ≥12 years of age with JME). It has been studied as monotherapy in 
pediatric subjects down to neonates and has been demonstrated to be effective and safe in all 
treatment settings. Evaluation of this target age group will provide long-term systematic 
assessments of important safety issues, eg, chronic metabolic acidosis and effects on growth, 
bone mineralization, and nephrolithiasis. Subjects will be stratified by country and by age (2 to 
5 years of age, 6 to 9 years of age, 10 to 12 years of age, and 13 to 15 years of age) in order to 
examine any differences in the safety profile between prepubescent children and postpubescent
adolescents. A study duration of 1 year is appropriate in order to detect clinically important 
treatment-related effects on key safety parameters (growth retardation, bone mineralization, or 
kidney stone formation). See also Section 16.1, Study-Specific Design Considerations.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
45
Approved, Date: 3 November 2017
3.2.1.
Blinding
The study is designed as an open-label study to enhance subject participation and completion and 
to simulate a naturalistic treatment setting. Given the technical challenges regarding blinding of 
study drug, along with the prolonged blinding required in young children and possible 
consequent impact on study conduct and results (eg, difficult regimens requiring too many 
tablets may result in poor compliance, protocol violations, or subjects prematurely dropping out 
of the study), a double-blind approach is not optimal. An open-label study is considered to be 
optimal given that the study population will include pediatric subjects down to 2 years of age and 
the study duration will be 1 year. An open-label design allows flexibility in dosing regimens.
To minimize any bias in measurement, after randomization 3 of the safety assessments will be 
obtained in a blinded fashion, including the DEXA scan, renal ultrasound, and height. These are 
the key assessments that are being evaluated on the basis of the biological effects associated with 
topiramate, and are necessary for achieving the primary objective.
3.2.2.
Active Control
An active control will be used as opposed to a placebo control because of obvious ethical 
concerns of placebo treatment in a long-term monotherapy treatment setting for epilepsy, a 
chronic and potentially life-threatening disorder. Randomization will be used to minimize bias in 
the assignment of subjects to treatment groups, to increase the likelihood that known and 
unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced 
across treatment groups, and to enhance the validity of statistical comparisons across treatment 
groups.
Levetiracetam is an appropriate comparator because of its established efficacy for target seizure 
types, relatively low toxicity, and lack of significant known risk of kidney stones or possible 
deleterious effects on bone or growth. Levetiracetam is not approved as monotherapy for 
epilepsy; however, studies of children with epilepsy support its use in this indication. Notably, 
these monotherapy studies used the same titration and maintenance dosing as pivotal adjunctive 
studies; overall efficacy and safety outcomes were similar in both treatment settings.21,24,29,43 On 
this basis, the FDA-approved dosing recommendations for levetiracetam (titration schedule, 
dosing frequency) will be used in this study. 
Study drug will be given as monotherapy only, since use of any concomitant AED may
potentially confound results. However, subjects will not be discontinued from the study if 1 or 
more concomitant AEDs are added after initiating treatment with study drug. Data will be 
collected prior to the use of the concomitant AED(s) for the primary analysis. Data subsequently 
collected while on the concomitant AED(s) will be analyzed in a secondary analysis for each 
safety outcome of interest.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
46
Approved, Date: 3 November 2017
4.
SUBJECT SELECTION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. 
For a discussion of the statistical considerations
of subject selection, refer to 
Section 11.2, Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be a child or adolescent (male or female) 2 to 15 years of age with a 
clinical diagnosis of new-onset or recent-onset epilepsy characterized by POS (with or 
without secondary generalization) or PGTCS in accordance with criteria of the 
International League Against Epilepsy.12 The epilepsy diagnosis must be within the 
previous 2 years before screening.
2.
Subject must have clinical or electroencephalogram (EEG) evidence of POS (simple or 
complex), with or without secondary generalization, or PGTCS within 5 months prior to 
the first day of screening. Subjects should have at least 1, but no more than 10, 
unprovoked seizures during the 5 months prior to screening. Unprovoked seizure 
clustering within a 24-hour period will be considered as a single unprovoked seizure for 
the purposes of counting seizures to determine eligibility.16
Acceptable evidence of POS includes 1 of the following:

Documented recurrent clinical seizures with asymmetric motor features or 
characteristic behavioral alterations. The interictal EEGs may be negative or 
inconclusive, provided that the clinical criterion for POS is met.

A routine EEG or video EEG showing focal or asymmetric EEG findings 
(epileptiform discharges, focal slowing, focal attenuation, or a combination), with or 
without secondary generalization. Clinical seizures with symmetric or behavioral 
features are acceptable in the presence of EEG evidence of an asymmetric origin.
Acceptable evidence of PGTCS includes 1 of the following: 

Documented recurrent clinical seizures with seizures that are initially generalized, 
associated with tonic contractions and clonic movements

EEG expression that is a generalized, synchronous, symmetrical discharge

Interictal EEGs may be normal or show generalized discharges such as spikes, 
polyspike, spike-wave, and polyspike wave.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
47
Approved, Date: 3 November 2017
3. 
At screening, subject must have weight and height values within the 5th to 95th
percentile for chronological age (based on standard Child Height and Weight Charts 
from the CDC).25
4. 
Subject must never have been treated for epilepsy (treatment-naïve) or have been treated 
with no more than 1 standard AED if temporary or urgent AED use was necessary. 
Previous AED exposure must not exceed either of the following:

Thirty-one days immediately preceding enrollment, or 

A total of 6 months of previous AED exposure in the past if the AED has been 
discontinued for at least 1 year prior to enrollment
5. 
If subject is currently treated with an AED, inadequacy of current epilepsy treatment 
must be documented on a worksheet provided to the investigator. Criteria for 
inadequacy include:

AED dosage is considered optimized (including, if clinically appropriate, recent 
demonstration of adequate blood levels) in the opinion of the investigator and 
unchanged for at least 5 half-lives prior to the first day of screening and found to be:

Inadequate in controlling seizures in the opinion of the investigator, as 
shown in part by a retrospective history of at least 1 seizure in the 3 months 
prior to screening, or 

Not well tolerated
6. 
Parents (or legally acceptable representatives) of the subject must sign an informed 
consent/permission document, indicating that they understand the purpose of and 
procedures required for the study and are willing to give permission for their child to 
participate in the study. Subjects 7 years of age and older, capable of understanding the 
nature of the study, must provide assent for their participation.
7. 
Caregivers (parents or legally acceptable representatives) of the subject must be able to 
accurately maintain the subject take-home record and seizure diary.
8. 
Subject must have had a computerized tomography or magnetic resonance imaging scan 
within 2 years prior to study entry, to confirm the absence of a progressive lesion, such 
as a tumor, with the exception of lesions of tuberous sclerosis and Sturge-Weber 
syndrome, which are allowed. The report must be included in the source documents.
9. 
Subject must have an electrocardiogram (ECG) at screening with no “abnormal, 
clinically significant” interpretations by a local cardiologist.
10.
Subject must be otherwise healthy on the basis of physical examination, medical 
history, vital signs, clinical laboratory tests, and 12-lead ECG performed at screening. If 
there are abnormalities, they must be consistent with the underlying illness in the study 
population. This determination must be recorded in the subject's source documents and 
initialed by the investigator.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
48
Approved, Date: 3 November 2017
11.
Subject must be ambulatory and must have normal activity levels based on the Habitual 
Activity Estimation Scale (HAES; see Attachment 1) at screening, according to 
recommended levels.
12.
Before randomization, a girl must be either:

Not of childbearing potential: premenarchal; permanently sterilized (eg, tubal 
occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of 
pregnancy

Of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for 
subjects participating in clinical studies, eg, established use of oral, injected, or 
implanted hormonal methods of contraception; placement of an intrauterine device 
or intrauterine system; male partner sterilization (the vasectomized partner should be 
the sole partner for that subject); true abstinence (when this is in line with the 
preferred and usual lifestyle of the subject).
Note: Male partners must use a barrier method, such as a condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault cap) 
with spermicidal foam/gel/film/cream/suppository. 
Note: If the childbearing potential changes after start of the study (eg, girl who is not 
heterosexually active becomes active, premenarchal girl experiences menarche), the 
subject must begin a highly effective method of birth control, as described above.
13.
A girl of childbearing potential must have a negative serum -human chorionic 
gonadotropin pregnancy test at screening, and a negative urine pregnancy test at 
randomization/baseline and at all subsequent visits of the open-label treatment phase.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.
Subject has a surgically implanted and functioning vagus nerve stimulator.
2.
Subject has a history of seizures as a result of a correctable medical condition, such as 
metabolic disturbance, toxic exposure, neoplasm, or active infection within 2 weeks 
prior to the first day of screening.
3. 
Subject has had uncontrolled seizures while previously taking either topiramate or 
levetiracetam.
4.
Subject has a history of nonepileptic seizures within 2 weeks prior to the first day of 
screening.
5. 
Subject has myoclonic or absence seizures.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
49
Approved, Date: 3 November 2017
6. 
Subject has a history of status epilepticus within 2 weeks prior to first day of screening. 
Status epilepticus is defined as 30 minutes of continuous motor seizures.
7.
Subject has had epilepsy surgery within 3 months prior to the first day of screening.
8. 
Subject has any progressive neurologic disorder, including malignancy, brain tumor, 
active central nervous system infection, demyelinating disease, or degenerative or 
progressive central nervous system disease, with the exception of tuberous sclerosis and 
Sturge Weber syndrome.
9.
Subject has any clinically significant uncontrolled medical illness, including hepatic or 
renal failure, ischemic cardiac disease, bone disorders, growth and maturation disorders 
of any type, malignancy, physical impairments that prevent normal ambulation, or any 
disorder that, in the opinion of the investigator, places the subject at risk through 
participation in a clinical study.
10. 
Subject has nephrocalcinosis, renal stones of any type, or hydronephrosis, as evidenced 
by medical history or screening examination.
11. 
Subject has a history of ≥2 long bone fractures if the subject is ≤10 years old; ≥3 long 
bone fractures if the subject is >10 years old, where at least 1 of the fractures was a low-
impact fracture, defined as slight trauma that may include:

Falling to the ground from <0.5 m (standing height)

Falling to a resilient surface (rubber or sand) from 0.5 to 3 m

Falling from a bed or cot

Playing injuries, including playground scuffles
12.
Subject has indwelling hardware, or has an abnormality of the skeleton or spine, such as 
scoliosis of 20 degrees or more, kyphosis, or skeletal dysplasia.
13. 
Subject has clinically relevant abnormalities noted on renal ultrasound or DEXA scans. 
Subjects with baseline BMD Z-scores ≤-2, for either posterior-anterior lumbar spine 
(L1-L4) or total body less head, will not be enrolled.
14.
Subject has congenital glaucoma or known ocular deficits, or is receiving any ocular 
medications except lubricating eye drops or topical antibiotics.
15.
Subject has a known history of central hyperthermia, dysautonomia, or other 
disturbances of autonomic function.
16.
Subject has a known history of inborn errors of metabolism, mitochondrial dysfunction, 
or prior evidence of hyperammonemia.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
50
Approved, Date: 3 November 2017
17. 
Subject has any clinically significant abnormality in laboratory tests at screening, 
including but not limited to:

WBC count <3,000/μL or absolute neutrophil count <1,000/μL in the last 6 months 

Aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase 
(ALT), 
or 
gamma-glutamyltransferase (GGT) 3 times the ULN

Total bilirubin 1.5 mg/dL or conjugated bilirubin 20% of total

Venous ammonia 2 times the ULN

25-hydroxy-vitamin D (level for clinically significant vitamin D deficiency is 
<12.0 ng/mL, conventional units [<30 nmol/L, SI units])19,42

Parathyroid hormone (normal reference range is 14.0 to 72.0 pg/mL)

1,25-dihydroxy-vitamin D, as determined by the age-dependent reference ranges 
(see lab manual)

Insulin-like growth factor 1 (IGF-1), as determined by the age-dependent reference 
ranges (see lab manual)
18.
Subject has a bicarbonate level <20 mEq/L, has a diagnosis of metabolic acidosis, or is 
on alkali therapy.
19.
Subject has refractory epilepsy and requires adjunctive AED therapy or is receiving 
>1 concurrent AED (including benzodiazepines, regardless of the reason for 
prescription).
20.
Subject is being treated with furosemide, hydrochlorothiazide, vigabatrin, vitamin B6 
therapy for epilepsy, monoamine oxidase (A or B) inhibitors, felbamate, zonisamide, or 
any other medication that is a potent carbonic anhydrase inhibitor (eg, acetazolamide). 
Past treatment with furosemide for more than 2 weeks must be discussed with the 
sponsor and the discussion documented.
21.
Subject is being treated with other drugs that may affect bone metabolism, eg, steroids
(intravenous 
or 
oral 
steroids), 
growth 
hormone, 
antacids, 
or 
nonsteroidal 
anti-inflammatory drugs (NSAIDs) for chronic or underlying disorders for more than 
7 consecutive days at least 1 month prior to the first day of screening.
22.
Subject has been treated with an investigational drug within 5 half-lives prior to the first 
day of screening.
23.
Subject has used topiramate or levetiracetam within 1 month prior to the first day of 
screening.
24.
Subject has a known allergy or hypersensitivity to formulations for either topiramate or 
levetiracetam.
25.
Subject is on a ketogenic diet to control epilepsy (eg, the ketogenic diet, the Atkins diet, 
the South Beach diet, or another low-carbohydrate diet).


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
51
Approved, Date: 3 November 2017
26.
Subjects with history of poor dietary intakes including requirements for special diets, 
inadequate caloric intake, inadequate nutrient intake, failure to thrive, growth 
abnormalities, poor weight gain, etc.
27.
For subjects with at least 2 previous measurements available prior to the first day of 
screening, if the subject’s length or weight has crossed (in a decreasing direction) 
2 major percentile lines on the standard CDC growth charts, enrollment must be 
discussed with the sponsor and the discussion must be documented. 
28.
For all subjects, if the weight-versus-length plot at screening is lower than the 
3rd percentile on the standard CDC chart, enrollment must be discussed with the sponsor
and the discussion must be documented. 
29.
Subject has a history of noncompliance with AEDs or clinic attendance that is 
sufficient, in the judgment of the investigator, to interfere with participation in this 
study.
30.
Subject is not reasonably expected to complete the study.
31.
Subject is a child or other family member of the investigator or of an employee of the 
study center, with direct involvement in the proposed study or other studies under the 
direction of that investigator or study center.
32.
Subject is pregnant, breast-feeding, or planning to become pregnant while enrolled in 
this study or within 4 weeks after the last dose of study drug.
33.
Subject has a history of any suicidal behavior (attempt, interrupted, aborted, or 
preparatory) in the past 6 months prior to the screening visit.
NOTE: Investigators should ensure that all randomization criteria have been met prior to 
baseline. If a subject's status changes (including clinical laboratory results or receipt of additional 
medical records) after screening but before the first dose of study drug is given such that he or 
she no longer meets all eligibility criteria, then the subject should be excluded from participation 
in the study. Section 17.4, Source Documentation, describes the required documentation to 
support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
A girl of childbearing potential who is heterosexually active must remain on a highly 
effective method of birth control (see Section 4.1, Inclusion Criteria).
2.
Subjects must refrain from using any of the prohibited medications, including:

Ocular medications, except lubricating eye drops or topical antibiotics


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
52
Approved, Date: 3 November 2017

Furosemide, hydrochlorothiazide, vigabatrin, vitamin B6 therapy for epilepsy, 
monoamine oxidase (A or B) inhibitors

Any other medication that is a potent carbonic anhydrase inhibitor (eg, 
acetazolamide, furosemide, zonisamide)

Citrate treatment

Medications that may affect bone metabolism if taken for more than a 10-day 
treatment course, including intravenous or oral steroids, growth hormone, NSAIDs, 
or antacids
5.
TREATMENT ALLOCATION AND BLINDING
Procedures for Randomization and Stratification
Subjects will be randomly assigned to 1 of 2 treatment groups based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. 
The randomization will be balanced using randomly permuted blocks and will be stratified by 
country and age group (2 to 5 years of age, 6 to 9 years of age, 10 to 12 years of age, and 13 to 
15 years of age). The enrollment will be monitored throughout the study to ensure that subjects 
are enrolled for each integer year in each treatment group. 
Based on this information, the interactive web-based response system (IWRS) will assign a 
unique treatment code, which will dictate the treatment assignment and matching study drug kit 
for the subject. As subjects are randomly assigned to treatment, the IWRS will assign a study 
drug kit to be dispensed at that visit. New study drug kits will be assigned each time the IWRS is 
accessed for dispensing additional study drug.
Blinding
As this is an open-label study, blinding procedures are not applicable for treatment assignment.
To minimize any bias in measurement, after randomization 3 of the safety assessments will be 
obtained in a blinded fashion, including the DEXA scan, renal ultrasound, and height. The 
location for these data should be kept separate from the rest of the study data. Procedures for 
maintaining the blind will include the following (further details will be provided in a separate 
Blinding Plan for this study):

Separate secure locations for blinded and unblinded study documents

A separate office or physical space for obtaining the height measurements

Blinded staff will not be permitted access to areas where unblinded activities are performed.

Measures will be required to ensure no overlap of equipment. Height will be measured by a 
trained individual who is blinded (unaware of the treatment); blinded height measures are not 
to overlap assessments of unblinded assessments (weight and vital signs). The same blinded 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
53
Approved, Date: 3 November 2017
person should obtain height measurements using the same technique on the same stadiometer 
at a given center. It is also recommended that the stadiometer be calibrated at least monthly 
and that this be documented. 

Blinded height measures are to be recorded in the source documents, or provided to the 
unblinded study coordinator for entry into the source documents. The unblinded study 
coordinator will then enter this data, along with other visit data, into the CRF.

Documented measures will be required to ensure that no communication of blinded vs. 
unblinded data takes place in the same office suite.
6.
DOSAGE AND ADMINISTRATION
Subjects will be randomly assigned to receive unblinded, flexible dosages of topiramate or 
levetiracetam as follows:

Topiramate: weight-based dosing for subjects 2 to <10 years of age, not to exceed 
350 mg/day, as tolerated; not to exceed 400 mg/day in subjects 10 to 15 years of age, as 
tolerated

Levetiracetam: weight-based dosing for all subjects 2 to 15 years of age, not to exceed 
60 mg/kg/day, as tolerated
Subjects will receive study drug in a twice-a-day regimen (BID). The first dose of study drug on 
Day 1 will be taken in the evening. After randomization, subjects will be titrated as tolerated to 
the maximum recommended dosage for optimal clinical effect over 6 to 8 weeks and will be 
maintained on that dosage through the open-label treatment phase, with the option for dosage
adjustment as required for optimal clinical effect. Changes to this schedule will be based on a 
risk-benefit assessment of the subject’s clinical condition by the investigator. 
Topiramate Titration in Subjects 2 to <10 Years of Age
Dosing in subjects 2 to <10 years of age is based on weight. During the titration period, the 
initial dosage of topiramate should be 25 mg/day, administered nightly for the first week. Based 
upon tolerability, the dosage can be increased to 50 mg/day (25 mg BID) in the second week (see 
Tables 1 to 3 in the titration schedules in Attachment 2). Dosage can be increased by 25 to 
50 mg/day each subsequent week as tolerated. Titration to the maximum recommended dosage
should be attempted over 6 to 8 weeks. Based upon tolerability and seizure control, the rate of 
titration may be adjusted to achieve optimal clinical response. The total daily dosage should not 
exceed the maximum maintenance dosage for each range of body weight (Table 1). Subjects 
with a body weight >38 kg will be assigned to the titration schedule for subjects 10 to 15 years of 
age, as described below.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
54
Approved, Date: 3 November 2017
Table 1:
Topiramate Monotherapy Target Total Daily Maintenance 
Dosing for Subjects 2 to <10 Years of Age
Weight (kg)
Total Daily Dosage (mg/day)a
Minimum Maintenance Dosage
Total Daily Dosage (mg/day)a
Maximum Maintenance Dosage
Up to 11
150
250
12 – 22
200
300
23 – 31
200
350
32 – 38
250
350
a.
Administered in 2 equally divided doses.
The topiramate sprinkle formulation will be provided for those subjects who cannot swallow 
tablets. Sprinkle capsules may be swallowed whole or may be administered by carefully opening 
the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This 
drug/food mixture should be swallowed immediately and not chewed. It should not be stored for 
future use.
Topiramate Titration in Subjects 10 to 15 Years of Age 
The recommended dosage for topiramate monotherapy in adults and pediatric patients 10 years 
of age and older is 400 mg/day in 2 divided doses. The dosage should be achieved by titration 
according to the schedule shown in Table 4 in the titration schedules in Attachment 2. 
Levetiracetam Titration in Subjects 2 to 15 Years of Age
Treatment should be initiated with a daily dosage of 20 mg/kg/day in 2 divided doses (10 mg/kg 
BID). The daily dosage may be increased every 2 weeks by increments of 20 mg/kg/day to the 
recommended daily dosage of 60 mg/kg/day (30 mg/kg BID). The maximum recommended 
daily dosage is 3,000 mg (1,500 mg BID). Subjects with a body weight ≤20 kg should be dosed 
with oral solution. Subjects with body weight above 20 kg can be dosed with either tablets or 
oral solution. See Tables 5, 6, and 7 in the titration schedules in Attachment 2 for dosing for oral 
solution for subjects with a body weight ≤20 kg, and Table 8 in the titration schedules in 
Attachment 2 for dosing for tablets for subjects with a body weight >20 kg. 
The following calculation should be used to determine the appropriate daily dosage of oral 
levetiracetam solution for pediatric subjects based on a daily dosage of 20 mg/kg/day, 
40 mg/kg/day, or 60 mg/kg/day: 
Total daily dosage (mL/day) = Daily dosage (mg/kg/day) x subject weight (kg)
100 mg/mL
All study drugs will be provided in child-resistant packaging during the study. It is recommended 
that tablets not be broken. Both topiramate and levetiracetam can be taken without regard to 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
55
Approved, Date: 3 November 2017
meals. Study staff will instruct subjects and/or parents/caregivers on how to store medication for 
at-home use as indicated for this study. If a subject vomits within 30 minutes of receiving a dose, 
the dose will be repeated. If a subject vomits a second time or more than 1 hour later, the dose 
will not be repeated. All cases of vomited doses and action taken must be recorded in the 
subject’s take-home record. Subjects will be instructed to take any missed doses of study drug as 
soon as possible. However, if the subject is within 6 hours of taking the next scheduled dose, he 
or she should wait until then to take the usual dose of study drug and skip the missed dose.
Subjects should not take a double dose in case of a missed dose.
Subjects should be titrated and maintained according to clinical response, eg, titration may be 
slowed on the basis of tolerability and may be accelerated for the purposes of seizure control. 
Maintenance dosages should be based on optimal clinical response and may be adjusted at any 
time during the open-label treatment phase. Subjects are recommended not to exceed maximum 
recommended maintenance dosages; however, subjects will not be discontinued from the study if 
higher doses are required for optimal clinical effect as judged by the investigator. Data collected 
while on dosages that exceed maximal recommendations may be analyzed separately, as 
appropriate.
Once a subject completes the study or discontinues early from the study, at the discretion of the 
investigator, he or she will either continue on commercially available topiramate or levetiracetam 
or be tapered off of topiramate or levetiracetam over a period of up to 2 weeks.
7.
TREATMENT COMPLIANCE
The investigator or designated study personnel will maintain a log of all drug dispensed and 
returned. Drug supplies for each subject will be inventoried and accounted for throughout the 
study (at each visit). Subjects will receive instructions on compliance with study treatment at the 
screening visit (eg, subject take-home record). During the course of the study, the investigator or 
designated study research staff will be responsible for providing additional instruction to 
reeducate any subject who is not compliant with taking the study drug.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy AEDs and other medications taken within 2 years prior to the study must be recorded at 
screening.
Concomitant therapies must be recorded throughout the study beginning with the start of the first 
dose of study drug. Concomitant therapies should also be recorded beyond 30 days after the last 
dose of study drug, but only in conjunction with new or worsening adverse events or serious 
adverse events that meet the criteria outlined in Section 12.3.2, Serious Adverse Events.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
56
Approved, Date: 3 November 2017
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the CRF. 
Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a subject into the study.
For subjects receiving an AED at baseline, this AED should be tapered down and discontinued 
during the titration period. Concomitant AEDs at baseline used for any purpose will be 
withdrawn in one-third decrements during the 6- to 8-week titration period.
Only AED monotherapy will be used for both treatment groups. In the event of insufficient 
seizure control or intolerability, it should be explored first if a dosage adjustment of the study 
drug might be useful before adding another AED. However, subjects will not be discontinued 
from the study if 1 or more concomitant AEDs are added after initiating treatment with study 
drug. Data will be collected prior to the use of the concomitant AED(s) for the primary analysis. 
Data subsequently collected while on the concomitant AED(s) will be analyzed in a secondary 
analysis for each safety outcome of interest.
Other prohibited concomitant medications include: 

Ocular medications, except lubricating eye drops or topical antibiotics

Furosemide, hydrochlorothiazide, vigabatrin, vitamin B6 therapy for epilepsy, monoamine 
oxidase (A or B) inhibitors, or felbamate

Any other medication that is a potent carbonic anhydrase inhibitor (eg, acetazolamide, 
furosemide, zonisamide)

Citrate treatment 

Medications that may affect bone metabolism taken for more than a 10-day treatment course, 
including intravenous or oral steroids, growth hormone, NSAIDs, antacids, calcium, 
vitamin D, or multivitamins
Subjects will be allowed to take calcium, vitamin D, and multivitamins as concomitant therapy 
provided the dosages fall within the range of recommended daily allowances for the age of the 
subject. These agents will only be allowed as prophylaxis against a deficiency, and not as a 
treatment for a previously diagnosed deficiency.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
57
Approved, Date: 3 November 2017
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule that follows the synopsis summarizes the frequency and timing 
of safety, PK, and other measurements applicable to this study.
The study includes 3 phases: a screening phase of up to 35 days, an open-label treatment phase 
of 1 year's duration (including titration and maintenance), and a posttreatment phase of 30 days, 
during which subjects will either continue on commercially available topiramate or levetiracetam
or will be tapered off of topiramate or levetiracetam over a period of up to 2 weeks. There may
be an optional post-study follow-up phase to obtain DEXA measurements in a subgroup of 
subjects who experience a clinically important reduction (change in Z-score of -0.5 or greater) in 
BMD, based on local DEXA scan results, after 1 year of treatment with topiramate, to determine 
whether a decrease in BMD after or during 1 year of treatment with topiramate is reversible.
These subjects will have a repeat DEXA scan 6 months after discontinuation of study drug.
The total blood volume to be collected from each subject will be approximately 44.7 mL 
(45.8 mL for adolescent girls who require serum pregnancy test at screening; Table 2). Blood 
samples for testing specific analytes are listed in order of priority, in the event of difficulties in 
obtaining the desired volume of blood for any reason at a specific visit. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples.
Table 2:  
Volume of Blood to be Collected From Each Subject (mL)
Visits
Screeninga
Month 1
Month 3
Month 6
Month 9
Month 
12
Total 
Volume of 
Bloodb
Blood chemistry 
profile, including 
electrolytes
1.1
1.1
1.1
1.1
1.1
1.1
6.6
CBC (EDTA whole 
blood)
1.2
1.2
1.2
1.2
1.2
1.2
7.2
25-hydroxy-vitamin Dc
1.1
1.1
1.1
3.3
IGF-1c
1.1
1.1
1.1
3.3
Parathyroid hormone 
(intact) c
1.1
1.1
1.1
3.3
1,25-dihydroxy-
vitamin Dc
3.0
3.0
3.0
9.0
Ammonia, venousc
1.2
1.2
1.2
1.2
1.2
1.2
7.2


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
58
Approved, Date: 3 November 2017
Table 2:  
Volume of Blood to be Collected From Each Subject (mL)
Visits
Screeninga
Month 1
Month 3
Month 6
Month 9
Month 
12
Total 
Volume of 
Bloodb
Pharmacokinetic 
samples (plasma; AED 
levels)
1.2
1.2
1.2
1.2
4.8
Serum pregnancy test
1.1
1.1
Total 
10.9 mL
4.7 mL
4.7 mL
11.0 mL
3.5 mL
11.0 mL
45.8 mL
a The optional use, during the screening period, of local laboratory evaluations for 25-hydroxy-vitamin D, 1,25-
dihydroxy-vitamin D, Parathyroid hormone (intact) and IGF-1 might lead to an increase in blood volume for the 
subject concerned. The total volume is dependent on the local laboratory requirements and on the number and 
type of individual assays.
b Calculated as number of samples multiplied by amount of blood per sample.
c All laboratory tests will be evaluated centrally except for venous ammonia, which will be evaluated locally 
(except in select countries where local testing is not possible, in which case the central laboratory will also 
evaluate venous ammonia). The laboratory tests for 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, 
Parathyroid hormone (intact) and IGF-1 at screening will be evaluated centrally but additional evaluation at local 
laboratory is allowed to reduce the duration of the screening phase. At the discretion of the investigator, one, or 
more of these laboratory parameters may be evaluated at the local laboratory. The volume of blood is based on 
reference laboratory minimal volumes.
AED=antiepileptic drug; CBC=complete blood count; EDTA= ethylene diamine tetra-acetic acid; IGF-1=insulin-
like growth factor 1.
9.1.2.
Screening Phase
The screening phase will last up to 35 days, during which subjects will be assessed for study 
qualifications and other measures as listed in the Time and Events Schedule following the 
synopsis. 
9.1.3.
Open-Label Treatment Phase
The open-label treatment phase includes randomization and distribution of study drug and 
titration instructions (Visit 2; Day 1), a 6- to 8-week titration period, and a maintenance period,
during which subjects will remain in the study until they either complete 1 year of open-label 
treatment or withdraw from the study. 
Subject take-home records and seizure diaries will be given to parents/guardians at Visit 1 and at 
each subsequent visit. Each subject's parent will record in the seizure diary the date, description, 
and number of seizures. The investigator or designated study personnel will review the data to be 
recorded in the subject take-home record with the subject’s parents/legally acceptable 
representatives at the beginning of the study. At each visit, the investigator will review the 
seizure data, and then transcribe the data onto the appropriate page of the CRF.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
59
Approved, Date: 3 November 2017
Titration intervals and dosages may be adjusted for individual subjects to achieve their optimal 
dosage. Subjects receiving 1 concomitant AED at baseline for any purpose will have their AED
tapered down and discontinued in one-third decrements during the 6- to 8-week titration period.
At the end of the titration period, the dosage of study drug should be maintained but may be 
adjusted at the investigator’s discretion for optimal clinical effect. 
Subjects will return for a clinic visit at Months 2 and 3, with subsequent visits to occur every 
3 months. 
9.1.4.
Posttreatment Phase (Follow-Up)
Subjects who complete the study or discontinue early from the study may at the discretion of the 
investigator either continue on commercially available topiramate or levetiracetam or be tapered 
off of topiramate or levetiracetam over a period of up to 2 weeks during the posttreatment phase. 
A final visit will be performed at the end of the 1-year open-label treatment period or upon early 
withdrawal, including review of seizure frequencies from the subject seizure diary and review of 
safety and adverse events.
Telephone contact will be made to assess adverse events and concomitant medications 30 days
after the last dose of study drug, unless the subject has died, is lost to follow-up, or has 
withdrawn consent/assent. If the information on adverse events and concomitant medications is 
obtained via telephone contact, written documentation of the communication must be available 
for review in the source documents. If the subject has died, the date and cause of death must be 
collected and documented on the CRF.
9.1.5.
Post-Study Phase (Follow-Up)
There may be an optional post-study follow-up phase to obtain DEXA measurements in a 
subgroup of subjects who experience a clinically important reduction (change in Z-score of -0.5 
or greater) in BMD, based on local DEXA scan results, after 1 year of treatment with topiramate, 
to determine whether a decrease in BMD after or during 1 year of treatment with topiramate is 
reversible. These subjects will have a repeat DEXA scan 6 months after discontinuation of study 
drug.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
60
Approved, Date: 3 November 2017
9.2.
Pharmacokinetics
9.2.1.
Sample Collection and Handling
Blood samples (1 mL per sample) for the determination of plasma topiramate and levetiracetam
concentrations will be obtained during clinic visits according to the Time and Events schedule. If 
possible, blood samples for PK evaluations should be trough samples (ie, taken immediately 
before the morning dose) and coincide with samples drawn for clinical laboratory tests. During 
each PK assessment, the dosing regimen, dose administered, time and date of dose 
administration, time of sample collection, and concomitant medications will be recorded in the 
CRF.
Attachment 3, Attachment 4, and Attachment 5 detail further information regarding handling and 
shipment of plasma samples.
9.2.2.
Analytical Procedures
Pharmacokinetics
All PK samples will be analyzed under the supervision of the sponsor’s Department of 
Bioanalysis. Plasma samples will be analyzed to determine concentrations of topiramate and 
levetiracetam using validated, specific and sensitive liquid chromatography-tandem mass 
spectrometry methods.
9.2.3.
Pharmacokinetic Parameters
Pharmacokinetic parameters will not be estimated. Topiramate and levetiracetam plasma 
concentration data will be determined by a validated bioanalytical method(s) and summarized. 
9.3.
Safety Evaluations
Details regarding the DMC are provided in Section 11.5.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule. For all evaluations, if possible, the same 
individual should evaluate the subject at all visits.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
61
Approved, Date: 3 November 2017
Take-Home Record/Seizure Diary
Throughout the study, caregivers (parents or legally acceptable representatives) of the subjects 
must maintain a subject take-home record and a seizure diary. The take-home record will include 
data on study drug administration, concomitant medications, and items of general health. The 
seizure diary contains instructions to record the date and description of each seizure and will be 
reviewed by the investigator at each study visit during the open-label treatment phase and at the 
end-of-study/early withdrawal visit. The information from the take-home record and seizure 
diary will be reviewed by the investigator and transcribed into the electronic case report form
(eCRF).
Adverse Events
Adverse events will be reported by the parent (or his or her legally acceptable representative) for 
the duration of the study, from the time of signing the consent/assent. Adverse events will be 
followed by the investigator as specified in Section 12, Adverse Event Reporting. Subjects will 
be monitored for signs of suicidal ideation and behavior with both adverse event reports and the 
C-SSRS (see below), and they (or their caregivers, as appropriate) will be advised to seek 
immediate medical attention should signs of suicidal ideation or behavior emerge.
Clinical Laboratory Tests 
Blood samples for serum chemistry (nonfasting) and hematology and a random urine sample for 
urinalysis will be collected. The investigator must review the laboratory report, document this 
review, and record any clinically relevant changes occurring during the study in the adverse 
event section of the CRF. The following tests will be performed by the central laboratory except 
for venous ammonia, which will be evaluated locally (except in select countries where local 
testing is not possible, in which case the central laboratory will also evaluate venous ammonia). 
The laboratory tests for 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, Parathyroid hormone 
(intact) and IGF-1 at screening will be performed at a central laboratory, but additional 
evaluation at local laboratory is allowed in order to reduce the duration of the screening phase:

Hematology Panel
-hemoglobin
-WBC count with differential
-hematocrit
-platelet count
-red blood cell count


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
62
Approved, Date: 3 November 2017

Serum Chemistry Panel
-sodium
-creatine phosphokinase 
-potassium
-lactic acid dehydrogenase 
-chloride
-uric acid
-bicarbonate
-calcium
-blood urea nitrogen (BUN)
-phosphorus
-creatinine
-albumin
-glucose
-total protein
-AST
-cholesterol
-ALT
-triglycerides
-GGT
-magnesium
-total bilirubin
-25-hydroxy-vitamin D*
-ammonia
-1,25-dihydroxy-vitamin D*
-serum pregnancy test (at screening, for girls 
of childbearing potential)
-parathyroid hormone*
-alkaline phosphatase
-IGF-1*
* Only measured at visits for screening, Month 6, and Month 12/early withdrawal (see Bone Mineralization 
section below).

Special instructions for ammonia sample collection: Collect blood on ice, separate 
plasma from cells, and freeze ASAP (within 15 minutes of draw time). Specimens need 
to be spun in a refrigerated centrifuge and are unstable if thawed and refrozen. 

In addition to its routine assessment, free-flowing venous ammonia will be obtained on 
an immediate basis in the event of:
o
Clinical evidence of change in mental status consistent with a hyperammonemic 
encephalopathy (not seizures or post-ictal state)
o
Elevated hepatic enzymes as follows, unless a routine ammonia done at the same 
time was normal:
o
ALT, AST, or GGT 3 times the ULN (or 2 times the ULN for subjects 
taking valproic acid)
o
Total bilirubin 1.5 mg/dL
o
Conjugated bilirubin 20% of the total
o
Any other appropriate clinical indication


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
63
Approved, Date: 3 November 2017

25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, Parathyroid hormone (intact) and IGF-1:
At the discretion of the investigator, one or more of these laboratory parameters may be 
evaluated at the local laboratory to reduce the duration of the screening phase. In such 
instances, the local laboratory instructions should be followed and local reference ranges 
should be applied. The local laboratory results would be used for decision regarding 
randomization. The central laboratory evaluation results will be used for study data analysis. 
The additional use of a local laboratory might lead to an additional amount of blood volume 
to be drawn from the subject at screening.

Urinalysis will be performed by the central laboratory, and will include dipstick and sediment 
as noted below. If dipstick result is abnormal, flow cytometry will be used to measure 
sediment. In case of discordance between the dipstick results and the flow cytometric results, 
the sediment will be examined microscopically.
Dipstick
Sediment
-specific gravity
-RBCs
-pH
-WBCs
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-nitrite

Urine Pregnancy Testing (for girls of childbearing potential only) to be obtained at all visits 
after screening during the open-label treatment phase. If a girl starts menstruating and 
becomes of childbearing potential during the study, urine pregnancy tests should be obtained 
at all subsequent visits during the open-label treatment phase.

24-Hour Urine Collection: A 24-hour urine collection will be analyzed for pH, calcium, 
citrate, phosphorus, and creatinine levels. Collection instructions and storage conditions will 
be specified in the laboratory manual. A 14-day window on either side of the scheduled 
Month 6 visit will be allowed for 24-hour urine collection. The collection at Month 12 should 
be completed before the Month–12 visit as this evaluation should be obtained while the 
subject is still receiving study–drug therapy.
Additional use of local laboratories is allowed in cases where safety follow-up is time-critical 
and the central laboratory results are not expected before the need to take actions for safety 
reasons.
After consultation with the medical monitor, investigators may obtain additional laboratory
assessments and/or advice from local medical consultants in the event of any clinically important 
safety concern.
Bone Age Radiograph
A hand/wrist x-ray will be obtained in the nondominant hand/wrist to determine bone age at 
baseline and at Month 12 (or final study visit if a subject discontinues prematurely).20 This will 
be read and interpreted locally.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
64
Approved, Date: 3 November 2017
Electrocardiogram
A single 12-lead ECG will be collected at screening only. To be enrolled, subjects must have an 
ECG at screening with no “abnormal, clinically significant” interpretations by a local 
cardiologist.
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG, vital signs, blood draw.
Vital Signs
Vital signs will be recorded at the times given in the Time and Events Schedule. Measurement of 
vital signs includes axillary temperature, heart rate, respiratory rate, and blood pressure.
Temperature will be assessed using an axillary thermometer; if temperature is ≥38.0C, the 
temperature should be repeated immediately and both values recorded in the CRF. Respiration 
measurements will be assessed over at least 30 seconds. Blood pressure and heart rate 
measurements should be assessed with a completely automated device (if available) consisting of 
an inflatable cuff and an oscillatory detection system. All values will be registered on a built-in 
recorder so that measurements are observer-independent. If an automated device is not available, 
all manual heart rate measurements will be measured each time for a full minute to minimize the 
effects of heart rate variability. Blood pressure will be measured with the cuff placed on the right 
arm. An appropriate size cuff has 1) an inflatable cuff bladder width that is at least 40% of the 
arm circumference (at a point midway between the olecranon and the acromion) and 2) a cuff 
bladder length that covers 80% to 100% of the circumference of the arm. 
Orthostatic vital signs will be obtained for all subjects pending cooperation of subjects. A set of 
3 measurements will be obtained at baseline only, separated by intervals of 10 minutes. 
Thereafter, only 1 orthostatic vital sign measurement will be taken at all subsequent visits. The 
method for obtaining orthostatic vital signs will be as follows: subject will be supine for 
5 minutes prior to measurement, and standing for 2 minutes prior to measurement.
Physical Examination
Physical examinations and anthropometric measurements, including weight, height, and pubertal 
stage according to Tanner’s classification,37 will be performed at the times specified in the Time 
and Events Schedule.

Height will be assessed using a wall-mounted stadiometer. Height will be read to the nearest 
0.1 cm; measures are to be repeated at least 3 times. Based on previous measurements and 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
65
Approved, Date: 3 November 2017
clinical judgment, the healthcare professional should discard any extreme results and make 
additional measurements until 3 approximately consistent measurements are obtained. All 
3 final measurements will be recorded in the CRF; all measurements will be recorded into the 
source documents. To obtain accurate measures, shoes and hair adornments should be 
removed and the child should be positioned with heels, buttocks, and back of head against 
the stadiometer.
The healthcare professionals who measure height at each visit must be trained in the 
standardized procedure. If possible, the same individual and the same equipment should 
collect all height measurements at each study site, to help ensure consistency of 
measurements. 
All study site personnel performing the height assessment must be blinded to study treatment 
assignment and the rest of the subjects’ data to avoid/minimize bias. A blinded study nurse or 
other staff will measure the height of the subject and record it in the source documents, or 
provide it to the unblinded study coordinator for entry into the source documents. The 
unblinded study coordinator will then enter this data, along with other visit data, into the 
CRF. The location for the height measurement data should be kept separate from the rest of 
the study data, and procedures must be in place to ensure maintenance of the blind.

Body weight will be measured using digital electronic or beam balance scale to the nearest 
0.1 kg. Prior to weight measurements, the scale should be set to zero to avoid drift in 
equipment functioning. Subjects will be weighed in examination gowns or in lightweight 
clothing and without shoes. If possible, weight measurements should be taken at the same 
time of day after the bladder is emptied so subjects are always evaluated in the same 
physiologic state.

Tanner staging of subjects of age 8 years and above will be conducted by a qualified 
pediatric endocrinologist or by a physician trained in the method.27
Any abnormalities present at baseline, or subsequent changes, will be documented in the 
appropriate sections of the eCRF. Any clinically significant abnormalities persisting at the end of 
the study will be followed by the investigator until resolution or until reaching a clinically stable 
endpoint.
Neurologic Examination
Neurologic examinations (including mental status, cranial nerves, motor examination [muscle 
tone, strength, deep tendon reflexes], cerebellar functions, and gait) will be performed by the 
investigators at all visits except Month 2.
Any abnormalities present at baseline, or subsequent changes from baseline, will be documented
in the appropriate sections of the eCRF. Any clinically significant abnormalities persisting at the 
end of the study will be followed by the investigator until resolution or until reaching a clinically 
stable endpoint.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
66
Approved, Date: 3 November 2017
Bone Mineralization
Monitoring changes in bone mineralization will include: DEXA scans of the posterior-anterior 
lumbar spine (L1-L4) and total body less head area BMD and bone mineral content (BMC), and 
serum biochemical parameters of bone metabolism, including serum levels of alkaline 
phosphatase, calcium, phosphorus, parathyroid hormone (intact), 25-hydroxy-vitamin D, 
1,25-dihydroxy-vitamin D, and IGF-1. Biochemical assessments will be obtained at screening, 
Month 6, and Month 12/early withdrawal. DEXA scans (without sedation) will be obtained at 
baseline, Month 6, and Month 12/early withdrawal. For all scans, up to 3 DEXA scan attempts 
will be performed all on the same day with the goal of obtaining 2 complete, movement-free 
scans, recognizing that it might not be possible to obtain 2 adequate scans in some younger 
children.
All scans will be centrally analyzed; central analysis will be performed by one highly trained 
technologist at the DEXA reading center with International Society for Clinical Densitometry 
(ISCD) certification, a license to operate a DEXA scanner, and 3 to 5 years of experience with 
whole body and spine scans. In addition, the baseline and M12 scans will be read locally to 
determine eligibility for randomization and for the Post-Study Follow-Up phase.
If any subject shows a clinically important reduction (change in Z-score of -0.5 or greater) at 
6 months or 12 months, the central reader will reassess the scan for quality and to determine the 
presence of any artifacts, and will provide recommendations based on the Z-score and BMD.
Abnormalities will be reported to parents and primary-care physicians, and appropriate referrals 
for further evaluation will be made by the investigator, if needed.
Short-term precision testing will be performed for DEXA measurements according to standard 
protocols. The same DEXA machine will be used at each site for all subjects and all 
measurements; only clinical sites using recent-generation Hologic systems (Discovery and 
Delphi systems) or General Electric Lunar systems will participate in the study; the GE/Lunar 
systems will only be used for subjects ≥5 years of age. The same technician should acquire all 
scans for any particular subject. All technicians should be certified by the ISCD or have similar 
competency training with specific knowledge of the DEXA system, including a degree program 
in radiologic technology. Technicians must also pass a written competency test and undergo 
specific training for this study, either online or in person, for scanning of young children. Further 
details regarding the DEXA measurements, including the reference databases to be used, will be 
provided in the DEXA Manual for this study.
Both the technicians administering the DEXA scans and the central reader will be blinded to the 
treatment group.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
67
Approved, Date: 3 November 2017
Physical Activity Evaluation
Information regarding physical activity will be obtained at screening from the HAES (see 
Attachment 1 for an example). Parents/caregivers will be asked how many hours their children 
spent in a 24-hour day in 1 of 4 categories of activity/inactivity to assess physical activity levels 
on the basis of the standardized and validated activity questionnaire. The total number of hours 
each subject spends in each category will be processed to determine the activity score on a scale 
of -100 (100% inactive) to +100 (100% active). A value of 0 indicates that the subject spent 
12 hours of the day active and an equal number of hours inactive.22
Renal Stone Evaluation 
Renal ultrasounds (at screening, Month 6, and Month 12/early withdrawal; without sedation and 
after a 3-hour period during which only water, juice, or electrolyte solution will be permitted, as 
clinically indicated) will be performed under blinded conditions (after randomization) by a 
qualified radiologist or nephrologist at each site with age-appropriate inducers. The ultrasounds 
will be read/interpreted centrally (local reading at the screening visit is acceptable to determine 
eligibility for randomization; both the local and central readers will be blinded to the study 
treatment group). If possible, examinations should be done by the same individual at any given 
site. 
Subjects with definite renal stones, nephrocalcinosis, or hydronephrosis at screening will be 
excluded from the study. Other abnormalities will be followed in subsequent examinations, 
which may occur more frequently at the discretion of the investigator in collaboration with the 
sponsor’s medical monitor. Abnormalities will be reported to parents and primary-care 
physicians, and appropriate referrals will be made by the investigator if needed. 
Cognitive, Developmental, and Behavioral Assessments
Cognitive, developmental, and behavioral assessments will be conducted as follows:

Cogstate Battery (2 practice sessions, 1 at screening and 1 baseline prior to the baseline 
assessment; assessed at baseline, Month 6, and Month 12/early withdrawal):

For subjects 6 to 15 years of age, the Detection Test, Identification Test, One Card 
Learning Test, One Back Test, and Groton Maze Learning Test will be administered.

For cooperative subjects 4 to 5 years of age, the Detection Test and the Identification 
Test will be administered.

Language function test (Animal Fluency NEPSY-II (A Developmental NEuroPSYchological 
Assessment) Test - subjects 6 to 15 years of age; 1 practice session at screening; assessed at 
baseline, Month 6, and Month 12/early withdrawal) 

Vineland Adaptive Behavior Scale (to be completed by a parent or guardian for subjects 2 to 
5 years of age, assessed at baseline, Month 3, Month 6, and Month 12/early withdrawal)


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
68
Approved, Date: 3 November 2017

Child Behavior Checklist (CBCL)-Parent version (Achenbach System of Empirically Based 
Assessment [ASEBA]) (assessed at baseline, Month 3, Month 6, and Month 12/early 
withdrawal)

Preschool version - subjects 2 to 5 years of age

School-age version - subjects 6 to 15 years of age
Note: For subjects who turn 6 years of age during the study, the Vineland Adaptive Behavior 
Scale, the preschool version of the CBCL, and only the Detection Test and Identification Test of 
the Cogstate Battery will continue to be administered throughout the study.
Cognitive Assessments
The Cogstate Computerized Test Battery15,26,30 requires less than 30 minutes to administer, and 
will be administered by non-expert (non-psychologist) study site personnel trained in the 
Cogstate administration method. All tests will be managed and scored centrally by Cogstate. The 
Battery includes tests that assess information processing speed and fine motor skills, attention, 
learning and memory, working memory, and executive functions. The tests were designed for 
multiple assessments over a short time period, with virtually no practice effects in adults and 
children. The pediatric version of the card tests (Detection Test, Identification Test, One Card 
Learning Test, and One Back Test) use cards with age-appropriate designs (ie, colors, shapes, 
and numbers) rather than using cards from a French playing card deck. However, the paradigms 
are the same.

The Detection Test is a measure of information processing speed and fine motor skills, and 
uses a well-validated simple reaction time paradigm with card stimuli. In this test, the playing 
cards are all red and black. The subject is asked to press the Yes key as soon as the card in 
the center of the screen flips over.

The Identification Test is a measure of visual attention and uses a well-validated choice 
reaction time paradigm with card stimuli. In this test, the playing cards are all either red or 
black. The subject is asked whether the card currently being presented in the center of the 
screen is red. The subject responds by pressing the Yes key when the card is red and the No 
key when it is black.

The One Card Learning Test is a measure of visual recognition memory and uses a well-
validated pattern separation paradigm using card stimuli. In this test, the cards are similar to 
those found in a deck of playing cards. The subject is asked whether the card currently being 
presented in the center of the screen was seen previously in this test. The subject responds by 
pressing the Yes or No key. Because no card has been presented yet, the first response is 
always No.

The One Back Test is a measure of working memory and uses a well-validated n-back
paradigm using card stimuli. In this test, the cards are similar to those found in a deck of 
playing cards. The subject is asked whether the card currently being presented is the same as 
the one presented immediately previously. The subject responds by pressing the Yes or No 
key. Because no card has been presented yet, the first response is always No.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
69
Approved, Date: 3 November 2017

The Groton Maze Learning Test is a measure of problem solving and reasoning and uses a 
well-validated maze learning paradigm. In this test, the subject is shown a grid of boxes on a 
computer screen. A pathway is hidden among these possible locations. Each box represents 
move locations, and the grid refers to the box array (eg, 10 × 10). Subjects are required to 
find the hidden pathway guided by search rules. Feedback is given with visual and auditory 
cues (green check marks and red crosses) to indicate whether the selected box is correct or 
incorrect. There are a specific number of well-matched alternative pathways available. The 
software records each move as an error or as a correct move. 
The Cogstate pediatric normative database consists of cognitive tests from over 55,000 healthy 
children. The majority of the data are from select test scales (One Card Learning Test, One Back
Test, Detection Test, Identification Test) in 10- to 18-year-old children, but there are data on the 
Groton Maze Learning Test in younger children. Furthermore, the Cogstate tests have been 
shown to have demonstrated utility in pediatric clinical studies in oncology, and in the treatment 
of disorders such as attention-deficit/hyperactivity disorder, HIV, neurodevelopmental disorders, 
and sickle cell disease.
The semantic item “Animals” from the Word Generation subtest of the NEPSY-II (A 
Developmental NEuroPSYchological Assessment) will be included in this study. This test 
measures verbal productivity through the ability to generate words within specific categories and 
is a commonly used and standardized measure of language and executive functioning in children 
and adolescents. This will be administered by study site personnel who are trained according to a 
study-specific rater training plan. The test will be scored by the site rater and the data will be 
transferred to Cogstate.
Developmental Assessments in Subjects 2 to 5 Years of Age
The Vineland Adaptive Behavior Scale will be administered for subjects 2 to 5 years of age, to 
assess developmental level and adaptive functioning. For very young children, the behaviors 
assessed are closely correlated with developmental milestones.
The Vineland Adaptive Behavior Scale, version II focuses on behaviors needed to operate in an
age-appropriate manner in the individual’s environment. It is age-specific and provides an 
assessment of function in the domains of communication, daily living, socialization, and motor 
skills, as well as a composite scale. The Vineland scores have a mean of 100 and a standard 
deviation of 15, based on a normative population sample.6,36
The interview will be completed by the parent/guardian and will be scored by a trained rater at 
screening, at Month 3, Month 6, and Month 12/early withdrawal.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
70
Approved, Date: 3 November 2017
Behavioral Assessments
The CBCL is a widely used method of identifying problem behavior in children.1,2 It is a 
component in the ASEBA. It is a detailed, specific measure of competencies, adaptive 
functioning, and behavioral/emotional problems in children, split into competencies and 
problems. The CBCL has been shown to have good reliability and validity,2 and has been used in 
many pediatric populations with different disorders, including epilepsy.5,13,34
Problems are identified by a respondent who knows the child well, usually a parent. There are 
two versions of the CBCL-Parent version. The preschool checklist (CBCL/1½-5) is intended for 
use with children 18 months to 5 years of age (see Attachment 6 for an example). The school-age 
version (CBCL/6-18) is for children 6 to 18 years of age (see Attachment 7 for an example).
The checklists consist of a number of statements about the child's behavior, eg, "Acts too young 
for his/her age." Responses are recorded on a Likert scale: 0=not true, 1=somewhat or sometimes 
true, 2=very true or often true. The preschool checklist contains 99 questions and the school-age 
checklist contains 112 questions.
Similar questions are grouped into a number of syndromes, eg, Aggressive behavior, and their 
scores are summed to produce a score for that syndrome. Some syndromes are further summed to 
provide scores for Internalizing (Anxious/Depressed, Withdrawn/Depressed, and Somatic 
Complaints) and Externalizing problem scales (Rule-Breaking Behavior and Aggressive 
Behavior). A total score from all questions is also derived. For each syndrome, problem scale,
and the total score, tables are given that determine whether the score represents normal, 
borderline, or clinical behavior. These categorizations are based on quantiles from a normative 
sample.
Suicidality
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and will be 
administered at every visit, to assess suicidal ideation, intent, and behavior.31 The scale will be 
administered by study personnel (either non-expert, eg, study coordinator, or clinical expert, eg, 
MD or PhD psychologist), asking questions of the subjects (preferable, if cooperative) or 
parents/caregivers for subjects who are not cooperative. If possible, the same individual should 
evaluate the subject at all visits. The assessment will be administered for subjects 6 to 15 years of 
age and will not be administered for subjects 2 to 5 years of age. Examples of the scales are 
provided in Attachment 8 (Baseline) and Attachment 9 (Since Last Visit).


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
71
Approved, Date: 3 November 2017
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed 1 year of 
open-label treatment. Subjects who prematurely discontinue study treatment for any reason 
before completion of the 1-year open-label treatment phase will not be considered to have 
completed the study. Subjects who require a concomitant AED(s) after initiating treatment with 
study drug and continue in the study until Month 12 will also not be considered to have 
completed the study.
10.2.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

The investigator or sponsor believes (eg, that for safety or tolerability reasons such as an 
adverse event) it is in the best interest of the subject to discontinue treatment.

Death

Other reasons

If a female subject becomes pregnant during the study, she must be discontinued from the 
study and the pregnancy followed to term, if applicable.
During the study, subjects will also be withdrawn if:

Subject develops status epilepticus not controlled by a single rescue agent.

At the discretion of the investigator, subject develops any new seizure types or any clinically 
relevant safety issue.

Subject requires greater than a 10-day course of medications that may impact bone 
metabolism, including intravenous or oral steroids, furosemide, growth hormone, NSAIDs, 
antacids, or calcium/vitamin D supplements.

Subject develops nephrocalcinosis (diagnosed in any way) or develops a significant clinical 
adverse event (eg, serious event, treatment-limiting event, or other consideration) diagnosed 
as being related to a new kidney stone. Ultrasound results that suggest an asymptomatic 
kidney stone will not necessarily serve as a reason for withdrawal from the study.

The investigator believes the subject to be at significant risk of suicidal or violent behavior.
If a subject discontinues treatment before the end of the open-label treatment phase, the 
end-of-study assessments should be obtained.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
72
Approved, Date: 3 November 2017
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the study data is outlined below. 
Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
All subjects who are randomized will be included in the analysis population. 
11.2.
Sample Size Determination
A total of 282 randomized subjects, 141 in each treatment group, will be recruited to the study. 
The sample size takes into account a 1-year dropout rate of 29%, which is a conservative 
estimate based on the dropout rates observed in a previous monotherapy study in the 6- to 
15-year-old age group, Study TOPMAT-EPMN-106, including a dropout rate of 22% in the 
study overall (both double-blind and open-label phases) and a dropout rate of 35% for the 
double-blind phase. The sample size was estimated in order to achieve a sufficient precision for 
the estimates of the treatment effect on the key endpoints. The precision of the confidence 
interval (CI) estimates for the key safety parameters are shown below:

Annual change in BMD (L1-L4) Z-score: In the Bone Mineral Density in Childhood Study 
(BMDCS), mean annual change in BMD (L1-L4) Z-score in 6- to 15-year-old healthy 
subjects was, as expected, minimal (0.01-0.07).35 The standard deviation (SD) varied from 
0.3 to 0.48 across sex and age groups.35 Assuming an SD of 0.4, with 100 completed subjects 
per group, the 95% CI for the treatment difference will have a precision of 0.12.

Annual change in height Z-score in the 2- to 9-year-old age group: In the monotherapy 
epilepsy study TOPMAT-EPMN-106, the observed change from baseline in mean height 
Z-score at 1 year among the 2- to 9-year-old subjects treated with topiramate 400 mg/day 
was -0.18, with an SD of 0.28.40 Assuming that 53% of the subjects will be recruited in the 
2- to 9-year-old age group, ie, 53 completed subjects per treatment group, the 95% CI for the 
treatment difference will have a precision of 0.11.

Incidence of kidney stone formation:
In the studies TOPMAT-PEP-3001 and 
TOPMAT-PEP-1002 in infants (1 month to 2 years of age), a 7% incidence of kidney stones 
was observed during the 1-year topiramate adjunctive treatment period.11,38 A sample size of 
100 completed subjects per treatment group will provide a 95% CI (Wilson score CI) for the 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
73
Approved, Date: 3 November 2017
treatment difference with a width of 0.12, assuming that the incidence of kidney stone 
formation is 7% and near zero in the topiramate group and the levetiracetam group, 
respectively.

Change in weight Z-score in the 2- to 15-year-old age group: In the monotherapy epilepsy 
study TOPMAT-EPMN-106, a -0.59 decrease from baseline in weight Z-score, with an SD 
of 0.43, was observed after 1 year of treatment with topiramate 400 mg/day. Assuming an SD 
of 0.43, a sample size of 100 completed subjects per treatment group will provide a 95% CI 
with a precision of 0.12.
11.3.
Pharmacokinetic Analyses 
Data will be listed for all subjects with available plasma concentrations per treatment group. 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. Concentrations below the lowest quantifiable 
concentration will be treated as zero in the summary statistics. All subjects and samples excluded 
from the analysis will be clearly documented in the study report.
For each treatment group, descriptive statistics, including arithmetic mean, SD, coefficient of 
variation, geometric mean, median, minimum, and maximum will be calculated for the
topiramate or levetiracetam plasma concentrations at each sampling time.
Topiramate and levetiracetam plasma concentrations will be provided as listings.
11.4.
Safety Analyses
The key safety endpoints will include:

Percentage of subjects with kidney stones 

Change from baseline in weight Z-score over time

The following height analyses will be conducted for prepubertal subjects (2 to 9 years of 
age), subjects 10 to 15 years of age, and subjects 2 to 15 years of age:
o
Height at 1 year postbaseline
o
Height change from baseline over time
o
Height Z-score at 1 year postbaseline
o
Change from baseline in height Z-score over time
o
Height velocity at 1 year postbaseline
o
Height velocity Z-score at 1 year postbaseline
o
Percentage of outlier subjects with height Z-score decrease of >0.5, >1.0, and 
>2.0 over time

The following BMD and BMC endpoints:


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
74
Approved, Date: 3 November 2017
o
BMD and BMC over time 
o
BMD and BMC change from baseline over time
o
Z-score for BMD and BMC over time
o
Change from baseline in Z-score for BMD and BMC over time
o
Percent change from baseline in BMD and BMC over time
o
Percentage of outlier subjects with BMD Z-score decrease of >0.5, >1.0, and >2.0 
over time

Change from baseline in biochemical markers of bone mineralization including: serum levels 
of alkaline phosphatase, calcium, phosphorus, parathyroid hormone (intact), 25-hydroxy-
vitamin D, 1,25-dihyroxy vitamin D, and IGF-1

Change from baseline in serum and urine laboratory tests, eg, bicarbonate, ammonia, renal 
function tests, and LFTs

Change from baseline in bone age
Z-scores for the DEXA scans will be calculated locally at baseline and at M12 to determine 
eligibility for the study and the Post-Study Follow-Up phase, and centrally for all statistical 
analyses. The Z-score calculation will take the DEXA machine and the subject’s age, sex, height, 
and ethnicity into consideration. The reference databases for calculating the Z-scores are 
provided in the DEXA Manual for this study.
Longitudinal endpoints will be analyzed using a mixed-model repeated measures (MMRM) 
analysis. The MMRM model will include treatment group, age group, visit, treatment-by-visit 
interaction, baseline measure, and baseline-by-visit interaction. An unstructured covariance will 
be used. Other appropriate covariance structures will be explored as needed. Confidence 
intervals with 95% confidence for the estimated treatment differences will be provided at each 
time point as appropriate. For proportion endpoints, 95% confidence intervals will be provided 
for the treatment difference. Each of the endpoints will also be summarized by age group.
Seizure counts, cognitive, developmental level, and behavioral assessments will be summarized 
by treatment group and age group. The incidence of suicide-related thoughts and behaviors as 
determined by the C-SSRS will be summarized by treatment group and age group.
For the cognitive assessments, standardized change from baseline scores will be calculated by 
computing the change for each postdose assessment score from the baseline assessment score, 
relative to the expected within-subject standard deviations for each Cogstate task. For the tasks 
for which lower scores indicate improvement (eg, Detection Test and Identification Test), the 
score will be multiplied by (-1), so that negative standardized scores represent a decline in 
cognitive performance consistently across all tasks. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
75
Approved, Date: 3 November 2017
A meaningful decline in cognition has been defined as a standardized change of less than -1.65 
from the baseline assessment. These calculations will indicate meaningful decline at the subject 
level. For each individual score assessment, standardized change scores that meet the definition 
of a meaningful decline will be identified using a binary flag, where 1 represents a meaningful 
decline from baseline and 0 otherwise. 
Group-based summary data (frequency distribution of the binary flags) will also be presented by 
computing the proportion of subjects who meet the criteria for meaningful decline at each 
postdose assessment.
In addition to the above endpoints, other safety-related endpoints may be included in the 
analyses and summarized if deemed necessary.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the treatment phase (ie, treatment-emergent adverse events, and adverse events 
that have worsened since baseline) will be included in the analysis. For each adverse event, the 
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment group and by age group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Adverse events of clinical interest for topiramate are: effects on liver function; metabolic 
acidosis; effects on growth and maturation;
vision abnormalities;
oligohidrosis with 
hyperthermia and rash; hyperammonemia and encephalopathy; kidney stones; cognitive 
disorders; and suicidality.
Adverse events of clinical interest for levetiracetam are as listed previously, notably somnolence, 
asthenia, and behavior disturbances (especially hostility and nervousness).
Subjects with adverse events of special interest may be counted or listed.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and at each scheduled time point. Changes from baseline results will be presented in pre- versus 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
76
Approved, Date: 3 November 2017
posttreatment cross-tabulations (with classes for below, within, and above normal ranges). A 
listing of subjects with any laboratory results outside the reference ranges will be provided. A 
listing of subjects with any markedly abnormal laboratory results will also be provided. 
Vital Signs
Descriptive statistics of temperature, heart rate, respiratory rate, and blood pressure (systolic and 
diastolic) values and changes from baseline will be summarized at each scheduled time point. 
The percentage of subjects with values beyond clinically important limits (using age-appropriate 
ranges) will be summarized.
Physical Examination/Neurologic Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
11.5.
Data Monitoring Committee
An external, independent DMC will be established to review safety data on at least a semiannual 
basis (or more frequently, if necessary) and ensure the continuing safety of the subjects enrolled 
in this study. After the review, the DMC will make recommendations regarding the continuation 
of the study. The details will be provided in a separate DMC charter.
The DMC will include experts from pediatric subspecialties and one statistician. The DMC 
responsibilities, authorities, and procedures will be documented in its charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
77
Approved, Date: 3 November 2017
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the informed 
consent/assent form (refer to Section 12.3.1, All Adverse Events, for time of last adverse event 
recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dosage:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above.
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For topiramate, the expectedness of an adverse 
event will be determined by whether or not it is listed in the Investigator's Brochure.33 For 
levetiracetam, the expectedness of an adverse event will be determined by whether or not it is 
listed in the package insert.24
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
78
Approved, Date: 3 November 2017
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, eg,
concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor medicinal product that may require expedited reporting 
and/or safety evaluation include, but are not limited to:


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
79
Approved, Date: 3 November 2017

Overdose of a sponsor medicinal product

Suspected abuse/misuse of a sponsor medicinal product

Inadvertent or accidental exposure to a sponsor medicinal product

Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor medicinal product, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated informed consent form is obtained until completion of 
the subject's last study-related procedure (which may include contact for follow-up of safety).
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.
All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, subjects or 
parents/caregivers must be provided with a "wallet (study) card" and instructed to carry this card 
with them for the duration of the study, indicating the following:


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
80
Approved, Date: 3 November 2017

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves.

The event stabilizes.

The event returns to baseline, if a baseline value/status is available.

The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct.

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a clinical study must be reported as a 
serious adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF) 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
81
Approved, Date: 3 November 2017
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the investigational agent, is considered a serious 
adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, congenital anomaly) 
are considered serious adverse events and must be reported using the Serious Adverse Event 
Form. Any subject who becomes pregnant during the study must be promptly withdrawn from 
the study and discontinue further study treatment.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the investigational staff must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
82
Approved, Date: 3 November 2017
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
TOPAMAX® tablets and sprinkle capsules will be supplied for topiramate; KEPPRA® tablets and 
solution will be supplied for levetiracetam.
The topiramate tablets supplied for this study are debossed, round, coated tablets in the following 
strengths and colors: 25 mg white or cream, 50 mg light yellow, 100 mg yellow. The tablets are 
imprinted as follows:

25 mg - “OMN” on one side, “25” on the other

50 mg - “OMN” on one side, “50” on the other

100 mg - “OMN” on one side, “100” on the other
Topiramate sprinkle capsules are provided as small, white to off-white spheres in gelatin capsules 
consisting of white bodies with clear caps. The capsules are printed with black pharmaceutical ink 
as follows:

25 mg - “TOP” on the cap and “25 mg” on the capsule body
Refer to the topiramate prescribing information for a list of excipients.38
Levetiracetam tablets are provided as oblong-shaped, scored, film-coated tablets in the following 
strengths and colors: 250 mg blue, 500 mg yellow, 750 mg orange. The tablets are imprinted as 
follows:

250 mg - "ucb 250" on one side

500 mg - "ucb 500" on one side

750 mg - "ucb 750" on one side
Levetiracetam oral solution is a clear, colorless, grape-flavored liquid (100 mg/mL). 
Refer to the levetiracetam prescribing information for a list of excipients.24


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
83
Approved, Date: 3 November 2017
14.2.
Packaging
Topiramate tablets and sprinkle capsules will be packaged in high-density polyethylene bottles. 
Levetiracetam tablets will be supplied in blister cards packed in cartons; levetiracetam 
(100 mg/mL) oral solution will be provided in glass bottles.
All study drugs will be dispensed in child-resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study drug should be stored and handled per the labelled storage conditions. Both formulations 
should be stored in tightly closed containers and protected from moisture. Topiramate drug product 
formulations are not sterile. While topiramate sprinkle capsules are designed for use by subjects 
who require that the administered drug be dispensed with food, neither this formulation nor tablets 
are intended for storage in food mixtures, as this practice may create the risk of bacterial 
contamination. This particular risk is relevant to subjects whose comorbidities make them 
susceptible to infections (systemic or enteral) by pathogens capable of growing in food mixtures 
such as enteric or infant formulas. To prevent the possibility for bacterial contamination, the 
topiramate sprinkle capsules drug/food mixture should be used immediately and not stored for later 
use.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects or their legally acceptable representatives where applicable, must 
be instructed to return all original containers, whether empty or containing study drug. The 
subjects must return unused study drug to the site.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug will be documented on the drug return form. When 
the site is an authorized destruction unit and study drug supplies are destroyed on site, this must 
also be documented on the drug return form.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
84
Approved, Date: 3 November 2017
Potentially hazardous materials, such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the investigational staff, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Whenever a subject brings his or her study drug to the site for pill count, this is not 
seen as a return of supplies. Study drug may not be relabeled or reassigned for use by other 
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site 
other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Topiramate Investigator's Brochure

Topiramate Prescribing Information

Levetiracetam Prescribing Information

Laboratory manual

IWRS manual

Electronic data capture (eDC) manual

Blinding Plan for TOPMATEPY4067

DEXA Manual for TOPMATEPY4067

CDC growth charts

Subject take-home records

Seizure diaries

Subject recruitment materials

Subject information materials

Sample scale, instructions and workbook (if applicable) for the following outcome
assessments: Tanner scale; CBCL; HAES; Vineland Adaptive Behavior Scale, version II;
C-SSRS, NEPSY-II

Worksheet for inadequacy of current epilepsy treatment

Preprinted labels for blood samples 

Computers, software, and thumb drives for the Cogstate battery

Refrigerated centrifuge, if not available locally


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
85
Approved, Date: 3 November 2017
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This study is a postmarketing requirement that is being conducted to evaluate long-term safety 
issues associated with topiramate monotherapy in children 2 to 15 years of age with newly or 
recently diagnosed epilepsy. Of particular concern is the potential for chronic metabolic acidosis 
and the potential impact on growth, bone mineralization, and kidney stone formation. The study 
is designed to assess these issues in comparison with levetiracetam monotherapy. The study is 
designed as a randomized, active-controlled, open-label study; however, to eliminate bias, after 
randomization the key safety outcomes (DEXA scan, renal ultrasound, and height) will be 
obtained in a blinded fashion.
Ethical concerns include the enrollment of pediatric subjects and the requirement for them to 
taper off their current AED. Performing this study in children is justified because it remains 
unclear how long term AED may impact normal bone mineralization and development. Overall, 
an extensive clinical database that included children from age 1 month and above in different 
clinical settings has not demonstrated bone-related adverse clinical outcomes, but more 
quantitative and systemic safety data are desirable in this population. The concern of tapering off 
an existing AED is mitigated by the requirement that investigators document the inadequacy of 
the subject’s current AED treatment.
Levetiracetam is an appropriate comparator because it has demonstrated efficacy and safety in a 
number of investigator-initiated studies when used as monotherapy in dosages similar to those 
used in the current study. It also has relatively low toxicity, and specifically a lack of significant 
concerns for risks for kidney stones or possible deleterious effects on bone or growth. Other 
AEDs that might be considered as a comparator beside levetiracetam include carbamazepine, 
lamotrigine, or valproic acid. However, there are possible concerns with all of these AEDs. 
There are many publications in the literature that suggest carbamazepine may decrease BMD, 
increase serum alkaline phosphatase and decrease serum calcium and phosphorus, which might 
suggest problems with bone development. Lamotrigine has potentially serious toxicity especially 
serious rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis) and there are various 
publications that suggest that valproic acid may also have deleterious effects on decreasing 
BMD.
A 1-year study duration is justified based on the following:

The American Academy Pediatrics Clinical Report Bone Densitometry in children and 
adolescents states that the recommended interval between repeat DEXA scans depends on 
progression of bone disorder, with a minimal interval between scans of 6 months, but often 
1 year or more may be appropriate to allow measurable change to occur.3 The Position 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
86
Approved, Date: 3 November 2017
statement on DEXA scans in children and adolescents from ISCD states that in pediatric 
patients, repeat scans should generally be obtained within 1 to 2 years for clinical purposes 
and in some settings, such as a patient in a research study and/or receiving a therapeutic 
skeletal agent, every 6 months.18 The shorter 6-month interval may reveal trends in skeletal 
losses and gains, reflecting variations in bone turnover from either a chronic disease or 
intervention, but ones not yet clinically significant. The ISCD suggests a minimum 
monitoring time interval of 6 months for repeating BMD measurement.4

Abnormalities in height have been detected during 1 year of treatment in children treated 
with topiramate monotherapy. Topiramate as monotherapy for newly or recently diagnosed 
POS has been evaluated in 3 double-blind Phase 3 studies, each of which included subjects 
between the ages of 6 and 15 years of age at enrollment.33 One of these 3 studies included 
post-baseline height or BMI data and also included an open-label extension phase.9 During 
the combined double-blind and open-label extension, there was a small percentage of 
children who met height criteria for growth delay.

Renal stones as documented by renal ultrasound have been demonstrated within a 1-year 
treatment duration with topiramate. Results from the open-label extension study performed in 
284 infants with epilepsy 1 to 24 months of age treated with topiramate for 1 year showed 
that 18 of 284 subjects (6.3%) had nephrolithiasis detected by sonogram approximately 4 to 
5 months into the study.11
Additional ethical concerns relate to consent/assent and ensuring that ethical principles related to 
pediatric subjects as vulnerable subjects are in effect, primarily to ensure that total allowable 
blood volumes are not exceeded during study conduct.
Potential subjects and their guardians will be fully informed of the risks and requirements of the 
study and, during the study, they will be given any new information that may affect their decision 
to continue participation. They will be told that their consent/assent to participate in the study is 
voluntary and may be withdrawn at any time with no reason given and without penalty or loss of 
benefits to which they would otherwise be entitled. Enrollment will only be allowed if 
parents/legally acceptable representatives or subjects are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent/assent voluntarily. 
When referring to the signing of the informed consent form, the terms legal guardian and legally 
acceptable representative refer to the legally appointed guardian of the child with authority to 
authorize participation in research. For each subject, his or her parent(s) (preferably both parents, 
if available) or a legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has 
been fully explained and before the performance of any study-related assessments. Assent must 
be obtained from children (minors) capable of understanding the nature of the study, typically 
subjects 7 years of age and older, depending on the institutional policies. For the purposes of this 
study, all references to subjects who have provided consent/assent refers to the subjects (assent 
as applicable) and his or her parent(s) or the subject's legal guardian(s) or legally acceptable 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
87
Approved, Date: 3 November 2017
representative(s) who have provided consent according to this process. Minors who assent to a 
study and later withdraw their assent should not be maintained in the study against their will, 
even if their parents still want them to participate.
The total blood volume to be collected during the study is less than 3 mL/kg body weight per 
8-week period (approximately 11.0 mL or less at each visit), consistent with the guidelines for 
total allowable blood volumes drawn from pediatric subjects from multiple sources, including NIH 
IRB, US Department of Health and Human Services, Alliance Laboratory Services, and Harvard's 
Massachusetts General Hospital (Boston, Massachusetts).23
Although a subject could be exposed to as many as 18 DEXA scans over the 12-month course of 
the study, the additional amount of radiation is less than the yearly natural background radiation in 
the United States (3 mSV), and involves minimal risk. Further details, including the radiation dose 
by machine, scan, and age, are provided in the DEXA Manual for this study.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents:

Final protocol and, if applicable, amendments

Sponsor-approved informed consent form and assent forms (and any other written materials 
to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
88
Approved, Date: 3 November 2017

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any), the informed consent form, assent forms, applicable recruiting 
materials, and subject compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments

Revision(s) to informed consent form, assent forms, and any other written materials to be 
provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
investigational drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Annual Safety Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct), the amendment and applicable informed 
consent/assent form revisions must be submitted promptly to the IEC/IRB for review and 
approval before implementation of the change(s).


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
89
Approved, Date: 3 November 2017
At least once a year, the IEC/IRB will be asked to review and reapprove this clinical study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Parents (or a legally acceptable representative) and pediatric subjects must give written consent
and assent, respectively, according to local requirements, after the nature of the study has been 
fully explained. Assent must be obtained from children (minors) capable of understanding the 
nature of the study, typically subjects 7 years of age and older, depending on the institutional 
policies, as described below. The consent and assent forms must be signed before performance of 
any study-related activity. The consent form and assent forms that are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the parents or legally 
acceptable representative and subject can read and understand. The informed consent and assent 
should be in accordance with principles that originated in the Declaration of Helsinki, current 
ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the investigational 
staff must explain to potential subjects and their parents or legally acceptable representatives the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. Subjects will be informed that their participation 
is voluntary and that they may withdraw consent to participate at any time. They will be 
informed that choosing not to participate will not affect the care the subject will receive for the 
treatment of his or her disease. Subjects will be told that alternative treatments are available if 
they refuse to take part and that such refusal will not prejudice future treatment. Finally, they will 
be told that the investigator will maintain a subject identification register for the purposes of 
long-term follow-up if needed and that their records may be accessed by health authorities and 
authorized sponsor staff without violating the confidentiality of the subject, to the extent 
permitted by the applicable law(s) or regulations. By signing the informed consent and assent
forms the subject and parents or legally acceptable representative is authorizing such access, and 
agrees to allow his or her study physician to recontact the subject for the purpose of obtaining 
consent and assent for additional safety evaluations, if needed.
The subject and parents or legally acceptable representative will be given sufficient time to read 
the informed consent form and the opportunity to ask questions. After this explanation and 
before entry into the study, consent and assent should be appropriately recorded by means of 
either the subject's or his or her legally acceptable representative's personally dated signature. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
90
Approved, Date: 3 November 2017
After having obtained the consent, a copy of the informed consent form must be given to the 
subject.
If the subject and parents or legally acceptable representative is unable to read or write, an 
impartial witness should be present for the entire informed consent process (which includes 
reading and explaining all written information) and should personally date and sign the informed 
consent and assent forms after the oral consent of the subject and parents or legally acceptable 
representative is obtained.
Children (minors) or subjects who are unable to comprehend the information provided can be 
enrolled only after obtaining consent from parents or a legally acceptable representative. Assent 
must be obtained from children (minors) capable of understanding the nature of the study, 
typically subjects 7 years of age and older, depending on the institutional policies. Written assent 
should be obtained from subjects who are able to write. A separate assent form written in 
language the subject can understand should be developed for adolescents. After having obtained 
the assent, a copy of the assent form must be given to the subject, and to the subject's parent 
and/or legally acceptable representative.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of study subjects confidential.
The informed consent and assent obtained from the subject or parent (or his or her legally
acceptable representative) includes explicit consent for the processing of personal data and for 
the investigator to allow direct access to his or her original medical records for study-related 
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the 
transfer of the data to other entities and to other countries.
The subject or parent has the right to request through the investigator access to his or her 
personal data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps will be taken to respond to such a request, taking into consideration the nature 
of the request, the conditions of the study, and the applicable laws and regulations.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
91
Approved, Date: 3 November 2017
Exploratory research is not conducted under standards appropriate for the return of data to 
subjects. In addition, the sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not be returned to 
subjects or investigators, unless required by law. Privacy and confidentiality of data generated in 
the future on stored samples will be protected by the same standards applicable to all other 
clinical data.
16.2.5.
Country Selection
This study will only be conducted in those countries where the 2 study drugs are commercially 
available for the treatment of epilepsy.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor or its designee. When the change(s) involves only logistic or administrative aspects of 
the study, the IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
92
Approved, Date: 3 November 2017
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
investigational site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed, written IEC/IRB approval of the protocol, amendments, 
informed consent form, assent forms, any recruiting materials, and if applicable, subject 
compensation programs. This approval must clearly identify the specific protocol by title and 
number and must be signed by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the investigational staff is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all clinical subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
93
Approved, Date: 3 November 2017
reports and communications relating to the study will identify subjects by dummy initials and 
assigned number only.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of informed consent and assent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable.
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care. Specific 
details required as source data for the study will be reviewed with the investigator before the 
study and will be described in the monitoring guidelines (or other equivalent document).
The following data will be recorded directly in the source documents and then entered into the 
CRF: 

Race

Blood pressure and heart rate

Height – A blinded study nurse or other staff will measure the height of the subject and 
record it in the source documents, or provide it to the unblinded study coordinator for entry 
into the source documents. The unblinded study coordinator will then enter this data, along 
with other visit data, into the CRF.

Weight 

Details of physical examination
Subject- and investigator-completed scales and assessments designated by the sponsor below 
will be recorded separately from the CRF and will be considered source data:

Vineland Adaptive Behavior Scale

CBCL - Parent version (preschool and school-age versions)

Seizure diary


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
94
Approved, Date: 3 November 2017

C-SSRS
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic data capture will be used for this study. The study data will be transcribed by study 
personnel from the source documents onto an eCRF, and transmitted in a secure manner to the 
sponsor within the timeframe agreed upon between the sponsor and the site. The electronic file 
will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Designated site personnel must complete the CRF as soon as possible after a subject 
visit, and the forms should be available for review at the next scheduled monitoring visit.
Every effort should be made to ensure that all subjective measurements (eg, pain scale 
information or other questionnaires) to be recorded in the CRF are completed by the same 
individual who made the initial baseline determinations. The investigator must verify that all data 
entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
an authorized member of the investigational staff must adjust the CRF (if applicable) and 
complete the query.
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:

Site personnel can make corrections in the eDC tool at their own initiative or as a response to 
an auto query (generated by the eDC tool).

Site manager can generate a query for resolution by the investigational staff.

Clinical data manager can generate a query for resolution by the investigational staff.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
associated personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of DEXA, and clinical laboratory data from a central laboratory into the sponsor's 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
95
Approved, Date: 3 November 2017
database. Written instructions will be provided for collection, preparation, and shipment of 
samples. 
Guidelines for CRF completion will be provided and reviewed with study personnel before the 
start of the study. The sponsor will review CRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate. After upload of the data into the clinical study
database they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s).
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or clinic records (source 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
96
Approved, Date: 3 November 2017
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the CRF are known to the sponsor and 
investigational staff and are accessible for verification by the sponsor site contact. If electronic 
records are maintained at the investigational site, the method of verification must be discussed 
with the investigational staff. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the investigational staff. 
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the investigational site will be sent to the sponsor
(or designee) after completion of the final subject assessment at that site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at any time
for any reason at the sole discretion of the sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed.
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further drug development


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
97
Approved, Date: 3 November 2017
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the site at any 
time during or after completion of the study to conduct an audit of the study in compliance with 
regulatory guidelines and company policy. These audits will require access to all study records, 
including source documents, for inspection and comparison with the CRFs. Subject privacy 
must, however, be respected. The investigator and staff are responsible for being present and 
available for consultation during routinely scheduled site audit visits conducted by the sponsor or 
its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding topiramate or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data generated as a result of this study, are considered confidential 
and remain the sole property of the sponsor. The investigator agrees to maintain this information 
in confidence and use this information only to accomplish this study, and will not use it for other 
purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the clinical study will be used by 
the sponsor in connection with the continued development of topiramate, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all investigational sites that participate in the study and data from 
DEXA, and clinical laboratory tests, which will be directly transmitted from a central laboratory
into the sponsor's database. Recruitment performance or specific expertise related to the nature 
and the key assessment parameters of the study will be used to determine a coordinating 
investigator for the study. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work. 


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
98
Approved, Date: 3 November 2017
The sponsor shall have the right to publish such data and information without approval from the 
investigator. If an investigator wishes to publish information from the study, a copy of the 
manuscript must be provided to the sponsor for review at least 60 days before submission for 
publication or presentation. Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials. If requested by the sponsor in writing, the investigator will 
withhold such publication for up to an additional 60 days to allow for filing of a patent 
application. In the event that issues arise regarding scientific integrity or regulatory compliance, 
the sponsor will review these issues with the investigator. The sponsor will not mandate 
modifications to scientific content and does not have the right to suppress information. For
multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual site until the combined results from the completed study have been submitted 
for publication, within 12 months of the availability of the final data (tables, listings, graphs), or 
the sponsor confirms there will be no multicenter study publication. Authorship of publications 
resulting from this study will be based on the guidelines on authorship, such as those described 
in the ICMJE Recommendations for the Conduct, Reporting, Editing and Publication of 
Scholarly Work in Medical Journals, which state that the named authors must have made a 
significant contribution to the conception or design of the work; or the acquisition,  analysis, or 
interpretation of the data for the work; and drafted the work or revised it critically for important 
intellectual content; and given final approval of the version to be published; and agreed to be 
accountable for all aspects of the work in ensuring that questions related to the accuracy or 
integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
99
Approved, Date: 3 November 2017
REFERENCES
1.
Achenbach TM, Rescorla LA. Manual for the ASEBA Preschool Forms and Profiles. 1991;Burlington, VT: 
University of Vermont Department of Psychiatry.
2.
Achenbach TM, Rescorla LA. Manual for the ASEBA School-Age Forms and Profiles. 1991;Burlington, VT: 
University of Vermont, Research Center for Children, Youth, and Families.
3.
Bachrach LK, Sills IN; Section on Endocrinology. Clinical report—bone densitometry in children and 
adolescents. Pediatrics. 2011;127(1):189-194.
4.
Bishop N, Braillon P, Burnham J, et al. Dual-energy X-ray absorptiometry assessment in children and 
adolescents with diseases that may affect the skeleton: the 2007 ISCD Pediatric Official Positions. J Clin 
Densitom. 2008;11(1):29-42.
5.
Caplan R, Sagun J, Siddarth P, et al. Social competence in pediatric epilepsy: Insights on underlying 
mechanisms. Epilepsy Behav. 2005;6:218-228.
6.
Ciochetti DV, Sparrow SS, Carter A. Development and validation of the Vineland Adaptive Behavior 
screening instruments. 1991;San Francisco, CA: American Psychological Association.
7.
Clinical Study Report TOPMAT-EPMN-104. Topiramate monotherapy clinical trial in subjects with recently 
diagnosed partial onset seizures. RWJPRI (22 Apr 1999).
8.
Clinical Study Report TOPMAT-EPMN-105. Topamax (Topiramate) monotherapy comparison trial to 
standard monotherapy in the treatment of newly diagnosed epilepsy. RWJPRI (26 Oct 2000).
9.
Clinical Study Report TOPMAT-EPMN-106. A randomized, double blind, parallel group, monotherapy study 
to compare the safety and efficacy of two doses of topiramate in the treatment of newly diagnosed or recurrent 
epilepsy. J&JPRD (20 Aug 2002).
10.
Clinical Study Report TOPMAT-MIG-3006. A randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of topiramate for the prophylaxis of migraine in pediatric subjects 12 to 17 
years of age. J&JPRD (20 Aug 2007).
11.
Clinical Study Report TOPMAT-PEP-1002 and TOPMAT-PEP-3001. Long-term safety of topiramate 
administered as the oral liquid and sprinkle capsule formulations as an adjunct to concurrent anticonvulsant 
therapy in infants (aged 1 to 24 months, inclusive) with refractory partial-onset seizures (Interim Report Based
on Available Data as of 15 June 2007). J&JPRD (14 Jan 2008).
12.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for 
revised classification of the epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399.
13.
Connolly AM, Northcott E, Cairns DR, et al. Quality of life of children with benign rolandic epilepsy. Ped 
Neurol. 2006;35:240-245.
14.
Drug Metabolism Research Report DM97328. Topiramate metabolite profiling and identification in infant 
subjects. RWJPRI. (20 Jan 1998).
15.
Falleti MG, Maruff P, Collie A, Darby DG. Practice effects associated with the repeated assessment of 
cognitive function using the Cogstate Battery at 10-minute, one week and one month test-retest intervals. J 
Clin Exp Neuropsychol. 2006;28(7):1095-1112.
16.
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE Official Report A practical clinical definition of epilepsy. 
Epilepsia. 2014;55(4):475-482.
17.
Girgis IG, Nandy P, Nye JS, et al. Pharmacokinetic–pharmacodynamic assessment of topiramate dosing 
regimens for children with epilepsy 2 to <10 years of age. Epilepsia. 2010;51:1954–1962.
18.
Gordon CM, Bachrach LK, Carpenter TO, et al. Dual energy X-ray absorptiometry interpretation and 
reporting in children and adolescents: The 2007 ISCD Pediatric Official Positions. J Clin Densitometry: 
Assessment of Skeletal Health. 2008;11:43-58.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
100
Approved, Date: 3 November 2017
19.
Greer FR. Defining vitamin D deficiency in children: beyond 25-OH vitamin D serum concentrations. 
Pediatrics. 2009;124(5):1471-3.
20.
Greulich W, Pyle S. Radiographic Atlas of Skeletal Development of the Hand and Wrist. 2nd edition. (1959) 
Stanford, CA: Stanford University Press.
21.
Grosso S, Cordelli DM, Franzoni E, et al. Efficacy and safety of levetiracetam in infants and young children 
with refractory epilepsy. Seizure. 2007;16:345—350.
22.
Hay JA. Development and testing of the Habitual Activity Estimation Scale. In Armstrong N, Welsman J, 
Kirby B (eds). Children and Exercise. XIX: Promoting Health and Well-being. XIXth International 
Symposium of Pediatric Work Physiology, Exeter, London: E&FN Spon, 1997;II:125–129.
23.
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ. 
2011;89(1):46-53.
24.
Keppra® (levetiracetam) Package Insert. UCB, Inc. Apr 2009.
25.
Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data. 
2000;314:1-27.
26.
Maruff P, Thomas E, Cysique L, et al. Validity of the Cogstate brief battery: relationship to standardized tests 
and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia 
complex. Arch Clin Neuropsychol. 2009;24(2):165-178.
27.
Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of adolescent development. 
J Youth Adolesc. 1980;9:271-280.
28.
Nonclinical Safety Study Report TOX6898. Oral toxicity study in juvenile rats. CIT Study No. 29067 RSR. 
J&JPRD (22 Dec 2006).
29.
Opp J, Tuxhorn I, May T, et al. Levetiracetam in children with refractory epilepsy: a multicenter open label 
study in Germany. Seizure. 2005;14:476-484.
30.
Pietrzak RH, Olver J, Norman T, Piskulic D, Maruff P, Snyder PJ. A comparison of the Cogstate 
schizophrenia battery and the measurement and treatment Research to improve cognition in Schizophrenia 
(MATRICS) battery in assessing cognitive impairment in chronic schizophrenia. J Clin Exp Neuropsychol. 
2009;31(7): 848-859. doi:10.1080/13803390802592458.
31.
Posner K, Oquendo M, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): Classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164:1035-1043.
32.
Rosenfeld WE, Doose, DR, Walker SA, Baldassarre JS, Reife RA. A study of topiramate pharmacokinetics 
and tolerability in children with epilepsy. Pediatr Neurol. 1999;20:339-344.
33.
RWJ-17021-000 (topiramate) Investigator's Brochure Edition 15. Janssen R&D (15 March 2017).
34.
Sabaz M, Cairns DR, Bleasel AF, et al. The health-related quality of life of childhood epilepsy syndromes. J 
Paediatr Child Health. 2003;39:690-696.
35.
Shepherd JA, Wang L, Fan B, et al. Optimal monitoring time interval between DXA measures in children. J 
Bone Miner Res. 2011;26:2745-2752.
36.
Sparrow SS, Balla DA, Cicchetti DV. Vineland Adaptive Behavior Scales: Interview Edition Survey Forms 
Manual. Circle Pines, MN. American Guidance Service 1984.
37.
Tanner JM. Growth at Adolescence, 2nd ed. (1962). London, England Oxford: Blackwell Scientific. 
38.
TOPAMAX® (topiramate) Prescribing Information. Janssen Pharmaceuticals, Inc., Jul 2011.
39.
Topiramate Integrated Summary of Safety. Topiramate as monotherapy for pediatric and adult subjects with 
newly diagnosed epilepsy. J&JPRD (30 Sep 2002).
40.
Topiramate Pediatric Monotherapy sNDA Integrated Summary of Safety. J&JPRD (9 Dec 2009).


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
101
Approved, Date: 3 November 2017
41.
Vega D, Maalouf NM, Sakhaee K. Increased propensity for calcium phosphate kidney stones with topiramate 
use. Expert Opinion Drug Safety. 2007;6(5):547-557.
42.
Vitamin D fact sheet for health professionals. http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. 
Accessed 08 Jun 2015.
43.
von Stuelpnagel C, Holthausen H, Kluger G. Long-term use of levetiracetam in patients with severe 
childhood-onset epilepsy. Eur J Paed Neur. 2007;11:341–345.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
102
Approved, Date: 3 November 2017
ATTACHMENTS
Attachment 1: Habitual Activity Estimation Scale


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
103
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
104
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
105
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
106
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
107
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
108
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
109
Approved, Date: 3 November 2017
Attachment 2: Titration Schedules for Topiramate and Levetiracetam
Topiramate Monotherapy Titration Schedule for Subjects 2 to <10 Years of Age
Table 1: Topiramate Monotherapy Titration Schedule for Subjects 2 to <10 Years of Age – Body Weight up to 
11 kg (Maximum Recommended Maintenance Dosage 250 mg/day)
Total Daily Dosage 
(mg)
Morning Dose (mg)
Evening Dose (mg)
Week 1
25
0
25
Week 2
50
25
25
Week 3
75
25
50
Week 4
100
50
50
Week 5
125
50
75
Week 6
150
75
75
Week 7
200
100
100
Week 8
250
100
150
Table 2: Topiramate Monotherapy Titration Schedule for Subjects 2 to <10 Years of Age – Body Weight 12 to 
22 kg (Maximum Recommended Maintenance Dosage 300 mg/day)
Total Daily Dosage 
(mg)
Morning Dose (mg)
Evening Dose (mg)
Week 1
25
0
25
Week 2
50
25
25
Week 3
75
25
50
Week 4
100
50
50
Week 5
150
75
75
Week 6
200
100
100
Week 7
250
125
125
Week 8
300
150
150
Table 3: Topiramate Monotherapy Titration Schedule for Subjects 2 to <10 Years of Age – Body Weight 23 to 
38 kg (Maximum Recommended Maintenance Dosage 350 mg/day)
Total Daily Dosage 
(mg)
Morning Dose (mg)
Evening Dose (mg)
Week 1
25
0
25
Week 2
50
25
25
Week 3
75
25
50
Week 4
100
50
50
Week 5
200
100
100
Week 6
250
125
125
Week 7
300
150
150
Week 8
350
175
175


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
110
Approved, Date: 3 November 2017
Topiramate Monotherapy Titration Schedule for Subjects 10 to 15 Years of Age
Table 4: Topiramate Monotherapy Titration Schedule for Subjects 10 to 
15 Years of Age
Morning Dose (mg)
Evening Dose (mg)
Week 1
25 
25 
Week 2
50 
50 
Week 3
75 
75 
Week 4
100 
100 
Week 5
150 
150 
Week 6
200 
200 
Levetiracetam Weight-Based Titration Dosing Guide (Oral Solution, 100 mg/mL) for Subjects With 
a Body Weight ≤20 kg
Table 5: Levetiracetam Weight-Based Titration Dosing Guide (Oral Solution; 100 mg/mL) for Subjects With a 
Body Weight ≤20 kg – Weeks 1 to 2 (20 mg/kg/day)
Body Weight (kg)
Total Daily Dosage 
(mg)
Morning Dose (mg)
Evening Dose (mg)
Dosage Regimen
10
200
100
100
1.0 mL BID
11
220
110
110
1.1 mL BID
12
240
120
120
1.2 mL BID
13
260
130
130
1.3 mL BID
14
280
140
140
1.4 mL BID
15
300
150
150
1.5 mL BID
16
320
160
160
1.6 mL BID
17
340
170
170
1.7 mL BID
18
360
180
180
1.8 mL BID
19
380
190
190
1.9 mL BID
20
400
200
200
2.0 mL BID
Table 6: Levetiracetam Weight-Based Titration Dosing Guide (Oral Solution; 100 mg/mL) for Subjects With a 
Body Weight ≤20 kg – Weeks 3 to 4 (40 mg/kg/day)
Body Weight (kg)
Total Daily Dosage 
(mg)
Morning Dose (mg)
Evening Dose (mg)
Dosage Regimen
10
400
200
200
2.0 mL BID
11
440
220
220
2.2 mL BID
12
480
240
240
2.4 mL BID
13
520
260
260
2.6 mL BID
14
560
280
280
2.8 mL BID
15
600
300
300
3.0 mL BID
16
640
320
320
3.2 mL BID
17
680
340
340
3.4 mL BID
18
720
360
360
3.6 mL BID
19
760
380
380
3.8 mL BID
20
800
400
400
4.0 mL BID


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
111
Approved, Date: 3 November 2017
Table 7: Levetiracetam Weight-Based Titration Dosing Guide (Oral Solution; 100 mg/mL) for Subjects With a 
Body Weight ≤20 kg – Weeks 5 to 8 and Maintenance (60 mg/kg/day)
Body Weight (kg)
Total Daily Dosage 
(mg)
Morning Dose (mg)
Evening Dose (mg)
Dosage Regimen
10
600
300
300
3.0 mL BID
11
660
330
330
3.3 mL BID
12
720
360
360
3.6 mL BID
13
780
390
390
3.9 mL BID
14
840
420
420
4.2 mL BID
15
900
450
450
4.5 mL BID
16
960
480
480
4.8 mL BID
17
1,020
510
510
5.1 mL BID
18
1,080
540
540
5.4 mL BID
19
1,140
570
570
5.7 mL BID
20
1,200
600
600
6.0 mL BID
Levetiracetam Weight-Based Titration Dosing Guide (Tablets) for Subjects With a Body Weight 
>20 kg
Table 8: Levetiracetam Weight-Based Titration Dosing Guide (Tablets) for Subjects With a Body Weight >20 kg 
Morning Dose (mg)
Evening Dose (mg)
20.1 to 40 kg
>40 kg
20.1 to 40 kg
>40 kg
Week 1
250
500
250
500
Week 2
250
500
250
500
Week 3
500
500
500
1,000
Week 4
500
500
500
1,000
Week 5
750
1,000
750
1,500
Week 6
750
1,000
750
1,500


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
112
Approved, Date: 3 November 2017
Attachment 3: Pharmacokinetic Collection and Handling Procedure
Materials and Labeling
The central laboratory will provide the investigational site with blood collection tubes, storage tubes, preprinted 
labels (or tubes labeled with preprinted labels), and related supplies for the collection and shipment of PK samples. 
Labels should be attached to the storage tubes at least 12 hours before being frozen to ensure proper adherence.
Use of alternative materials will not result in a protocol amendment if preapproved by the Bioanalysis Scientist.
Detailed information regarding the collection and storage containers will be provided in the laboratory manual from 
the central laboratory.
Preparation of Plasma Pharmacokinetic Samples for Topiramate

Collect 1 mL of blood into the appropriate K2-EDTA-containing collection tube (eg, Vacutainer) at each time 
point.

Record the exact date and time of sampling in the CRF or laboratory requisition form, as appropriate.

Gently invert the tubes 8 to 10 times to afford mixing, before processing.

Centrifuge blood samples at room temperature within 1 hour(s) of collection at 1,300 g for 10 minutes, unless 
otherwise specified by the supplier, to yield approximately 0.4 mL of plasma from each 1 mL whole blood 
sample.

Transfer all separated plasma immediately with a clean, disposable glass or polyethylene pipette (use 1 new 
pipette per sample) to a pre-labeled storage tube (3.6-mL NUNCCryotube, Cat. No. 366524 or 379189).

Store plasma samples in an upright position in a freezer, at a set temperature of –20C until transfer to the central 
laboratory.

The time between blood collection and freezing the plasma should not exceed 2 hours.

Ship specimens to the central laboratory according to the instructions provided.

Questions regarding handling the plasma PK specimens should be addressed to the contact person for the 
sponsor.

Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis Scientist.
Preparation of Plasma Pharmacokinetic Samples for Levetiracetam

Collect 1 mL of blood into the appropriate K3-EDTA-containing collection tube (eg, Vacutainer) at each time 
point.

Record the exact date and time of sampling in the CRF or laboratory requisition form, as appropriate.

Gently invert the tubes 8 to 10 times to afford mixing, before processing.

Centrifuge blood samples at room temperature within 1 hour(s) of collection at 1,300 g for 10 minutes, unless 
otherwise specified by the supplier, to yield approximately 0.4 mL of plasma from each 1 mL whole blood 
sample.

Transfer all separated plasma immediately with a clean, disposable glass or polyethylene pipette (use 1 new 
pipette per sample) to a pre-labeled storage tube (3.6-mL NUNCCryotube, Cat. No. 366524 or 379189).

Store plasma samples in an upright position in a freezer, at a set temperature of –20C until transfer to the central 
laboratory.

The time between blood collection and freezing the plasma should not exceed 2 hours.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
113
Approved, Date: 3 November 2017

Ship specimens to the central laboratory according to the instructions provided.

Questions regarding handling the plasma PK specimens should be addressed to the contact person for the 
sponsor.

Alternative procedures will not result in a protocol amendment if approved by the Bioanalysis Scientist.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
114
Approved, Date: 3 November 2017
Attachment 4: Labeling Instructions for Pharmacokinetic Samples
STRUCTURE OF THE LABEL:
1. Each label has 2 identical parts. 
2. The backing of the label and the label itself are 
perforated.
STEP 1: Remove part 1 of the label and 
completely attach it to the Vacutainer, 
lengthwise. Centrifuge the Vacutainer.
STEP 2: Remove part 2 of the label and attach it to the 
empty plasma storage tube. The label must be attached to 
the tube lengthwise. Labels should be attached to the 
storage tubes at least 12 hours before being frozen to 
ensure proper adherence. You are now able to match the 
alphanumeric code, subject identification, and time point 
on the plasma collecting tube with the corresponding 
information on the Vacutainer. After the tubes are 
matched, the plasma may be transferred from the 
Vacutainer to the plasma storage tube.
STEP 3: Freeze the sample in an upright position. 
Pack and ship the samples as instructed in the protocol.


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
115
Approved, Date: 3 November 2017
Attachment 5: Shipment of Pharmacokinetic Samples
All PK samples will be sent to the central laboratory at the intervals agreed upon. The laboratory manual from the 
central laboratory provides details regarding packaging and shipment of the samples. The following general 
guidelines should be considered:

For all international shipments, World Courier will be used. For domestic shipments, a domestic courier, as 
recommended by the central laboratory, will be used.

Notify central laboratory and courier at least 24 hours in advance of the planned shipment. Provide the courier 
with the appropriate account number to be used, if applicable.

Place the frozen samples for each subject in the appropriate containers, as specified in the central laboratory 
manual.

Pack the frozen samples in sufficient quantity of dry ice, to maintain a frozen state for at least 3 days.

Avoid direct contact between sample bags and dry ice, by separating them with a dry ice resistant material (eg, 
newspaper).

For all biological samples, follow the International Air Transport Association (IATA) regulations for shipment.

Ensure that the total package weight does not exceed 27.2 kg (60 lb).

Label the package with the study number and all other information required by the central laboratory.

Include a return address (which includes the investigator’s name) on the outside of each shipping container.

Comply with all courier regulations for the shipment of biological specimens (include all paperwork).

Retain all documents indicating date, time, and signature(s) of person(s) making the shipment, in the study files.
Samples should be shipped via overnight delivery only on Monday through Wednesday, excluding holidays. As 
soon as shipment day and air bill number(s) are available, the site will call, fax, or e-mail the central laboratory. The 
call, fax, or e-mail must specify the study number, the number of PK samples, and the time of shipment pick-up.
Samples must be sent to the name and address indicated in the central laboratory manual.
NOTE: If there are changes regarding the courier or location to which samples are shipped during the course of the 
clinical study, written notification will be provided to the investigator and will not require (a) protocol 
amendment(s).


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
116
Approved, Date: 3 November 2017
Attachment 6: CBCL-Preschool


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
117
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
118
Approved, Date: 3 November 2017
Attachment 7: CBCL School Age


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
119
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
120
Approved, Date: 3 November 2017
Attachment 8: Columbia Suicide Severity Scale: Baseline Version


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
121
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
122
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
123
Approved, Date: 3 November 2017
Attachment 9: Columbia Suicide Severity Scale: Since Last Visit Version


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
124
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
125
Approved, Date: 3 November 2017


RWJ-17021-000 (topiramate)
Clinical Protocol TOPMATEPY4067 Amendment INT-6
126
Approved, Date: 3 November 2017
INVESTIGATOR AGREEMENT
LAST PAGE
PPD

SAP_001.pdf: 
Janssen Research &
Development Statistical Analysis Plan
A Randomized, Active-Controlled, Open-Label, Flexible-Dose Study to Assess the Safety
and Tolerability of Topiramate as Monotherapy Compared With Levetiracetam as
Monotherapy in Pediatric Subjects with New or Recent-Onset Epilepsy
Protocol TOPMATEPY4067; Phase 3
Amendment 3
RWJ-17021-000 (topiramate)
Status:
Approved
Date:
June 8, 2020
Prepared by:
Janssen Research and Development
Document No.: EDMS-ERI-199060224: 4.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP).
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company customarily
holds close and treats as confidential.  The information is being provided under the assurance that the recipient will maintain the
confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 08 June 2020
NCT02201251


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
2
TABLE OF CONTENTS
TABLE OF CONTENTS.............................................................................................................................................2
LIST OF IN-TEXT TABLES .......................................................................................................................................4
AMENDMENTHISTORY ...........................................................................................................................................5
ABBREVIATIONS..............................................................................................................................................................................................6
1.
CHANGES IN CONDUCT OF THE STUDY ..................................................................................................7
2.
INTRODUCTION ...............................................................................................................................................................7
2.1.
TrialObjectives..............................................................................................................................................7
2.2.
Trial Design....................................................................................................................................................8
2.3.
Statistical Hypotheses for Trial Objectives.................................................................................................8
2.4.
Sample Size Justification .............................................................................................................................8
2.5.
Randomization and Blinding........................................................................................................................9
2.6.
Time and Events Schedule ........................................................................................................................11
3.
GENERAL ANALYSISDEFINITIONS .........................................................................................................15
3.1.
VisitWindows...............................................................................................................................................15
3.2.
Pooling Algorithm for Analysis Centers ....................................................................................................18
3.3.
Analysis Sets ...............................................................................................................................................18
3.3.1.
EfficacyAnalysis Set(s) ..........................................................................................................................18
3.3.1.1.
PrimaryEfficacyAnalysis Set .............................................................................................................18
3.3.1.2.
Secondary Efficacy Analysis Set........................................................................................................18
3.3.2.
All Randomized Set.................................................................................................................................18
3.3.3.
Safety Analysis Set .................................................................................................................................18
3.3.4.
Pharmacokinetics Analysis Set..............................................................................................................18
3.3.5.
PharmacodynamicsAnalysisSet ..........................................................................................................18
3.4.
Definition of Subgroups..............................................................................................................................19
4.
INTERIM ANALYSIS AND DATAMONITORING COMMITTEE REVIEW..............................................19
5.
SUBJECT INFORMATION ........................................................................................................................................ 20
5.1.
Demographics and Baseline Characteristics...........................................................................................20
5.2.
DispositionInformation...............................................................................................................................21
5.3.
TreatmentCompliance ...............................................................................................................................21
5.4.
Extent of Exposure......................................................................................................................................21
5.5.
ProtocolDeviations.....................................................................................................................................21
5.6.
Prior and Concomitant Medications ..........................................................................................................22
5.7.
MedicalHistory............................................................................................................................................22
6.
EFFICACY.................................................................................................................................................................................22
6.1.
AnalysisSpecifications...............................................................................................................................22
6.1.1.
Level of Significance ...............................................................................................................................22
6.1.2.
Data Handling Rules ...............................................................................................................................22
6.2.
PrimaryEfficacyEndpoint(s)......................................................................................................................22
7.
SAFETY............................................................................................................................................................................ 22
7.1.
KidneyStones .............................................................................................................................................24
7.2.
Weight .......................................................................................................................................................................... 24
7.3.
Height ........................................................................................................................................................................... 24
7.4.
Bone Mineral Density (BMD) and Bone Mineral Content (BMC)...........................................................24
7.5.
Biochemical Markers of Bone Mineralization...........................................................................................25
7.6.
Bone Age .....................................................................................................................................................25
7.7.
SeizureCount..............................................................................................................................................25
7.8.
Cognitive, Developmental, and Behavioral Assessments......................................................................25


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
3
7.9.
Adverse Events...........................................................................................................................................27
7.10.
Clinical Laboratory Tests...........................................................................................................................28
7.11.
Vital Signs and Physical Examination Findings .....................................................................................28
7.12.
Electrocardiogram ......................................................................................................................................29
7.13.
Other Safety Parameters...........................................................................................................................29
8.
PHARMACOKINETICS/PHARMACODYNAMICS ...................................................................................30
8.1.
Pharmacokinetics .......................................................................................................................................30
8.2.
Immune Response .....................................................................................................................................30
8.3.
Pharmacodynamics....................................................................................................................................30
8.4.
Pharmacokinetic/Pharmacodynamic Relationships ..............................................................................30
9.
HEALTH ECONOMICS .................................................................................................................................30
10.
APPENDICES.................................................................................................................................................30
Appendix 1: Cogstate Pediatric Normative Data............................................................................................31
Appendix 2: Markedly Abnormal Laboratory Parameter Values ..................................................................34
11.
URINALYSIS...................................................................................................................................................43
Appendix 3: AE of clinical interest....................................................................................................................44
Appendix 4: Vineland scores ............................................................................................................................73
12.
VARIABLE DESCRIPTION ..........................................................................................................................75
Appendix 5: CBCL scoring instruction ............................................................................................................81
Appendix 6: Method for computing height velocity values and z-scores for individual subjects ...............89
Appendix 7: List of generic and brand names of AED medications .............................................................99


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
LIST OF IN-TEXT TABLES
Table 1:
Time and Events Schedule .................................................................................................................11
Table 2:
Definition of windows for height, weight, exposure, vital signs, laboratory tests, physical
examination and neurological examinations:....................................................................................15
Table 3:
Definition of windows for Renal Ultrasound, Cogstate, Tanner Staging and 24 hour urine
collection: ...............................................................................................................................................15
Table 4:
Definition of windows for C-SSRS:.....................................................................................................16
Table 5:
Definition of windows for Vineland Scale and CBCL:......................................................................16
Table 6:
Definition of windows for Bone age:...................................................................................................16
Table 7:
Definition of windows for seizure count:............................................................................................16
Table 8:
Definition of windows for DEXA:.........................................................................................................17
Table 9:
Definition of windows for Pharmacokinetics......................................................................................17
Table 10:
Clinically Important Vital Sign Values.................................................................................................29
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 08 June 2020


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
AMENDMENT HISTORY
SAP version
issue date
------------------------------------------------------------------------------
Original
December 03, 2019
1st Amendment
February 24, 2020
2nd Amendment
May 13, 2020
3rd Amendment
June 4, 2020
The overall reason for the amendment 1:
Major: 1. re-insertion of MMRM analysis in a pre-specified way of analysis & 2. additional
sensitivity analysis for subjects who took concomitant AED after the first study medication
intake.
MMRM analysis:
An MMRM analysis is included as sensitivity analysis to explore longitudinal safetydata and
will be analyzed in the following order.
1.
The model includes treatment group, study center, age group (4 age groups), visit,
treatment-by- visit interaction, baseline measure, and baseline-by-visit interaction with
the unstructured covariance matrix.
2.
If this model experiences convergence issues, then the same model with compound
symmetric matrix followed by AR1 will be explored instead of unstructured.
3.
If the above doesn’t work, then a reduced model with treatment group, age group, visit,
treatment-by-visit interaction, and baseline measure will be explored. Age will be
collapsed to two categories: 2-9 years of age (pre-pubertal) and 10-15 years of age
(pubertal). The unstructured covariance matrix will be explored first and if it doesn’t
work, then compound symmetric followed by AR1 will be applied.
4.
If above doesn’t work, then no additional MMRM analysis will be performed.
Sensitivityanalyses:
Sensitivity analyses for height z-scores, weight-z-scores and BMD z-scores will be conducted for
subset of safety analysis set: for subjects who started taking at least one concomitant AED, data
collected after the start of taking AED medication will be excluded from the analysis.
Minor: 1. Insertion of correct schedule of events, 2. Addition of AED medication list in the
Appendix, 3. Widening of screening window. 4. Age calculation at each visit for markedly
abnormal labs and vital signs. 5. Update to SAS code for Vineland score calculation.
The overall reason for the amendment 2:
1.
Widen the interval for DEXA scan to include 4 subject whose scans were done after baseline but
within 1 month post-baseline
2.
Calculate the exact age at each dosing visit
3.
Total daily dose calculation for overlapping intervals: capped at their maximum allowed dose


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
The overall reason for the amendment 3:
1. Baseline is defined as the last non-missing observation (including an unscheduled visit) prior to or 
equal to Day 1 (except for DEXA and Bone age, where baseline includes up to 30 days and 180 
days post-baseline, respectively).
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 08 June 2020


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
ABBREVIATIONS
AE
Adverse event
AED
anti-epileptic drug
ATC
Anatomical Therapeutic Chemical
BMC
bone mineral content
BMD
bone mineral density
BMDCS
Bone Mineral Density in Childhood Study
BMI
Body Mass Index
CBCL
Child Behavior Checklist
CDC
Centers for Disease Control
CI
confidence interval
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
DEXA
dual energy x-ray absorptiometry
DMC
data monitoring committee
IWRS
interactive web-based response system
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
PGTCS
primary generalized tonic-clonic seizures
POS
partial-onset seizures
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis system
SD
standard deviation
SOC
system organ class
SSG
statistical support group
TEAE
treatment-emergent adverse event
TLF
table, listing, figure
WHO
World Health Organization
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 08 June 2020


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
7
1.
CHANGES IN CONDUCT OF THE STUDY
On 12 December 2018, the independent Data Monitoring Committee (DMC) recommended to stop
the TOPMATEPY4067 study because of futility of study enrollment. On 12 August 2019, Janssen
has received the US FDA decision as follows:

Stop enrolling new subjects at all sites and discontinue the study at all the sites that do not
have either subject under study treatment or subjects who require a repeat bone mineral
density (BMD) measurement 6 months after discontinuing study treatment.

All sites with any subject on treatment in the study should continue following the subject
according to the protocol until treatment has been completed, the subject has discontinued
prematurely, or a repeat
DEXA scan (which is indicated 6 months after treatment
discontinuation) has been completed.
The US FDA decision is based on the slow rate of study enrollment of subjects despite continuous
efforts to improve recruitment in the study. The decision is not related to any safety issues.
Interim analyses on the key endpoints (change in BMD z-score at Month 12, change in height z- score
at Month 12 and change in weight z-score at Month 12) were conducted on 13 December 2018. This
SAP has been modified based on the early termination of the study.
2.
INTRODUCTION
Protocol TOPMATEPY4067 is a randomized (1:1), active-controlled, open-label, flexible-dose,
multicenter, Phase 3 study of approximately 282 eligible subjects to evaluate the effects of
topiramate monotherapy compared with levetiracetam, another standard antiepileptic drug (AED),
as monotherapy for new-onset or recent-onset epilepsy on pediatric growth and maturation, bone
mineralization, and kidney stone formation in children 2 to 15 years of age.
The purpose of the Statistical Analysis Plan is to lay out key elements including definition,
statistical methods, and tables, listings, and graphs (TLFs).
2.1.
Trial Objectives
Primary Objective:
The primary objective is to evaluate the effects of topiramate monotherapy compared with
levetiracetam, another standard AED, as monotherapy for new-onset or recent-onset epilepsy on
pediatric growth and maturation and bone mineralization, in children 2 to 15 years of age.
Secondary Objective:
To evaluate the effects of topiramate monotherapy compared with levetiracetam, another standard
AED, as monotherapy for new-onset or recent-onset epilepsy on kidney stone formation in children 2
to 15 years of age.
Overall safety will be assessed.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
8
2.2.
Trial Design
This is a 1-year, active-controlled, randomized, outpatient, multicenter, open-label, 2-arm flexible-
dose monotherapy study of topiramate compared with 1 other AED (levetiracetam) in pediatric
subjects with epilepsy. Subjects will be required to have newly or recently diagnosed epilepsy
characterized by partial-onset seizures (POS) with or without secondary generalized tonic-clonic
seizures or primary generalized tonic-clonic seizures (PGTCS).
The study will include the following 3 phases: a screening phase of up to 28 days, an open-label
treatment phase of 1 year's duration, and a posttreatment phase of 30 days’ duration. There may be an
optional
post-study follow-up
phase
to
obtain
dual
energy x-ray
absorptiometry
(DEXA)
measurements in a subgroup of subjects who experience a clinically important reduction in bone
mineral density (BMD) (change in Z-score of -0.5 or greater) after 1 year of treatment with
topiramate, to determine whether a decrease in BMD after or during 1 year of treatment with
topiramate is reversible. These subjects will have a repeat DEXA scan 6 months after discontinuation
of study drug.
To minimize any bias in measurement, after randomization 3 of the safety assessments will be
obtained in a blinded fashion, including the DEXA scan, renal ultrasound, and height.
An external, independent Data Monitoring Committee (DMC) will be commissioned for this study
and will evaluate safety data periodically throughout the study.
2.3.
Statistical Hypotheses for Trial Objectives
The study will test the hypothesis that flexible dosages of topiramate monotherapyhave the same effect
as flexible dosages of levetiracetam monotherapy on pediatric growth and bone mineralization, in
children 2 to 15 years of age with new-onset or recent-onset epilepsy, versus the alternative hypothesis
that the effect of topiramate is different from that of levetiracetam.
2.4.
Sample Size Justification
A total of 282 randomized subjects, 141 in each treatment group, will be enrolled in the study. The
sample size takes into account a 1-year dropout rate of 29%, which is a conservative estimate
based on the dropout rates was observed in a previous monotherapy study in the 6- to 15-year-old
age group, Study TOPMAT-EPMN-106, including a dropout rate of 22% in the study overall
(both double-blind and open-label phases) and a dropout rate of 35% for the double-blind phase.
The sample size was estimated in order to achieve a sufficient precision for the estimates of the
treatment effect on the key endpoints. The precision of the confidence interval (CI) estimates for
the key safety parameters are shown below:

Annual change in BMD (L1-L4) Z-score: In the Bone Mineral Density in Childhood Study
(BMDCS), mean annual change in BMD (L1-L4) Z-score in 6- to 15-year-old healthy
subjects was, as expected, minimal (0.01-0.07). The standard deviation (SD) varied from 0.3 to
0.48 across sex and age groups. Assuming an SD of 0.4, with 100 completed subjects per group,
the 95% CI for the treatment difference will have a precision of 0.12.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
9

Annual change in height Z-score in the 2- to 9-year-old age group: In the monotherapy
epilepsy study TOPMAT-EPMN-106, the observed change from baseline in mean height Z-
score at 1 year among the 2- to 9-year-old subjects treated with topiramate 400 mg/day was -
0.18, with an SD of 0.28. Assuming that 53% of the subjects will be recruited in the 2 to 9-
year-old age group, i.e., 53 completed subjects per treatment group, the 95% CI for the
treatment difference will have a precision of 0.11.

Change in weight Z-score in the 2- to 15-year-old age group: In the monotherapy epilepsy
study TOPMAT-EPMN-106, a -0.59 decrease from baseline in weight Z-score, with an SD of
0.43, was observed after 1 year of treatment with topiramate 400 mg/day. Assuming an SD of
0.43, a sample size of 100 completed subjects per treatment group will provide a 95% CI with a
precision of 0.12.
2.5.
Randomization and Blinding
Procedures for Randomization and Stratification
Subjects will be randomly assigned to 1 of 2 treatment groups based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor. The
randomization will be balanced using randomly permuted blocks and will be stratified by country
and age group (2 to 5 years of age, 6 to 9 years of age, 10 to 12 years of age, and 13 to 15 years of
age). The enrollment will be monitored throughout the study to ensure that subjects are enrolled for
each integer year in each treatment group.
Based on this information, the interactive web-based response system (IWRS) will assign a unique
treatment code, which will dictate the treatment assignment and matching study drug kit for the subject.
As subjects are randomly assigned to treatment, the IWRS will assign a study drug kit to be dispensed
at that visit. New study drug kits will be assigned each time the IWRS is accessed for dispensing
additional studydrug.
Blinding
As this is an open-label study, blinding procedures are not applicable for treatment assignment.
To minimize any bias in measurement, after randomization 3 of the safety assessments will be obtained
in a blinded fashion, including the DEXA scan, renal ultrasound, and height.
Renal ultrasound will be read/interpreted centrally (local reading at the screening visit is acceptable to
determine eligibility for study enrollment). Both the technicians administering the renal ultrasound scans
and the local and central readers will be blinded to the study treatment group.
All DEXA scans will be centrally analyzed (the baseline scans will be read locally to determine
eligibility for the study). Both the technicians administering the DEXA scans and the central reader will
be blinded to the treatment group.
Height will be measured by a trained individual who is blinded (unaware of the treatment).


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
10
Nominal blinding or “non-disclosure” of study treatment (i.e., study assessor is not aware of the
subject’s study treatment assignment) will also be made for assessments related to bone age and
cognitive studies (excluding CBCL and Vineland). Nominal blinding will also be applicable to Tanner
Staging, in the event site has available a pediatric endocrinologist/trained physician obtaining
assessments. The assessors’ non-disclosure status at each visit of these assessments will be captured
in the eCRF. A sensitivity analysis of these endpoints (bone age, cogstate batteries and Tanner
staging) based on nominal blinding may be considered if deemed necessary.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 08 June 2020
2.6.
Time and Events Schedule
The flow chart showing trial phases and timing of treatment and assessments is given in Table 1.
Table 1:
Time and Events Schedule
Phase
Screening
Open-Label Treatmenta
End-of-
Study/Early
Withdrawal
Follow-up
Telephone
Contact
Week(W)/Month(M)
Baseline/
W1
M1
M2
M3
M6
M9
M12
M13
StudyDay
≤-28
1c
30
60
90
180
270
360
390d
StudyDayWindow
-7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
Visite
1
2
3
4
5
6
7
8
NA
Screening/Administrative
Informedconsentandassent
X
Inclusion/exclusion criteria
X
X
Medical/seizurehistory
X
X
Physicalactivityevaluationf
X
PrestudyAEDandothertherapyg
X
Randomization
X
StudyDrug
Dispensestudydrug
X
X
X
X
X
X
Studydrug accountability
X
X
X
X
X
X
Pharmacokinetics
Bloodsamplecollectionfor
quantitationofstudydrugh
X
X
X
X
Safety
Physicalexamination
X
X
X
X
X
X
X
Neurologicexamination
X
X
X
X
X
X
X
12-leadECG
X
Height/weighti
X
X
X
X
X
X
X
Vitalsigns(temperature,HR,RR,
BP)j
X
X
X
X
X
X
X
Clinicallaboratorytestsk
X
X
X
X
X
X
Pregnancy testl
X
X
X
X
X
X
X
X
24-hour urinecollectionm
X
X
X
Tannerstagingn
X
X
X


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Status: Approved, Date: 08 June 2020
Table 1:
Time and Events Schedule
Phase
Screening
Open-Label Treatmenta
End-of-
Study/Early
Withdrawal
Follow-up
Telephone
Contact
Week(W)/Month(M)
Baseline/
W1
M1
M2
M3
M6
M9
M12
M13
StudyDay
≤-28
1c
30
60
90
180
270
360
390d
StudyDayWindow
-7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
±7days
Visite
1
2
3
4
5
6
7
8
NA
Renalultrasoundo
X
X
X
Biochemicalbonemarkersp
X
X
X
DEXAscanb,q
X
X
X
Bone age x-rayr
X
X
Dispense seizure diaryand take-
X
X
X
X
X
X
Reviewseizure diaryand take-
X
X
X
X
X
X
CogstateBatteryt
X
X
X
X
AnimalFluencyTestNEPSY-IIu
X
X
X
X
VinelandAdaptiveBehaviorScalev
X
X
X
X
CBCL–Parent Versionw
X
X
X
X
C-SSRSx
X
X
X
X
X
X
X
OngoingReview
Concomitanttherapy
X
X
X
X
X
X
X
X
X
Adverseeventmonitoring
X
X
X
X
X
X
X
X
X
Footnotesappearonthefollowingpage.
a Includes a titration period ofapproximately6 to 8 weeks,followed bya maintenance period.
b There maybe anoptional post-studyfollow-up phase toobtainDEXA measurementsina subgroup ofsubjects whoexperience a clinicallyimportantreduction
(changeinZ-scoreof-0.5 or greater) inBMD, based on localDEXAscan results, after 1 year oftreatment withtopiramate; these subjects willhave a repeat
DEXA scan6 monthsafter discontinuation ofstudydrug.
c The Day1 visit willserve as the baseline visit. Allprocedures on Day1 (except dispensing ofstudydrug) should be completed beforerandomization.
d The site willcontact the subject via telephone at Month 13, to collect data onadverse events and concomitant medications.
e  Windowfor all visits willbe ±7 days.
f Adequacyofphysical activitywillbe assessed withthe Habitual ActivityEstimationScale.
g Investigator willdocument inadequacyofanyepilepsytreatmentthat the subjectisreceivingat the timeofscreening.Informationregarding AED use and
other medications within2 years prior tothe studywill also be collected.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved, Date: 08 June 2020
h Ifpossible, blood samplesfordeterminationofplasma topiramateandlevetiracetamconcentrationsshould betroughsamples(takenimmediatelybefore the
morningdose)andshould coincide withsamplesdrawnfor clinicallaboratorytests.
i  Subjects willbe weighedin examination gowns or inlightweight clothing and without shoes.
Height willbeassessed usingawall-mountedstadiometer.
Allstudysitepersonnelmeasuringheight willbe blinded totreatmenttoavoid/minimize bias.
j  Orthostatic vital signs willbe obtained for all subjects pendingcooperation ofsubjects. Aset of3 measurements willbe obtained at baseline onlyat intervals
of 10 minutes.Thereafter, only1 orthostaticvitalsign measurement willbe taken at all subsequent visits.The method forobtainingorthostatic vital signs
willbe as follows: subject will be supine for 5 minutesprior to measurement, and standing for 2 minutesprior to measurement.
k Clinicallaboratorytests(nonfasting)includeserumchemistry,hematology,venousammoniaandurinalysis.Insulin-likegrowthfactor1,1,25-dihydroxy-vitamin
D,
25-hydroxy-vitaminD, and parathyroid hormone willbe measured at screeningand atMonths6 and12/earlywithdrawal.Thelaboratorytests for
25-hydroxy-vitaminD,1,25-dihydroxy-vitaminD,Parathyroidhormone(intact)andIGF-1atscreeningwillbeevaluatedcentrally,butadditionalevaluationata
locallaboratoryis allowed inorder toreduce thedurationofthe screeningphase.
l  Serumpregnancytest at screening; urine pregnancytest at all other visits.
m A24-hoururine collectionwillbe analyzedforpH,calcium,citrate, phosphorus,andcreatinine levels. Collectioninstructionsand storage conditions willbe
specified inthe laboratorymanual. A14-day windowoneither sideofthe scheduled Month6 visit willbe allowed for24-hour urine collection.The collection
at Month12 should becompleted beforethe Month–12 visitas thisevaluationshould be obtained whilethe subjectis stillreceiving study–drugtherapy.
n Tanner staging ofsubjects of age 8 years and above willbe conducted bya qualified pediatric endocrinologistor bya physician trained in the method.
o Renalultrasound willbe obtained under blinded conditions afterrandomizationand willbe read/interpreted centrally(local readingat the screening visit is
acceptabletodetermineeligibilityfor randomization). Boththe techniciansadministeringthe renalultrasoundscansandthe localandcentralreaders willbe
blinded to the studytreatment group.
p Biochemicalbonemarkerswillincludeserumcalcium,phosphorus,parathyroidhormone[intact],25-hydroxy-vitaminD,and1,25-dihydroxy-vitaminD.
q DEXAmeasurements willinclude posterior-anterior spine(lumbar) and totalbodyless head arealBMDandBMC. Short-termprecisiontesting willbe
performed forDEXA measurementsaccordingto standard protocols.ThesameDEXA machine willbe used at eachsiteforall subjectsand all measurements;
onlyclinical sitesusing recent-generationHologicor GeneralElectric Lunar systems willparticipate inthe study; the GE/Lunar systems willonlybe used for
subjects≥5 years ofage. Ifpossible, the sametechnician should acquire all scans foranyparticular subject.
Boththe techniciansadministering the DEXAscans and the centralreader willbe blinded to thetreatmentgroup.
For each timepoint, up to 3 scanattempts willbe performed all on the sameday(with repositioning between each scan), with the goal ofobtaining 2
complete, movement-freescansofboththe spineand wholebodyat screening.
r  Ahand/wrist x-ray(in the nondominant hand/wrist) willbe used todetermine bone age.
s Subjects willbe givena take-homerecord, to capture dataonstudydrug administration,concomitant medications,and itemsofgeneralhealth, and aseizure
diary withinstructionsto record seizurecounts and the dateand descriptionofeach seizure.
t ThecomputerizedCogstateBatterywillbeadministered bynon-expert(non-psychologist)studysitepersonneltrained intheCogstateadministration method,
with 2 practice sessions, 1 at screeningand 1 atbaseline prior to the baseline assessment. For subjects 6 to 15 yearsofage, the Detection Test, Identification
Test, One Card LearningTest,One BackTest, and GrotonMaze LearningTest willbe administered. For cooperative subjects 4 to 5 yearsofage, theDetection
Test and IdentificationTest willbeadministered.
u The AnimalFluencyTest NEPSY-II willbe administered for subjects 6 to15 yearsofage, with1 practice sessionat screening.
v The Vineland Adaptive Behavior Checklist willbe completed bya parent or guardian for subjects 2 to 5 yearsofage.
w  The CBCL-Parentversion will be used for all subjects. For subjects 2 to 5 yearsofage, the preschool version willbe administered. For subjects 6 to 15 yearsof
age, theschool-ageversion willbeadministered.
x The C-SSRS willbe administered for subjects 6 to 15 years ofage and willnot be administered for subjects 2 to 5 years ofage.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status: Approved, Date: 08 June 2020
AED=antiepilepticdrug;BMC=bonemineralcontent;BMD=bonemineraldensity;BP=bloodpressure;CBCL=ChildBehaviorChecklist;C-SSRS=Columbia
Suicide SeverityRatingScale;DEXA=dualenergyx-rayabsorptiometry;ECG=electrocardiogram;HR=heartrate;IGF-1=insulin-likegrowthfactor1;NEPSY
=ADevelopmentalNEuroPSYchologicalAssessment;RR=respiratoryrate.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
15
3.
GENERAL ANALYSIS DEFINITIONS
Unless otherwise specified, all continuous endpoints (e.g., height, weight, BMD [observed and
change from baseline values], etc.) will be summarized using descriptive statistics, which will
include the number of subjects with a valid measurement (n), mean, SD, median, minimum, and
maximum. Pharmacokinetics will be summarized using descriptive statistics including geometric
mean and coefficient of variation (CV in percent will be defined as CV(%) = 100* SD / mean). All
categorical endpoints (e.g., sex, adverse events, BMD Z-score decrease [>0.5, >1.0, >2.0], etc.)
will be summarized using frequencies and percentages. In general, percentages will be calculated
by dividing the number of subjects with the characteristic of interest by the number of subjects in the
analysis population.
3.1.
Visit Windows
The statistical analysis for safety will be based on time intervals that are constructed according to the
number of days in trial from day 1. (See table 2-8)
The analysis windows for height, weight, exposure, vital signs, laboratory tests, physical
examination and neurological examinations is given in Table 2.
Table 2:
Definition of windows for height, weight, exposure, vital signs, laboratory tests, physical
examinationandneurologicalexaminations:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
a
The randomizationday is Day 1.
The analysis windows for Renal Ultrasound, Cogstate, Tanner Staging and 24 hour urine
collection is given in Table 3.
Table 3:
Definitionof windowsfor Renal Ultrasound, Cogstate, Tanner Staging and 24 hour urine collection:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
a
The randomizationday is Day 1.
The analysis windows for C-SSRS is given in Table 4.
1,2
Baseline
-35 to1
1
3
Month1
2 to 60
30
5
Month3
61 to 135
90
6
Month6
136 to 225
180
7
Month9
226 to 315
270
8
Month12
>=316
360
1, 2
Baseline
-35 to1
1
6
Month6
2 to 270
180
8
Month12
>=271
360


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
16
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
Table 4:
Definition of windows for C-SSRS:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
a
The randomizationday is Day 1.
The analysis windows for Vineland Scale and CBCL is given in Table 5.
Table 5:
Definition of windows for Vineland Scale and CBCL:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
a
The randomizationday is Day 1.
The analysis windows for Bone Age is given in Table 6.
Table 6:
Definition of windows for Bone age:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
a
The randomizationday is Day 1.
The analysis windows for seizure count is given in Table 7.
Table 7:
Definition of windows for seizure count:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
a
The randomizationday is Day 1.
1, 2
Baseline
-35 to1
1
3
Month1
2 to 45
30
4
Month2
46 to 75
60
5
Month3
76 to 135
90
6
Month6
136 to 225
180
7
Month9
226 to 315
270
8
Month12
>=316
360
1, 2
Baseline
-35 to1
1
5
Month3
2 to 135
90
6
Month6
136 to 270
180
8
Month12
>=271
360
1
Baseline
-35 to180
1
8
Month12
>=181
360
3
Month1
2 to 45
30
4
Month2
46 to 75
60
5
Month3
76 to 135
90
6
Month6
136 to 225
180
7
Month9
226 to 315
270
8
Month12
>=316
360


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
The analysis windows for DEXA is given in Table 8.
Table 8:
Definition of windows for DEXA:
ScheduledVisit
Number
TimeInterval
(labelonoutput)
TimeInterval
(Day)a
TargetTimePoint
1, 2
Baseline
-35 to30
1
6
Month6
31 to 270
180
8
Month12
>=271
360
a
The randomizationday is Day 1.
The analysis windows for Pharmacokinetics is given in Table 9.
Table 9:
Definition of windows for Pharmacokinetics
Scheduled Visit Number
Time Interval (label on
output)
TimeInterval
(Day)a
Target Time Point
3
Month1
2 to 45
30
5
Month3
46 to 135
90
6
Month6
136 to 270
180
8
Month12
>=271
360
a:   The randomization day is Day 1
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved, Date: 08 June 2020


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
18
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
Baseline is defined as the last non-missing observation (including an unscheduled visit) prior to or 
equal to Day 1 (except for DEXA and Bone age, where baseline includes up to 30 days and 180 days 
post-baseline, respectively).
For post baseline observations, if more than one visit (including an unscheduled visit) occurs in the
same time window, the visit nearest to the target day will be used in the analysis. In the case of an
equal distance in time, the latest visit will be used.
Data that are not used in the analysis due to multiple observations or being excluded from the
above defined time intervals will be displayed in the data listing.
3.2.
Pooling Algorithm for Analysis Centers
NA
3.3.
Analysis Sets
All analyses, except for subject disposition, will use data for the safety analysis set.
Demographics will also be summarized based on all randomized set and subject disposition will
be based on all subjects.
3.3.1.
Efficacy Analysis Set(s)
There will be no efficacy analysis set.
3.3.1.1.
Primary Efficacy Analysis Set
NA
3.3.1.2.
Secondary Efficacy Analysis Set
NA
3.3.2.
All Randomized Set
This will include all randomized subjects.
3.3.3.
Safety Analysis Set
This will include all randomized subjects who received at least 1 dose of study medication. This
population will be used for all analyses, including any DMC analyses.
All subjects
will be
analyzed according to treatment they received by first study drug dispensation.
3.3.4.
Pharmacokinetics Analysis Set
The PK analysis set will consist of all subjects in the safety analysis set with available plasma
concentrations.
3.3.5.
Pharmacodynamics Analysis Set
NA


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
19
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
3.4.     Definition of Subgroups
Data will be summarized in addition by age group of 2 to 5 years of age, 6 to 9 years of age, 10 to
12 years of age, and 13 to 15 years of age, separately. For height, Z-scores for height, height velocity
and height velocity Z-scores, data will also be summarized by 2 to 9 years of age.
4.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
There will be no interim analyses, but an external, independent DMC will be established
to
review safety data on a quarterly basis or less frequent basis (but not more than six months)
when deemed necessary and ensure the continuing safety of the subjects enrolled in this study.
Additional adhoc meetings can be requested by the DMC or the Sponsor. After the review, the
DMC will make recommendations regarding the continuation of the study. The details will be
provided in a separate DMC charter.
The DMC is comprised of four clinicians and one statistician. The Chairperson and one member are
pediatric endocrinologists with expertise in bone, growth and maturation; the other two clinicians
are a pediatric nephrologist and a pediatric neurologist. Mention one member is statistician. The
DMC responsibilities, authorities, and procedures will be documented in its charter.
The safety analyses will be performed by Statistical Support Group (SSG) independent of the
Sponsor. The output tables in the data package will be displayed by each age group (2-5, 6-9, 10- 12,
and 13-15) and overall. All data and output should be held in strict confidentiality with access
to DMC and SSG onlybefore they can be transferred to the Sponsor.
Separate outputs will be generated for the open- and closed-sessions of the DMC meetings. The
outputs in the data package for the open-session will be unblinded, except for Ultra Sound,
DEXA and height analyses. These will present summaries for all subjects combined (e.g., tables
will only present a Total column). All outputs in the data package for the closed-session will be
unblinded and will present the data by the subjects’ true treatment group assignment.
Before each scheduled DMC meeting, data cut-off dates (6 to 8 weeks prior to the meeting) will be
identified and the clinical database will be made as clean as possible, with particular focus on safety
data. For the purpose of the DMC review of the results, all available data needed for the TLFs up
to the time of data cut-off dates, unless otherwise specified will be included in the TLFs.
The Contract Research Organization, PAREXEL, will provide the SDTM datasets containing the
electronic case report form (eCRF) data, the cognitive battery data
(computerized cognitive
battery as well as NEPSY testing), and the central laboratory data to the SSG statistician using the
Janssen MBOX. The DEXA and US data will be provided directly to the SSG statistician by
Bioclinica. Given that this is an open-label study, the treatment assignment will be included in the
CRF data.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
20
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
5.
SUBJECT INFORMATION
5.1.
Demographics and Baseline Characteristics
Subject demographics and baseline disease characteristics will be listed and summarized for the
randomized analysis set by treatment group. Descriptive statistics (mean, standard deviation,
median, minimum, and maximum) will be presented for age, height, weight, body mass index
(BMI), and years since diagnosis of epilepsy. Frequency counts and percentages will be presented
for categorical variables sex, age group (2-5 years, 6-9 years, 10-12 years, 13-15 years),
ethnicity, race, geographic region, , seizure types present within the last 2 years, seizure occurred
within the last 2 years beyond 3 or 5 month , seizure occurred in last 3 or 5 months and any AED
drug/therapy at study entry and bicarbonate categories. Bicarbonate values are categorized as low
(<20 mEq/L at screening) and non-low bicarbonate values (>=20 mEq/L at screening).
Age in years will be used from eCRF. In case of missing eCRF for age, 15th of the month will be
used as day. Missing day and moth at date of birth will be imputed by June 30. Years since
diagnosis of epilepsy will be calculated based on year of Day 1 minus year of diagnosis (if both in
the same year it will be 0).

Age calculation:

For Height and Weight Z-Scores, it is given in CDC guidance document, age is in
month with one decimal.

For demographics, it is floor (ICF date minus birth date)/365.25), age is in full years.

For Vineland it is floor ((intck ('month', birth date, visit date)-(day (visit date)<day(birth
date)))), age is in full month.

For CBCL it is floor (visit date minus birth date)/365.25), age is in full years.

For Cogstate it is floor (visit date minus birth date)/365.25), age is in full years.

For vital signs it is floor (visit date minus birth date)/365.25), age is in full years.

For labs it is floor (visit date minus birth date)/365.25), age is in full years.

Age for determination of max daily dose for Topiramate or Levetiracetam it is floor
(date of dosing minus birth date)/365.25), age is in full years.

BMI is calculated as weight (kg) / height (m)2.
Geographic region will be summarized as North America, South America, Europe and Asia
Pacific.

North America: US, Canada

South America: Argentina, Mexico

Europe: Belgium, France, Germany, Hungary, Italy, Poland, Russian Federation, Austria,
South Africa, UK

Asia Pacific: Australia, Taiwan, Philippines


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
21
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
5.2.
Disposition Information
Distribution of subjects will be provided for the all randomized analysis set. The number of
subjects screened, screen failures, randomized, dosed, completed, and discontinued will be listed and
summarized.
Treatment
discontinuation
will
be
summarized
according
to
reasons
of
discontinuation as documented in the CRF. The screen failures and the reasons will be listed.
5.3.
Treatment Compliance
Treatment compliance will not be summarized.
5.4.
Extent of Exposure
Treatment duration is defined as time between the first dose date and last dose date of topiramate or
levetiracetam and will be presented as a continuous summary and classified into the following
categories by the amount of time on study medication: 0 to <3 months, 3 to <6 months, 6 to
<9 months, 9 to <12 months, and ≥12 months. The number and percentage of subjects in each
category will be reported.
A summary of the average total daily dose and the weight-adjusted average daily dose (mg/kg) will
also be presented. The weight will be used at start of the respective period (titration and
maintenance). For exposure with overlapping records, if a ‘total daily dose’ exceeds the maximum
dose allowed for the subject, a total daily dose of 350 mg or 400 mg for Topiramate will be used for
the subject with age <10 years or >=10 years, respectively. For Levetiracetam, the total daily dose of
3,000 mg will be used if the exposure with overlapping records exceeds the maximum allowed dose of
3,000 mg. It will also be summarized by the treatment period (titration and maintenance). The start
of maintenance period is defined as “date maintenance achieved” from titration CRF, and the end
of titration period is defined as “start of maintenance period minus 1”.
A listing of dispensed medication will also be provided.
5.5.
Protocol Deviations
The major protocol deviations will be listed and summarized by treatment group. A subject can
be counted under multiple deviation categories.
The major Protocol Deviation categories

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or dose deviation

Selection criteria not met

Informed consent not correctlysigned

Visit schedule is not followed according to protocol

Safety assessments not performed according to protocol


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
22
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067

Safety assessments not documented properly
The minor protocol deviations will not be summarized.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
23
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
5.6.
Prior and Concomitant Medications
Medications administered prior to the first dose of study medication will be considered prior
medications. Concomitant medications include those taken on or after first dose date. Incidence of
prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC)
code levels 2 and 4, and preferred term. Only prior anti-epileptic drugs (AEDs) will be
summarized. Concomitant medications will be listed and summarized separately for AED and
non-AED medications. Tables will be sorted by decreasing frequency in incidence (the highest to
lowest incidence) first within ATC code level 2, followed by ATC code level 4, 
and
then
preferred term. Medications with partial onset date will be handled as follows: a missing day
should be set to first of month. If month is missing the missing month should be set to January.
Please see Appendix 7 for the list of AED medications.
5.7.
Medical History
Medical history will be listed only.
6.
EFFICACY
There are no efficacy data collected for the study.
6.1.
Analysis Specifications
6.1.1.
Level of Significance
NA
6.1.2.
Data Handling Rules
NA
6.2.     Primary Efficacy Endpoint(s)
NA
7.
SAFETY
The safety variables to be summarized include kidney stones, height, weight, BMD and bone
mineral content (BMC), biochemical markers of bone mineralization, bone age
XR, seizure
counts, cognitive, developmental, and behavioral assessments, treatment-emergent AEs, Columbia-
Suicide Severity Rating Scale (C-SSRS), cognitive, developmental and behavioral assessments
(COGSTATE computerized battery and NEPSY Language scale; Vineland Adaptive Behavioral
Scale, Child Behavior Checklist (CBCL)), clinical laboratory tests (hematology, chemistry,
urinalysis, and 24-hour urine collection), vital signs and physical exam. Safety variables are to be
tabulated bydescriptive statistics (n, mean, median, SD, minimum, and maximum; or n and percent).
No formal statistical testing is planned.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
24
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
For markedly abnormal labs and vital signs, age will be calculated at each visit to determine the
criteria. Similarly, Vineland, CBCL and Cogstate will be calculated by age at each visit.
Z-scores for weight and height will be calculated using the SAS programs provided by the
Centers for Disease Control (CDC) for the calculation of the 2000 CDC growth charts. Z-scores for
the BMD and BMC will be provided by the central DEXA reading center (Bioclinica).
Z-scores for the DEXA scans will be calculated locally at baseline only to determine eligibility for
the study, and centrally for all statistical analyses. The Z-score calculation will take the DEXA
machine and the subject’s age, sex, height, and ethnicity into consideration. The reference databases
for calculating the Z-scores are provided in the DEXA Manual for this study (please see the imaging
charter of attachment 1 for more details).
Longitudinal endpoints will be analyzed using a mixed-model repeated measures (MMRM) analysis.
An MMRM analysis is included as sensitivity analysis to explore longitudinal safety data and will be
analyzed in the following order.
1.
The model includes treatment group, study center, age group (4 age groups), visit, treatment-by-
visit interaction, baseline measure, and baseline-by-visit interaction with the unstructured
covariance matrix.
2.
If this model experiences convergence issues, then the same model with compound symmetric
matrix followed by AR1 will be explored instead of unstructured.
3.
If the above doesn’t work, then a reduced model with treatment group, age group, visit, treatment-
by-visit interaction, and baseline measure will be explored. Age will be collapsed to two
categories: 2-9 years of age (pre-pubertal) and 10-15 years of age (pubertal). The unstructured
covariance matrix will be explored first and if it doesn’t work, then compound symmetric
followed dby AR1 will be applied.
4.
If above doesn’t work, then no additional MMRM analysis will be performed. 95% CI for the
estimated treatment differences will be provided.
Example of MMRM is as follows:
ods output estimates=est;
PROC MIXED data=dat method=REML noclprint=10;
CLASS trt center usubjid age_group visit;
MODEL change=trt base visit center age_group trt*visit base*visit /
solution; repeated visit / type=un subject=usubjid;
lsmeans trt/diff cl;
Sensitivity analyses for height z-scores, weight-z-scores and BMD z-scores will be conducted for
subset of safety analysis set: for subjects who started taking at least one concomitant AED, data
collected after the start of taking AED medication will be excluded from the analysis.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
25
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
7.1.
Kidney Stones
Percentage of subjects with kidney stones and other US findings suggestive of stones will be
summarized by treatment group.
The renal ultrasound findings will also be presented in a listing.
7.2.
Weight
Observed weight values, change from baseline, Z-scores for weight, and change from baseline in Z-
scores for weight will be listed and summarized by visit using descriptive statistics. The change
in weight z-scores will also be summarized by subject’s serum bicarbonate categories.
MMRM analysis will also be performed for changes from baseline and changes in Z-Scores from
baseline.
7.3.
Height
Observed height values, change from baseline, Z-scores for height, change from baseline in Z-
scores for height, height velocity at 1 year, and height velocity Z-score will be summarized by visit
using descriptive statistics. Height, Z-scores for height, height velocity and height velocity Z-scores
will be calculated as the mean of the three measurements. The number and percentage of subjects
with a height Z-score decrease of >0.5, >1.0, and >2.0 will be listed and summarized by visit using
descriptive statistics. MMRM analysis will also be performed for changes from baseline
and
changes in Z-Scores from baseline.
The change in height z-scores will also be summarized by subject’s serum bicarbonate categories.
Height velocity values and associated Z-scores will be computed for each post-baseline year in the
study, based on the methods described in Appendix 6.
7.4.
Bone Mineral Density (BMD) and Bone Mineral Content (BMC)
DEXA measurements will include posterior-anterior spine and total body less head areal (TBLH)
BMD and BMC. Observed BMD (spine and TBLH) and BMC (spine and TBLH) values change
from baseline, Z-scores as well as height adjusted Z-scores for BMD and BMC, change from
baseline in Z-scores and height adjusted Z-scores for BMD and BMC, and percent change from
baseline in BMD and BMC will be summarized by visit using descriptive statistics. The number and
percentage of subjects with a BMD Z-score and adjusted Z-score decrease of >0.5, >1.0, and >2.0
will be listed and summarized by visit using descriptive statistics. MMRM analysis will also be
performed for changes from baseline, changes in Z-Scores from baseline, and changes in height
adjusted Z-Scores from baseline.
Subjects with a clinically important reduction in BMD defined as change in Z-score and height
adjusted Z-score of -0.5 or greater) at 6 months or 12 months, will have a repeat DEXA scan 6
months after discontinuation of study drug. These subjects will be summarized and listed in the
DEXA table and listing.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
26
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
The change in BMD z-scores will also be summarized by subject’s serum bicarbonate categories.
7.5.
Biochemical Markers of Bone Mineralization
Observed and change from baseline in biochemical markers of bone mineralization (serum levels of
alkaline phosphatase, calcium, phosphorus, parathyroid hormone (intact), 25-hydroxy vitamin D,
1,25-dihyroxy vitamin D, and IGF-1) will be listed and summarized by visit using descriptive
statistics.
7.6.
Bone Age
Observed and change from baseline in bone age will be listed and summarized by visit using
descriptive statistics. Bone age will be summarized as “chronological age” and “bone age” as
reported as XR report.
7.7.
Seizure Count
Observed seizure counts will be listed and summarized by visit using descriptive statistics, for
both the overall seizure count and by seizure type (Partial, Partial Evolving into Secondary
Generalized, Primary Generalized Tonic-Clonic, and Other).
7.8.
Cognitive, Developmental, and Behavioral Assessments
Cognitive Assessments
For the cognitive assessments (Detection Test, Identification Test, One Card Learning Test, One
Back Test, and Groton Maze Learning Test) the standardized observed scores and change from
baseline in standardized scores will be listed and summarized by visit using descriptive statistics. The
standardized scores will be calculated by setting the observed raw score in relation to the expected
within-subject standard deviations for each Cogstate task (see table 1-5 of Appendix 1 for normative
data). For the tasks which lower scores indicate improvement (e.g., Detection Test and Identification
Test), the score will be multiplied by (-1), so that a negative change in standardized
scores
represent a decline in cognitive performance consistently across all tasks.
A meaningful decline in cognition has been defined as a change in standardized score of less
than -1.65 from the baseline standardized score. These calculations will indicate
meaningful
decline at the subject level. Each individual change in standardized scores that meet the definition
of a meaningful decline will be identified using a binary flag, where 1 represents a meaningful
decline from baseline and 0 otherwise. The number and percentage of subjects with a meaningful
decline in cognition will be listed and summarized by visit.
Cognitive assessments will be provided to subjects of 4 years and older. Cognitive data collected
after a subject turn 16 will not be included in the analysis.
For example, if a 10-year-old female subject has an observed raw score at baseline of 1.2 for the
detection test, then the standardized score will be 1.2/0.0882*(-1)=-13.605. For a post baseline
visit the subject had an observed raw score of 1.0, which is a standardized score of -11.338. The


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
27
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
change from baseline would be 2.267. The lower score at post baseline indicates an improvement in
Detection Test which is reflected by the positive change (see table 1 of Appendix 1).
Developmental Assessments
The Vineland Scales of Adaptive Behavior provide age-specific assessment of function in the
domains of communication, daily living, socialization, and motor skills, as well as a composite
scale. The subject’s sub-domain raw scores are entered on the CRF. The derived domain scores
(standardized scores) based on the national standardization sample must be obtained from these raw
scores. The derived scores are used in the analyses. The Vineland standardized scores for domain
scores have a mean of 100 and a standard deviation of 15.
The composite score will be the sum of 4 standardized domain scores. If a subject has only 3
domains, then the standardized score for the missing domain will be prorated and the composite
score will be calculated as sum of 4 domains. If a subject has less than 3 domains, then the
composite score will not be calculated.
The standardized scores and the changes in standardized scores from baseline will by listed and
summarized by visit using descriptive statistics.
For manuals and SAS program calculating the standardized domain scores, please see Appendix 4.
The Vineland Adaptive Behavior Scale will be administered for subjects 2 to 5 years of age only.
Behavioral Assessments
For CBCL preschool (up to 5 years of age), a raw total score will be sum of 99 non-missing
answers (range of 0-198).
For CBCL school age (6 to 18 years of age), a raw total score will be the sum of 112 non-
missing answers (range of 0-224).
The domains will be:


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
28
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CBCL preschool
CBCL school age
1.
EmotionallyReactive
2.
Anxious/Depressed
3.
Somatic Complaints
4.
Withdrawn
5.
Sleep Problems
6.
Attention Problems
7.
Aggressive Behavior
8.
Internalizing Problems
9.
Externalizing Problems
10. Total Problems
11. Anxious/depressed
12. Withdrawn/depressed
13. Somatic complaints
14. Social problems
15. Thought problems
16. Attention problems
17. Rule breaking behavior
18. Aggressive behavior
19. Internalizing Problems
20. Externalizing Problems
21. Total Problems
The standardized total scores (T score) for all domains will be derived using the charts based on the
raw scores (Appendix 5).
The standardized scores and the changes in standardized scores from baseline will by listed and
summarized by visit using descriptive statistics.
7.9.
Adverse Events
Adverse events are coded to System Organ Class (SOC) and preferred terms (PT) using the
Medical Dictionary for Regulatory Activities (MedDRA) coding system, version 21.1 or higher.
Treatment-emergent adverse events (TEAEs) are those AEs which start or worsen after receipt of the
first study drug and before the end of the REACH. REACH is defined as follows: AEs with onset
date within therapeutic reach (i.e. 3 days) or SAEs/deaths with onset date within 30 days, inclusive,
after end of treatment. AE’s with partial onset date will be handled as follows: a missing day
should be set to first of month. If month is missing the missing month should be set to January.
Summaries of TEAEs will be provided as incidence tables (number of subjects experiencing an
event) by treatment group within each age group and overall (age 2-15). For each TEAE, the
percentage of subjects who experience at least 1 occurrence of the given event will be summarized.
Tables will be sorted by decreasing frequency in incidence (the highest to lowest incidence) first
within the SOC and then the PT. Treatment-emergent serious AEs (SAEs), TEAEs leading to
discontinuation, TEAEs by severity, TEAEs by relationship and TEAEs of special interest will
be summarized. Adverse events of special interest for topiramate include: effects on liver function;
metabolic acidosis; effects on growth and maturation; vision
abnormalities;
oligohidrosis,
hyperthermia
and secondary rash;
hyperammonemia
and/or encephalopathy; kidney stones;
neuropsychiatric and cognitive disorders; and suicidality. Adverse events of clinical interest for
levetiracetam are as listed previously, notably somnolence, asthenia, and behavior disturbances


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
29
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
(especially hostility and nervousness). Please see Appendix 3 for the MedDRA codes for these AE
of clinical interest.
A listing of AEs will also be provided.
7.10.
Clinical Laboratory Tests
Figures of the mean change from screening (+/- Standard Error) values in continuous hematology,
urinalysis and serum chemistry laboratory parameters will be presented by visit. The observed
and change from baseline values of lab parameters will also be summarized by visit. For
calculation, the signs “<” or “>” will be removed and resulting numerical value will be used. The
reference ranges for labs from the SAP will be used, not the reference ranges provided from the
Covance.
The shift table of pre- vs. post-treatment with classes for below, within, and above normal ranges will
be presented.
The number and percentage of subjects with markedly abnormal (low, high) laboratory
hematology, urinalysis/24-hour urine and serum chemistry parameters during the study (from
treatment start to 30 days after last dose or the end of treatment visit date, whichever is later) that
were not present at baseline will be provided. Appendix 2 presents
the
markedly
abnormal
criteria. The conversion factors for 25 Vitamin D, 1, 25 Vitamin D and PTH are also listed.
The laboratory data will be listed. The subjects with any laboratory results outside the reference
ranges and the subjects with any markedly abnormal laboratory results will be listed.
7.11.
Vital Signs and Physical Examination Findings
At baseline, 3 orthostatic vital signs will be measured 10 min apart and the baseline score will be
calculated as the average of 3 scores.
Observed and change from baseline in vital sign parameters (temperature, pulse/heart rate, respiratory
rate, and blood pressure [standing and supine]]) will be summarized by visit using descriptive
statistics.
The number and percentage of subjects with any clinically important vital sign values during the
study will also be summarized by visit. Table 10 presents the criteria for the clinically important
values.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
30
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
Table 10: Clinically Important Vital Sign Values
Parameter
Agegroup(Years)
Low
High
SystolicBloodPressure
2-5 yrs
<75
>110
6-9 yrs
<80
>120
≥10 yrs
<90
>130
DiastolicBloodPressure
2-5 yrs
<35
>65
6-9 yrs
<45
>75
≥10 yrs
<50
>80
HeartRate
1-2 yrs
<89
>151
3-4 yrs
<73
>137
5-7 yrs
<65
>133
8-11 yrs
<62
>130
≥12 yrs
<60
>119
Respiratory Rate
1-3 yrs
<22
>30
4- 6 yrs
<20
>24
7-9 yrs
<18
>24
10-14yrs
<16
>22
15-18yrs
<14
>20
Temperature
Allages
< 35° C (95° F)
≥37.5° C (99.5° F)
The vital signs data will be listed. The subjects with any clinically important vital signs data will be
listed in addition.
The number and percentage of subjects with abnormal physical examination will be listed and
summarized by body system and visit.
7.12.
Electrocardiogram
ECG at screening will not be listed.
7.13.
Other Safety Parameters
Columbia-Suicide Severity Rating Scale (C-SSRS):
From the C-SSRS, the number and percentage of subjects reporting (1) at least one occurrence of
suicidal ideation or behavior, (2) any type of suicidal behavior, and (3) any type of suicidal
ideation during the study (from treatment start to 30 days after last dose or the end of treatment visit
date, whichever is later) will be summarized.
Tanner Staging:
Observed and change from baseline in Tanner Staging will be listed and summarized by visit
using descriptive statistics. Frequency distribution of tanner staging (1 thru 5) will also be
summarized by visit.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
31
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
8.
PHARMACOKINETICS/PHARMACODYNAMICS
8.1.
Pharmacokinetics
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration data presentation. Concentrations below the lowest quantifiable
concentration will be treated as zero in the summary statistics. All subjects and samples excluded
from the analysis will be clearly documented in the study report.
For each treatment group, descriptive statistics, including arithmetic mean, SD, coefficient of
variation, geometric mean, median, minimum, and maximum will be calculated for the Topiramate
or Levetiracetam plasma concentrations at each sampling time.
Topiramate and Levetiracetam plasma concentrations will be provided as listings.
8.2.
Immune Response
NA
8.3.
Pharmacodynamics
NA
8.4.
Pharmacokinetic/Pharmacodynamic Relationships
NA
9.
HEALTH ECONOMICS
NA
10.
APPENDICES


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
32
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
Appendix1:CogstatePediatricNormative Data
Table 1: CogState Pediatric Normative Data for the Detection Task.
Age (years)
N
Males
M
SD
N
Females
M
SD
2
_
_
_
_
_
_
3
–
–
–
1
2.9041
–
4
2
2.8775
0.0534
3
2.8581
0.1732
5
4
2.7714
0.1001
10
2.7341
0.0871
6
5
2.6002
0.0717
11
2.8240
0.1660
7
6
2.6733
0.1357
9
2.7294
0.0622
8
4
2.6115
0.1769
6
2.8202
0.1598
9
4
2.5632
0.1146
3
2.5398
0.0714
10
1224
2.5631
0.0870
210
2.5882
0.0882
11
1499
2.5388
0.0826
506
2.5641
0.0899
12
1882
2.5290
0.0842
816
2.5447
0.0831
13
2322
2.5177
0.0851
1076
2.5255
0.0767
14
6551
2.5121
0.0853
3315
2.5252
0.0826
15
6399
2.5086
0.0810
3347
2.5213
0.0821
Note:The primaryoutcome variable for theDetection taskis Reaction Time (Log10 transformation).
Table 2: CogState Pediatric Normative Data for the Identification Task.
Age (years)
N
Males
M
SD
N
Females
M
SD
2
_
_
_
_
_
_
3
–
–
–
1
3.1028
–
4
2
3.0312
0.0142
3
3.1244
0.0795
5
4
2.9061
0.0266
10
2.9546
0.1075
6
5
2.9199
0.0931
11
2.9938
0.1276
7
6
2.9238
0.1067
9
2.9310
0.0849
8
4
2.8885
0.1575
6
2.9726
0.1053
9
4
2.7421
0.0453
3
2.7632
0.0634
10
1198
2.7637
0.0759
203
2.7796
0.0735
11
1456
2.7323
0.0739
499
2.7453
0.0727
12
1823
2.7163
0.0712
811
2.7186
0.0726
13
2279
2.7007
0.0725
1073
2.6973
0.0711
14
6470
2.6889
0.0731
3300
2.6903
0.0719
15
6324
2.6809
0.0700
3335
2.6800
0.0717
Note:The primaryoutcome variable for theIdentificationtask is ReactionTime (Log10 transformation).


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CCOONNFFIIDDEENNTTIIAALL –––FOIA Exempptioons Apply in U.S.
Status: Approved, Date: 08 June 2020
323
Table 3: CogState Pediatric Normative Data for the One Card Learning Task.
Age (years)
N
Males
M
SD
N
Females
M
SD
6
5
1.0120
0.1845
11
1.0029
0.1441
7
6
0.9715
0.1175
9
0.9300
0.1616
8
4
1.1346
0.0765
6
0.9942
0.1889
9
4
1.0406
0.0376
3
0.9863
0.1306
10
1147
0.9639
0.0880
201
0.9636
0.0910
11
1449
0.9646
0.0889
485
0.9650
0.0892
12
1837
0.9719
0.0889
807
0.9692
0.0875
13
2249
0.9722
0.0858
1053
0.9767
0.0874
14
6435
0.9715
0.0870
3347
0.9679
0.0858
15
6559
0.9739
0.0868
3434
0.9718
0.0854
Note: The primaryoutcome variable for theOne Card Learningtask is Accuracy(arcsine square-root
transformation).
Table 4: CogState Pediatric Normative Data for the One Back Task.
Age (years)
N
Males
M
SD
N
Females
M
SD
6
5
3.0924
0.0965
11
3.1386
0.1728
7
6
3.0799
0.0686
9
3.0789
0.0926
8
4
2.9574
0.0691
6
3.1290
0.1488
9
4
2.9524
0.0589
3
2.9646
0.1824
10
1278
2.9597
0.0984
218
2.9840
0.0990
11
1576
2.9225
0.0958
548
2.9405
0.0962
12
1973
2.8977
0.0962
879
2.9139
0.0972
13
2437
2.8824
0.0945
1130
2.8931
0.0938
14
7000
2.8673
0.0935
3604
2.8851
0.0930
15
7061
2.8547
0.0926
3663
2.8716
0.0952
Note: The primaryoutcome variable for theOne Back task is Reaction Time (Log10 transformation).


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
Table 5: CogState Pediatric Normative Data for the Groton Maze Learning Test.
Males
Females
Note: The primaryoutcome variable for the Groton Maze Learning Test is Total Errors.
                                                           CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved, Date: 08 June 2020
Age (years)
6
N
–
M
–
SD
–
N
2
M
63.5000
SD
16.2635
7
1
102.0000
–
–
–
–
8
–
–
–
1
68.0000
–
9
3
64.6667
24.0069
1
27.0000
–
10
20
73.8500
31.0251
6
67.3333
25.5943
11
14
67.6429
22.4828
12
64.1667
14.9595
12
20
62.9500
18.9667
6
61.0000
14.0855
13
10
53.2000
19.0660
11
65.0000
15.7861
14
5
61.6000
16.7422
2
46.0000
19.7990
15
–
–
–
1
39.0000
–


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved, Date: 08 June 2020
Appendix2:MarkedlyAbnormalLaboratoryParameterValues
Chemistry
Laboratory Value
(SIUnit)
Lower Limit of
Normal(LLN)
Range
Upper Limit of
Normal(ULN)
Range
DNP
Recommended
Markedly
Abnormal:Low
DNP
Recommended
Markedly
Abnormal:High
AlanineAmino
Transferase– ALT
(SGPT)(U/L)
1
30
NA
> 3 X ULN, OR
> 5 X ULN, OR
> 10 X ULN
AspartateAmino
Transferase- AST
(SGOT)(U/L)
0
35
NA
> 3 X ULN, OR
> 5 X ULN, OR
> 10 X ULN
Albumin(g/L)
<5years:
<5years:
<5years:
<5years:
29
58
≤20
≥65
5years:
5years:
5years:
5years:
31
54
≤25
≥60
Alkaline
Females:
Females:
NA
> 3 X ULN
Phosphatase(U/L)
2-10years:
2-10years:
100
320
11-17years:
11-17years:
100
320
18years:
18years:
30
120
Males:
Males:
2-10years:
2-10years:
100
320
11-17years:
11-17years:
100
390
18 years:
18years:
30
120
Ammonia(umol/L)
18years:
18years:
21
50
NA
> 1.5 X ULN
>18years:
>18years:
0
35.7
Bicarbonate/
Value < 17, OR


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
35
Status: Approved, Date: 08 June 2020
`
Laboratory Value
(SIUnit)
Lower Limit of
Normal(LLN)
Range
Upper Limit of
Normal(ULN)
Range
DNP
Recommended
Markedly
Abnormal:Low
DNP
Recommended
Markedly
Abnormal:High
CarbonDioxide
(CO2)(mmol/L)
20
26
(Value <17 and
decrease from
pre-treatment
baseline >5 when
pre-treatment
baseline > 20)
> 31
Bilirubin– Total
(umol/L)
1.7
20.5
NA
> 41
BloodUrea
Nitrogen(BUN)
(mmol/L)
2.5
7.9
NA
> 16
Calcium(mmol/L)
2
2.6
≤1.7
> 3
Chloride(mmol/L)
96
109
NA
> 112 OR ≥115
TotalCholesterol
(mmol/L)
<18years:
0
<18years:
5.18
NA
> 1.2 X ULN
18years:
18years:
0
6.2
Creatinine
2-12years:
2-12years:
NA
> 1.6 X ULN
(umol/L)
27
62
13-17years:
13-17years:
44
88
18years:
18years:
Males
Males
53
115
Females
Females


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved, Date: 08 June 2020
(U/L)
18years:
Males
11
Females
7
18years:
Males
50
Females
32
44
106
CreatineKinase
Females:
Females:
NA
> 1.6 X ULN
(CK) (U/L) –
0-3 years:
0-3 years:
collected only in
18
134
TOPMAT-MIG-
4-6 years:
4-6 years:
3006
18
147
7-9 years:
8-9 years:
18
295
10-12years:
10-12years:
18
184
13-15years:
13-15years:
18
187
16-17years:
16-17years:
18
169
18years:
18years:
18
169
Males:
Males:
0-3 years:
0-3 years:
18
163
4-6 years:
4-6 years:
18
158
7-9 years:
7-9 years:
18
354
10-12years:
10-12years:
18
363
13-15years:
13-15years:
18
363
16-17years:
16-17years:
18
408
18years:
18years:
18
198
G-Glutamyl
Transferase(GGT)
<18years:
0
<18years:
23
NA
> 3 X ULN
Glucose (mmol/L)
<16years:
<16years:
3.3
16years:
3.9
5.8
16years:
6.4
< 0.8 X LLN
(e.g., < 2.6 for <
16 years and <
> 1.2 X ULN
(e.g., > 7.0 for < 16
years and > 7.7 for >
3.1 for > 16
years
16 years


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
37
Status: Approved, Date: 08 June 2020
Phosphorus Inorg.
<18years:
<18years:
< 0.8 X LLN
> 1.4 X ULN
(mmol/L)
1.03
2.10
18years:
18years:
0.87
1.45
Lactate
Dehydrogenase
<18years:
150
<18years:
300
NA
> 2 X ULN
(U/L)
18years:
18years:
0
220
Potassium
(mmol/L)
3.5
5
< 3.0
≥5.7
Sodium(mmol/L)
135
148
≤127
≥158
TotalProtein(g/L)
<6years:
<6years:
49
81
< 0.7 X LLN
> 1.25 X ULN
6years:
6years:
60
80
Triglycerides
(mmol/L)
Females:
0-5 years:
Females:
0-5 years:
NA
> 1.6 X ULN
0.3616
1.1187
6-11years:
6-11years:
0.3955
1.2882
12-15years:
12-15years:
0.4633
1.5594
16-19years:
16-19years:
0.452
1.4464
Males:
Males:
0-5 years:
0-5 years:
0.339
0.9718
6-11years:
6-11years:
0.3503
1.2204
12-15years:
12-15years:
0.4068
1.5594
16-19years:
16-19years:
0.452
1.8419
UricAcid
(umol/L)
140
380
≤80
≥570


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
38
Status: Approved, Date: 08 June 2020
Magnesium
Females:
1-3 years:
Females:
1-3 years:
<0.5
>2
0.7
0.98
4-6 years:
4-6 years:
0.7
0.90
7-12years:
7-12years:
0.7
0.90
13-15years:
13-15years:
0.66
0.94
16-18years:
16-18years:
0.62
0.90
Males:
Males:
1-3 years:
1-3 years:
0.7
0.98
4-6 years:
4-6 years:
0.7
0.98
7-12years:
7-12years:
0.7
0.90
13-15years:
13-15years:
0.66
0.94
16-18years:
16-18years:
0.62
0.90


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
39
Status: Approved, Date: 08 June 2020
In addition, the MAL low and high for additional parameters will be as follows:
Parameter
MAL low
MAL high
25 Vitamin D (ng/ml)
<20
>55
1, 25 D (pg/ml)
<15
>90
IGF-1 (nmol/L)
2-8: <6
>50
9-10: <8
>65
11-12: <15
>100
13-16: <20
>140
PTH (pg/mL)
2-7: <40
>350
8-10: <50
>490
11-12: <70
>750
13-16: <100
>1100
The conversion factors for 25 Vitamin D, 1, 25 Vitamin D and PTH are listed below.
Parameter
Units
Conversion factor
25 Vitamin D
nmol/L to ng/mL
0.4
1, 25 Vitamin D
Pmol/L to pg/ml
1.355
PTH
Pmol/L to pg/mL
9.434


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
40
Status: Approved, Date: 08 June 2020
Hematology
Laboratory
Value (SI Unit)
Lower Limit of
Normal(LLN)
Range
Upper Limit of
Normal(ULN)
Range
DNPRecommended
Markedly
Abnormal:Low
DNPRecommended
Markedly
Abnormal:High
Hemoglobin (g/L)
Females:
Females:
≤90
1-4 years:
1-4 years:
≥180
109
150
5-10years:
5-10years:
119
150
11-17years:
11-17years:
119
150
18years:
18years:
119
155
Males:
Males:
1-4 years:
1-4 years:
109
150
5-10years:
5-10years:
119
150
11-17years:
11-17years:
127
18years:
132
170
18years:
177


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
41
Status: Approved, Date: 08 June 2020
Hematocrit
(proportionof1.0)
Females:
1-4 years:
Females:
1-4 years:
< 0.85 X LLN
> 1.15 X ULN
0.31
0.44
5-10years:
5-10years:
0.35
0.44
11-17years:
11-17years:
0.34
0.44
18years:
18years:
0.35
0.47
Males:
Males:
1-4 years:
1-4 years:
0.31
0.44
5-10years:
5-10years:
0.35
0.44
11-17years:
11-17years:
0.37
0.48
18years:
18years:
0.40
0.52
RBC – Total
(10E12/L)
Females:
1-4 years:
Females:
1-4 years:
< 0.85 X LLN
> 1.15 X ULN
3.8
5.2
5-10years:
5-10years:
4.1
5.2
11-17years:
11-17years:
3.9
5.1
18years:
18years:
4.2
5.4
Males:
Males:
1-4 years:
1-4 years:
3.8
5.5
5-10years:
5-10years:
4.3
11-17years:
5.2
11-17years:
4.3
5.6
18years:
18years:
4.5
6.2


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
42
Status: Approved, Date: 08 June 2020
WBC – Total
2-5 years:
2-5 years:
< 0.85 X LLN
> 1.15 X ULN
(10E9/L)
5
15.5
6-17years:
6-17years:
4.5
13.5
18years:
18years:
4.5
11
Neutrophils–
WBCDifferential
Count(Proportion
of 1)
0.38
0.80
≤0.15
≥0.90
Lymphocytes–
WBCDifferential
Count(Proportion
of 1)
0.15
0.40
≤0.10
≥0.60
Monocytes–
WBCDifferential
Count(Proportion
of 1)
0
0.13
NA
≥0.20
Eosinophils–
WBCDifferential
Count(Proportion
of 1)
0
0.08
NA
≥0.10
Basophils – WBC
Differential Count
(Proportionof1)
0
0.02
NA
≥0.06
PlateletCount
(x10E9/L)
150
350
< 0.75 X LLN
> 1.3 X ULN


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
43
Status: Approved, Date: 08 June 2020
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
11.
URINALYSIS
Laboratory
Value (SI Unit)
Lower Limit of
Normal(LLN)
Range
Upper Limit of
Normal(ULN)
Range
Markedly
Abnormal:Low
Markedly
Abnormal:High
PH
4.5
8
≤4
≥8
SpecificGravity
1.007
1.03
≤1.001
≥1.035


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
44
Appendix 3: AEof clinical interest
AETERM
AEBODSYS in 
MedDRA 22.0
AEDECOD (PT) In MedDRA
22.1
5'nucleotidase increased
Investigations
5'nucleotidase increased
Abulia
Psychiatric disorders
Abulia
Accommodation disorder
Eye disorders
Accommodation disorder
Acidosis
Metabolism and 
nutrition disorders
Acidosis
Acidosis hyperchloraemic
Metabolism and 
nutrition disorders
Acidosis hyperchloraemic
Acquired epidermolysis bullosa
Skin and 
subcutaneous tissue 
disorders
Acquired epidermolysis bullosa
Acquired pigmented
retinopathy
Injury, poisoning and 
procedural
complications
Acquired pigmented retinopathy
Activation syndrome
Psychiatric disorders
Activation syndrome
Acute generalised
exanthematous pustulosis
Skin and 
subcutaneous tissue 
disorders
Acute generalised
exanthematous pustulosis
Acute hepatic failure
Hepatobiliary 
disorders
Acute hepatic failure
Renal failure acute
Renal and urinary 
disorders
Acute kidney injury
Adjustment disorder with 
anxiety
Psychiatric disorders
Adjustment disorder with 
anxiety
Adjustment disorder with 
depressed mood
Psychiatric disorders
Adjustment disorder with 
depressed mood
Adjustment disorder with 
mixed anxiety and depressed
mood
Psychiatric disorders
Adjustment disorder with mixed
anxiety and depressed mood
Adjustment disorder with 
mixed anxiety and depressed
mood
Psychiatric disorders
Adjustment disorder with mixed
anxiety and depressed mood
Affect lability
Psychiatric disorders
Affect lability
Agitated depression
Psychiatric disorders
Agitated depression
Agitation
Psychiatric disorders
Agitation
Alanine aminotransferase
abnormal
Investigations
Alanine aminotransferase
abnormal
Alanine aminotransferase
increased
Investigations
Alanine aminotransferase
increased
Albumin urine present
Investigations
Albumin urine present
Alpha 1 foetoprotein abnormal
Investigations
Alpha 1 foetoprotein abnormal
Alpha 1 foetoprotein increased
Investigations
Alpha 1 foetoprotein increased


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
45
Alpha 1 globulin increased
Investigations
Alpha 1 globulin increased
Alpha 2 globulin increased
Investigations
Alpha 2 globulin increased
Alpha globulin increased
Investigations
Alpha globulin increased
Alpha-2 macroglobulin
increased
Investigations
Alpha-2 macroglobulin
increased
Altered state of consciousness
Nervous system
disorders
Altered state of consciousness
Altered visual depth 
perception
Eye disorders
Altered visual depth perception
Amaurosis
Eye disorders
Amaurosis
Amaurosis fugax
Eye disorders
Amaurosis fugax
Ammonia abnormal
Investigations
Ammonia abnormal
Ammonia abnormal
Investigations
Ammonia abnormal
Ammonia increased
Investigations
Ammonia increased
Ammonia increased
Investigations
Ammonia increased
Amnesia
Nervous system
disorders
Amnesia
Global amnesia
Nervous system
disorders
Amnesia
Angle closure glaucoma
Eye disorders
Angle closure glaucoma
Anhedonia
Psychiatric disorders
Anhedonia
Anhidrosis
Skin and
subcutaneous tissue 
disorders
Anhidrosis
Anorexia and bulimia
syndrome
Psychiatric disorders
Anorexia and bulimia syndrome
Anorexia and bulimia
syndrome
Psychiatric disorders
Anorexia and bulimia syndrome
Anorexia nervosa
Psychiatric disorders
Anorexia nervosa
Anorexia nervosa
Psychiatric disorders
Anorexia nervosa
Anterograde amnesia
Nervous system
disorders
Anterograde amnesia
Anticipatory anxiety
Psychiatric disorders
Anticipatory anxiety
Antidepressant therapy
Surgical and medical 
procedures
Antidepressant therapy
Antimetropia
Eye disorders
Antimetropia
Anxiety
Psychiatric disorders
Anxiety
Anxiety disorder
Psychiatric disorders
Anxiety disorder
Apathy
Psychiatric disorders
Apathy
Dysphasia
Nervous system
disorders
Aphasia
Aphonia psychogenic
Nervous system
disorders
Aphonia psychogenic
Apocrine miliaria
Skin and 
subcutaneous tissue 
disorders
Apocrine miliaria


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
46
Apraxia
Nervous system
disorders
Apraxia
Ascites
Gastrointestinal
Ascites
disorders
Aspartate aminotransferase
abnormal
Investigations
Aspartate aminotransferase
abnormal
Aspartate aminotransferase
increased
Investigations
Aspartate aminotransferase
increased
Asterixis
Nervous system
disorders
Asterixis
Asterixis
Nervous system
disorders
Asterixis
Asthenia
General disorders and
administration site
conditions
Asthenia
Astigmatism
Eye disorders
Astigmatism
Attention deficit/hyperactivity
disorder
Psychiatric disorders
Attention deficit/hyperactivity
disorder
Atypical attention deficit 
syndrome
Psychiatric disorders
Atypical attention deficit 
syndrome
Autoimmune hepatitis
Hepatobiliary 
disorders
Autoimmune hepatitis
Beta 2 microglobulin increased
Investigations
Beta 2 microglobulin increased
Beta globulin increased
Investigations
Beta globulin increased
Bile duct obstruction
Hepatobiliary 
disorders
Bile duct obstruction
Bile duct pressure increased
Investigations
Bile duct pressure increased
Bile duct stenosis
Hepatobiliary 
disorders
Bile duct stenosis
Bile duct stent insertion
Surgical and medical 
procedures
Bile duct stent insertion
Bile output abnormal
Investigations
Bile output abnormal
Bile output decreased
Investigations
Bile output decreased
Biliary cirrhosis
Hepatobiliary 
disorders
Biliary cirrhosis
Biliary dyskinesia
Hepatobiliary 
disorders
Biliary dyskinesia
Biliary fibrosis
Hepatobiliary 
disorders
Biliary fibrosis
Bilirubin conjugated abnormal
Investigations
Bilirubin conjugated abnormal
Bilirubin conjugated increased
Investigations
Bilirubin conjugated increased
Bilirubin excretion disorder
Hepatobiliary 
disorders
Bilirubin excretion disorder
Bilirubinuria
Renal and urinary 
disorders
Bilirubinuria
Biopsy liver abnormal
Investigations
Biopsy liver abnormal


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
47
Blepharospasm
Eye disorders
Blepharospasm
Blindness
Eye disorders
Blindness
Blindness cortical
Eye disorders
Blindness cortical
Blindness day
Eye disorders
Blindness day
Blindness transient
Eye disorders
Blindness transient
Blindness traumatic
Injury, poisoning and 
procedural
complications
Blindness traumatic
Blindness unilateral
Eye disorders
Blindness unilateral
Blister
Skin and 
subcutaneous tissue 
disorders
Blister
Blood alkaline phosphatase 
abnormal
Investigations
Blood alkaline phosphatase 
abnormal
Blood alkaline phosphatase 
increased
Investigations
Blood alkaline phosphatase
increased
Blood bicarbonate abnormal
Investigations
Blood bicarbonate abnormal
Blood bicarbonate decreased
Investigations
Blood bicarbonate decreased
Blood bilirubin abnormal
Investigations
Blood bilirubin abnormal
Blood bilirubin increased
Investigations
Blood bilirubin increased
Blood bilirubin unconjugated 
increased
Investigations
Blood bilirubin unconjugated 
increased
Blood cholinesterase abnormal
Investigations
Blood cholinesterase abnormal
Blood cholinesterase decreased
Investigations
Blood cholinesterase decreased
Blood urine
Investigations
Blood urine
Blood urine present
Investigations
Blood urine present
Blunted affect
Psychiatric disorders
Blunted affect
Body height abnormal
Investigations
Body height abnormal
Body height below normal
Investigations
Body height below normal
Body height decreased
Investigations
Body height decreased
Body mass index decreased
Investigations
Body mass index decreased
Body temperature decreased
Investigations
Body temperature decreased
Body temperature increased
Investigations
Body temperature increased
Bone development abnormal
Musculoskeletal and 
connective tissue
disorders
Bone development abnormal
Bone development abnormal
Musculoskeletal and 
connective tissue
disorders
Bone development abnormal
Bone disorder
Musculoskeletal and 
connective tissue
disorders
Bone disorder
Bone disorder
Musculoskeletal and 
connective tissue
disorders
Bone disorder


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
48
Bone formation decreased
Musculoskeletal and 
connective tissue
disorders
Bone formation decreased
Bone metabolism disorder
Musculoskeletal and 
connective tissue
disorders
Bone metabolism disorder
Bone pain
Musculoskeletal and 
connective tissue
disorders
Bone pain
Borderline glaucoma
Eye disorders
Borderline glaucoma
Borderline mental impairment
Nervous system
disorders
Borderline mental impairment
Bradyphrenia
Psychiatric disorders
Bradyphrenia
Bromosulphthalein test
abnormal
Investigations
Bromosulphthalein test
abnormal
Budd-Chiari syndrome
Hepatobiliary 
disorders
Budd-Chiari syndrome
Cachexia
Metabolism and 
nutrition disorders
Cachexia
Calculus bladder
Renal and urinary 
disorders
Calculus bladder
Calculus bladder
Renal and urinary 
disorders
Calculus bladder
Calculus prostatic
Reproductive system
and breast disorders
Calculus prostatic
Calculus prostatic
Reproductive system
and breast disorders
Calculus prostatic
Calculus ureteric
Renal and urinary 
disorders
Ureterolithiasis
Calculus urethral
Renal and urinary 
disorders
Calculus urethral
Calculus urinary
Renal and urinary 
disorders
Calculus urinary
Carbon dioxide decreased
Investigations
Carbon dioxide decreased
Cardiac arrest
Cardiac disorders
Cardiac arrest
Cardiac death
General disorders and 
administration site
conditions
Cardiac death
Cardiac failure
Cardiac disorders
Cardiac failure
Cardiac failure acute
Cardiac disorders
Cardiac failure acute
Cardiac failure chronic
Cardiac disorders
Cardiac failure chronic
Cardiac failure congestive
Cardiac disorders
Cardiac failure congestive
Cardiac output decreased
Investigations
Cardiac output decreased
Cardiac ventriculogram
abnormal
Investigations
Cardiac ventriculogram
abnormal


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
49
Cardiac ventriculogram left
abnormal
Investigations
Cardiac ventriculogram left
abnormal
Cells in urine
Investigations
Cells in urine
Change in sustained attention
Psychiatric disorders
Change in sustained attention
Charles Bonnet syndrome
Eye disorders
Charles Bonnet syndrome
Childhood disintegrative
disorder
Psychiatric disorders
Child-Pugh-Turcotte score
increased
Child-Pugh-Turcotte score
increased
Investigations
Chills
General disorders and 
administration site
conditions
Chills
Chloropsia
Eye disorders
Chloropsia
Cholaemia
Hepatobiliary 
disorders
Cholaemia
Cholelithiasis
Hepatobiliary 
disorders
Cholelithiasis
Cholelithiasis obstructive
Hepatobiliary 
disorders
Cholelithiasis obstructive
Cholelithotomy
Surgical and medical 
procedures
Cholelithotomy
Cholestasis
Hepatobiliary 
disorders
Cholestasis
Cholestatic liver injury
Hepatobiliary 
disorders
Cholestatic liver injury
Cholestatic liver injury
Hepatobiliary 
disorders
Cholestatic liver injury
Cholestatic pruritus
Skin and 
subcutaneous tissue 
disorders
Cholestatic pruritus
Chorioretinitis
Infections and 
infestations
Chorioretinitis
Choroid tubercles
Infections and 
infestations
Choroid tubercles
Choroiditis
Eye disorders
Choroiditis
Urine colour abnormal
Renal and urinary 
disorders
Chromaturia
Chronic fatigue syndrome
General disorders and 
administration site
conditions
Chronic fatigue syndrome
Chronic hepatic failure
Hepatobiliary 
disorders
Chronic hepatic failure
Chronic hepatitis
Hepatobiliary 
disorders
Chronic hepatitis
Ciliary muscle spasm
Eye disorders
Ciliary muscle spasm
Circumstantiality
Psychiatric disorders
Circumstantiality


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
50
Clang associations
Psychiatric disorders
Clang associations
Cognitive disorder
Nervous system
disorders
Cognitive disorder
Cold sweat
Skin and 
subcutaneous tissue 
disorders
Cold sweat
Coma
Nervous system
disorders
Coma
Coma hepatic
Nervous system
disorders
Coma hepatic
Communication disorder
Psychiatric disorders
Communication disorder
Completed suicide
Psychiatric disorders
Completed suicide
Confabulation
Psychiatric disorders
Confabulation
Confusional arousal
Psychiatric disorders
Confusional arousal
Confusional state
Psychiatric disorders
Confusional state
Confusional state
Psychiatric disorders
Confusional state
Conjunctival ulcer
Eye disorders
Conjunctival ulcer
Conjunctivitis
Infections and 
infestations
Conjunctivitis
Consciousness fluctuating
Nervous system
disorders
Consciousness fluctuating
Constricted affect
Psychiatric disorders
Constricted affect
Coprolalia
Psychiatric disorders
Coprolalia
Corneal deposits
Eye disorders
Corneal deposits
Corneal exfoliation
Eye disorders
Corneal exfoliation
Corneal oedema
Eye disorders
Corneal oedema
Corneal opacity
Eye disorders
Corneal opacity
Corneal perforation
Eye disorders
Corneal perforation
Creatine urine abnormal
Investigations
Creatine urine abnormal
Creatine urine decreased
Investigations
Creatine urine decreased
Creatine urine increased
Investigations
Creatine urine increased
Creatinine urine decreased
Investigations
Creatinine urine decreased
Creatinine urine increased
Investigations
Creatinine urine increased
Crocodile tears syndrome
Nervous system
disorders
Crocodile tears syndrome
Crying
General disorders and 
administration site
conditions
Crying
Cryptogenic cirrhosis
Hepatobiliary 
disorders
Cryptogenic cirrhosis
Crystal urine
Investigations
Crystal urine
Crystal urine present
Investigations
Crystal urine present
Cyanopsia
Eye disorders
Cyanopsia
Cycloplegia
Eye disorders
Cycloplegia
Cysteine urine present
Investigations
Cysteine urine present
Cystine urine present
Investigations
Cystine urine present


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
51
Daydreaming
Psychiatric disorders
Daydreaming
Deaf mutism
Congenital, familial 
and genetic disorders
Deaf mutism
Decreased activity
General disorders and 
administration site
conditions
Decreased activity
Anorexia
Metabolism and 
nutrition disorders
Decreased appetite
Anorexia
Metabolism and 
nutrition disorders
Decreased appetite
Decreased interest
Psychiatric disorders
Decreased interest
Dehydration
Metabolism and 
nutrition disorders
Dehydration
Delirium
Psychiatric disorders
Delirium
Depressed level of
consciousness
Nervous system
disorders
Depressed level of consciousness
Depressed mood
Psychiatric disorders
Depressed mood
Depression
Psychiatric disorders
Depression
Depression postoperative
Injury, poisoning and 
procedural
complications
Depression postoperative
Depression suicidal
Psychiatric disorders
Depression suicidal
Depressive symptom
Psychiatric disorders
Depressive symptom
Derailment
Psychiatric disorders
Derailment
Dermatitis bullous
Skin and 
subcutaneous tissue 
disorders
Dermatitis bullous
Dermatitis exfoliative
Skin and 
subcutaneous tissue 
disorders
Dermatitis exfoliative
Dermatitis exfoliative 
generalised
Skin and 
subcutaneous tissue 
disorders
Dermatitis exfoliative 
generalised
Detachment of retinal pigment
epithelium
Eye disorders
Detachment of retinal pigment
epithelium
Developmental coordination 
disorder
Nervous system
disorders
Developmental coordination 
disorder
Developmental delay
General disorders and 
administration site
conditions
Developmental delay
Diplopia
Eye disorders
Diplopia
Disorientation
Psychiatric disorders
Disorientation
Disorientation
Psychiatric disorders
Disorientation
Dissociative amnesia
Psychiatric disorders
Dissociative amnesia
Distractibility
Psychiatric disorders
Distractibility


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
52
Disturbance in attention
Nervous system
disorders
Disturbance in attention
Disturbance in attention
Nervous system
disorders
Disturbance in attention
Drug eruption
Skin and 
subcutaneous tissue 
disorders
Drug eruption
Drug rash with eosinophilia
and systemic symptoms
Skin and 
subcutaneous tissue 
disorders
Drug reaction with eosinophilia 
and systemic symptoms
Dry eye
Eye disorders
Dry eye
Keratoconjunctivitis sicca
Eye disorders
Dry eye
Keratoconjunctivitis sicca
Eye disorders
Dry eye
Dry skin
Skin and 
subcutaneous tissue 
disorders
Dry skin
Duodenal varices
Gastrointestinal 
disorders
Duodenal varices
Dwarfism
Musculoskeletal and 
connective tissue
disorders
Dwarfism
Dysarthria
Nervous system
disorders
Dysarthria
Dysgraphia
Nervous system
disorders
Dysgraphia
Dyshidrosis
Skin and 
subcutaneous tissue 
disorders
Dyshidrotic eczema
Dyshidrosis
Skin and 
subcutaneous tissue 
disorders
Dyshidrotic eczema
Dyslalia
Nervous system
disorders
Dyslalia
Dysmetropsia
Eye disorders
Dysmetropsia
Dysphemia
Psychiatric disorders
Dysphemia
Dysphonia
Respiratory, thoracic
and mediastinal 
disorders
Dysphonia
Dysphonia psychogenic
Nervous system
disorders
Dysphonia psychogenic
Dysphoria
Psychiatric disorders
Dysphoria
Dysprosody
Nervous system
disorders
Dysprosody
Dyssomnia
Psychiatric disorders
Dyssomnia
Dysthymic disorder
Psychiatric disorders
Persistent depressive disorder
Echolalia
Psychiatric disorders
Echolalia


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
53
Electric shock
Injury, poisoning and 
procedural
complications
Electric shock
Electroconvulsive therapy
Surgical and medical 
procedures
Electroconvulsive therapy
Electroencephalogram
abnormal
Investigations
Electroencephalogram
abnormal
Emotional distress
Psychiatric disorders
Emotional distress
Encephalopathy
Nervous system
disorders
Encephalopathy
Epidermal necrosis
Skin and 
subcutaneous tissue 
disorders
Epidermal necrosis
Epidermolysis
Congenital, familial 
and genetic disorders
Epidermolysis
Epidermolysis bullosa
Congenital, familial 
and genetic disorders
Epidermolysis bullosa
Epiphyses delayed fusion
Musculoskeletal and 
connective tissue
disorders
Epiphyses delayed fusion
Erythema multiforme
Skin and 
subcutaneous tissue 
disorders
Erythema multiforme
Erythropsia
Eye disorders
Erythropsia
Excessive eye blinking
Eye disorders
Excessive eye blinking
Exfoliative rash
Skin and 
subcutaneous tissue 
disorders
Exfoliative rash
Eye disorder
Eye disorders
Eye disorder
Eye pain
Eye disorders
Eye pain
Eyelid function disorder
Eye disorders
Eyelid function disorder
Eyelid ptosis
Eye disorders
Eyelid ptosis
Eyelid retraction
Eye disorders
Eyelid retraction
Failure to thrive
Metabolism and 
nutrition disorders
Failure to thrive
Fanconi syndrome
Congenital, familial 
and genetic disorders
Fanconi syndrome
Fanconi syndrome acquired
Renal and urinary 
disorders
Fanconi syndrome acquired
Fanconi syndrome acquired
Renal and urinary 
disorders
Fanconi syndrome acquired
Fatigue
General disorders and 
administration site
conditions
Fatigue


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
54
Feeling cold
General disorders and
administration site
conditions
Feeling cold
Feeling drunk
General disorders and 
administration site
conditions
Feeling drunk
Feeling guilty
Psychiatric disorders
Feeling guilty
Feeling hot
General disorders and 
administration site
conditions
Feeling hot
Feeling of body temperature
change
General disorders and 
administration site
conditions
Feeling of body temperature
change
Feeling of despair
Psychiatric disorders
Feeling of despair
Feelings of worthlessness
Psychiatric disorders
Feelings of worthlessness
Flight of ideas
Psychiatric disorders
Flight of ideas
Floppy iris syndrome
Injury, poisoning and 
procedural
complications
Floppy iris syndrome
Flushing
Vascular disorders
Flushing
Folliculitis
Infections and 
infestations
Folliculitis
Fracture delayed union
Musculoskeletal and 
connective tissue
disorders
Fracture delayed union
Fracture malunion
Musculoskeletal and 
connective tissue
disorders
Fracture malunion
Fracture nonunion
Musculoskeletal and 
connective tissue
disorders
Fracture nonunion
Fundoscopy
Investigations
Fundoscopy
Fundoscopy abnormal
Investigations
Fundoscopy abnormal
Galactose elimination capacity
test abnormal
Investigations
Galactose elimination capacity
test abnormal
Galactose elimination capacity
test decreased
Investigations
Galactose elimination capacity
test decreased
Gallbladder cholesterolosis
Hepatobiliary 
disorders
Gallbladder cholesterolosis
Gallbladder disorder
Hepatobiliary 
disorders
Gallbladder disorder
Gallbladder enlargement
Hepatobiliary
disorders
Gallbladder enlargement
Gallbladder fistula
Hepatobiliary 
disorders
Gallbladder fistula


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
55
Gallbladder mucocoele
Hepatobiliary 
disorders
Gallbladder mucocoele
Gallbladder necrosis
Hepatobiliary 
disorders
Gallbladder necrosis
Gallbladder non-functioning
Hepatobiliary 
disorders
Gallbladder hypofunction
Gallbladder obstruction
Hepatobiliary 
disorders
Gallbladder obstruction
Gallbladder oedema
Hepatobiliary 
disorders
Gallbladder oedema
Gallbladder pain
Hepatobiliary 
disorders
Biliary colic
Gamma-glutamyltransferase
abnormal
Investigations
Gamma-glutamyltransferase
abnormal
Gamma-glutamyltransferase
increased
Investigations
Gamma-glutamyltransferase
increased
Gastric varices
Gastrointestinal 
disorders
Gastric varices
Generalised anxiety disorder
Psychiatric disorders
Generalised anxiety disorder
Genital ulceration
Reproductive system
and breast disorders
Genital ulceration
Gianotti-Crosti syndrome
Infections and 
infestations
Gianotti-Crosti syndrome
Glare
Eye disorders
Glare
Glaucoma
Eye disorders
Glaucoma
Glaucomatous optic disc
atrophy
Eye disorders
Glaucomatous optic disc
atrophy
Globulin urine present
Investigations
Globulin urine present
Globulins increased
Investigations
Globulins increased
Glucose urine
Investigations
Glucose urine
Glucose urine present
Investigations
Glucose urine present
Glyceric acid urine increased
Investigations
Glyceric acid urine increased
Gonioscopy
Investigations
Gonioscopy
Gonioscopy abnormal
Investigations
Gonioscopy abnormal
Granulomatous liver disease
Hepatobiliary 
disorders
Granulomatous liver disease
Growth retardation
Musculoskeletal and 
connective tissue
disorders
Growth retardation
Guanase increased
Investigations
Guanase increased
Haematuria
Renal and urinary 
disorders
Haematuria
Haemoglobin urine
Investigations
Haemoglobin urine
Haemoglobin urine present
Investigations
Haemoglobin urine present
Haemorrhagic ascites
Gastrointestinal 
disorders
Haemorrhagic ascites


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
56
Haemorrhagic hepatic cyst
Hepatobiliary 
disorders
Haemorrhagic hepatic cyst
Halo vision
Eye disorders
Halo vision
Heat exhaustion
Injury, poisoning and 
procedural
complications
Heat exhaustion
Heat illness
Injury, poisoning and 
procedural
complications
Heat illness
Heat oedema
Injury, poisoning and 
procedural
complications
Heat oedema
Heat stroke
Injury, poisoning and 
procedural
complications
Heat stroke
Hemianopia
Nervous system
disorders
Hemianopia
Hemianopia heteronymous
Nervous system
disorders
Hemianopia heteronymous
Hemianopia homonymous
Nervous system
disorders
Hemianopia homonymous
Hemiapraxia
Nervous system
disorders
Hemiapraxia
Hepaplastin abnormal
Investigations
Hepaplastin abnormal
Hepaplastin decreased
Investigations
Hepaplastin decreased
Hepatic atrophy
Hepatobiliary 
disorders
Hepatic atrophy
Hepatic calcification
Hepatobiliary 
disorders
Hepatic calcification
Hepatic cirrhosis
Hepatobiliary 
disorders
Hepatic cirrhosis
Hepatic congestion
Hepatobiliary 
disorders
Hepatic congestion
Hepatic encephalopathy
Nervous system
disorders
Hepatic encephalopathy
Hepatic encephalopathy
prophylaxis
Surgical and medical 
procedures
Hepatic encephalopathy
prophylaxis
Hepatic enzyme abnormal
Investigations
Hepatic enzyme abnormal
Hepatic enzyme decreased
Investigations
Hepatic enzyme decreased
Hepatic enzyme increased
Investigations
Hepatic enzyme increased
Hepatic failure
Hepatobiliary 
disorders
Hepatic failure
Hepatic fibrosis
Hepatobiliary 
disorders
Hepatic fibrosis
Hepatic function abnormal
Hepatobiliary 
disorders
Hepatic function abnormal


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
57
Hepatic haemorrhage
Hepatobiliary 
disorders
Hepatic haemorrhage
Hepatic hydrothorax
Respiratory, thoracic
and mediastinal 
disorders
Hepatic hydrothorax
Hepatic infarction
Hepatobiliary 
disorders
Hepatic infarction
Hepatic infiltration 
eosinophilic
Hepatobiliary 
disorders
Hepatic infiltration eosinophilic
Hepatic lesion
Hepatobiliary 
disorders
Hepatic lesion
Hepatic mass
Hepatobiliary 
disorders
Hepatic mass
Hepatic necrosis
Hepatobiliary 
disorders
Hepatic necrosis
Hepatic pain
Hepatobiliary 
disorders
Hepatic pain
Hepatic steatosis
Hepatobiliary 
disorders
Hepatic steatosis
Cytolytic hepatitis
Hepatobiliary 
disorders
Hepatitis
Hepatitis
Hepatobiliary 
disorders
Hepatitis
Hepatitis acute
Hepatobiliary 
disorders
Hepatitis B
Hepatitis fulminant
Hepatobiliary 
disorders
Hepatitis chronic active
Hepatitis toxic
Hepatobiliary 
disorders
Hepatitis toxic
Hepatobiliary disease
Hepatobiliary 
disorders
Hepatobiliary disease
Hepatobiliary scan abnormal
Investigations
Hepatobiliary scan abnormal
Hepatocellular foamy cell 
syndrome
Hepatobiliary 
disorders
Hepatocellular foamy cell 
syndrome
Hepatocellular injury
Hepatobiliary 
disorders
Hepatocellular injury
Hepatomegaly
Hepatobiliary 
disorders
Hepatomegaly
Hepatopulmonary syndrome
Respiratory, thoracic
and mediastinal 
disorders
Hepatopulmonary syndrome
Hepatorenal failure
Hepatobiliary 
disorders
Hepatorenal failure
Hepatorenal syndrome
Hepatobiliary 
disorders
Hepatorenal syndrome


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
58
Hepatosplenomegaly
Hepatobiliary
disorders
Hepatosplenomegaly
Hepatotoxicity
Hepatobiliary 
disorders
Hepatotoxicity
Hidradenitis
Skin and 
subcutaneous tissue 
disorders
Hidradenitis
Hippus
Eye disorders
Hippus
Holmes-Adie pupil
Eye disorders
Holmes-Adie pupil
Homocysteine urine
Investigations
Homocysteine urine
Homocysteine urine present
Investigations
Homocysteine urine present
Hot flush
Vascular disorders
Hot flush
Hydrocholecystis
Hepatobiliary 
disorders
Hydrocholecystis
Hydronephrosis
Renal and urinary 
disorders
Hydronephrosis
Hydronephrosis repair
Surgical and medical 
procedures
Hydronephrosis repair
Hyperammonaemia
Metabolism and 
nutrition disorders
Hyperammonaemia
Hyperammonaemic
encephalopathy
Nervous system
disorders
Hyperammonaemic
encephalopathy
Hyperbilirubinaemia
Hepatobiliary 
disorders
Hyperbilirubinaemia
Hypercalcaemia
Metabolism and 
nutrition disorders
Hypercalcaemia
Hypercalcaemic nephropathy
Renal and urinary 
disorders
Hypercalcaemic nephropathy
Hypercalciuria
Renal and urinary 
disorders
Hypercalciuria
Hypercholia
Hepatobiliary 
disorders
Hypercholia
Hypergammaglobulinaemia
Blood and lymphatic 
system disorders
Hypergammaglobulinaemia
Hyperglobulinaemia
Blood and lymphatic 
system disorders
Hyperglobulinaemia
Hyperhidrosis
Skin and 
subcutaneous tissue 
disorders
Hyperhidrosis
Hypermetropia
Eye disorders
Hypermetropia
Hyperplastic cholecystopathy
Hepatobiliary 
disorders
Hyperplastic cholecystopathy
Hyperpyrexia
General disorders and 
administration site
conditions
Hyperpyrexia


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
59
Hypersomnia
Nervous system
disorders
Hypersomnia
Hyperthermia
General disorders and 
administration site
conditions
Hyperthermia
Hyperthermia malignant
General disorders and 
administration site
conditions
Hyperthermia malignant
Hypertransaminasaemia
Hepatobiliary 
disorders
Hypertransaminasaemia
Hyperventilation
Respiratory, thoracic
and mediastinal 
disorders
Hyperventilation
Hyphaema
Eye disorders
Hyphaema
Hypoalbuminaemia
Metabolism and 
nutrition disorders
Hypoalbuminaemia
Hypohidrosis
Skin and 
subcutaneous tissue 
disorders
Hypohidrosis
Hypophosphataemia
Metabolism and 
nutrition disorders
Hypophosphataemia
Hypophosphataemic rickets
Musculoskeletal and 
connective tissue
disorders
Hypophosphataemic
osteomalacia
Hypophosphatasia
Congenital, familial
and genetic disorders
Hypophosphatasia
Hyposomnia
Psychiatric disorders
Hyposomnia
Hypothermia
General disorders and 
administration site
conditions
Hypothermia
Icterus index increased
Investigations
Icterus index increased
Illogical thinking
Psychiatric disorders
Illogical thinking
Impaired self-care
General disorders and 
administration site
conditions
Impaired self-care
Incoherent
Nervous system
disorders
Incoherent
Initial insomnia
Psychiatric disorders
Initial insomnia
Intentional self-injury
Psychiatric disorders
Intentional self-injury
Intentional self-injury
Psychiatric disorders
Intentional self-injury
Iridoplegia
Eye disorders
Iridoplegia
Iritis
Eye disorders
Iritis
Ischaemic hepatitis
Hepatobiliary 
disorders
Ischaemic hepatitis
Jaundice
Hepatobiliary 
disorders
Jaundice


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
60
Jaundice cholestatic
Hepatobiliary 
disorders
Jaundice cholestatic
Jaundice hepatocellular
Hepatobiliary 
disorders
Jaundice hepatocellular
Judgement impaired
Nervous system
disorders
Judgement impaired
Kayser-Fleischer ring
Eye disorders
Kayser-Fleischer ring
Keratitis
Eye disorders
Keratitis
Kussmaul respiration
Respiratory, thoracic
and mediastinal 
disorders
Kussmaul respiration
Lack of spontaneous speech
Psychiatric disorders
Lack of spontaneous speech
Lacrimal disorder
Eye disorders
Lacrimal disorder
Lacrimation decreased
Eye disorders
Lacrimation decreased
Lacrimation increased
Eye disorders
Lacrimation increased
Lactic acidosis
Metabolism and 
nutrition disorders
Lactic acidosis
Expressive language disorder
Nervous system
disorders
Language disorder
Mixed receptive-expressive
language disorder
Nervous system
disorders
Language disorder
Laurence-Moon-Bardet-Biedl
syndrome
Congenital, familial 
and genetic disorders
Laurence-Moon-Bardet-Biedl
syndrome
Learning disability
Social circumstances
Learning disability
Learning disorder
Psychiatric disorders
Learning disorder
Lenticular opacities
Eye disorders
Lenticular opacities
Lethargy
Nervous system
disorders
Lethargy
Leucine aminopeptidase
increased
Investigations
Leucine aminopeptidase
increased
Libido decreased
Psychiatric disorders
Libido decreased
Libido disorder
Psychiatric disorders
Libido disorder
Libido increased
Psychiatric disorders
Libido increased
Lip exfoliation
Gastrointestinal 
disorders
Lip exfoliation
Listless
Psychiatric disorders
Listless
Liver disorder
Hepatobiliary 
disorders
Liver disorder
Liver function test abnormal
Investigations
Liver function test abnormal
Liver induration
Hepatobiliary 
disorders
Liver induration
Liver injury
Hepatobiliary 
disorders
Liver injury
Liver palpable subcostal
Investigations
Liver palpable
Liver tenderness
Hepatobiliary 
disorders
Liver tenderness


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
61
Cluttering
Psychiatric disorders
Logorrhoea
Loose associations
Psychiatric disorders
Loose associations
Loss of consciousness
Nervous system
disorders
Loss of consciousness
Loss of libido
Psychiatric disorders
Loss of libido
Loss of visual contrast 
sensitivity
Eye disorders
Loss of visual contrast 
sensitivity
Low cardiac output syndrome
Cardiac disorders
Low cardiac output syndrome
Lupoid hepatic cirrhosis
Hepatobiliary 
disorders
Lupoid hepatic cirrhosis
Macular cyst
Eye disorders
Macular cyst
Macular degeneration
Eye disorders
Macular degeneration
Macular hole
Eye disorders
Macular hole
Macular ischaemia
Eye disorders
Macular ischaemia
Macular oedema
Eye disorders
Macular oedema
Macular opacity
Eye disorders
Macular opacity
Macular pseudohole
Eye disorders
Macular pseudohole
Macular scar
Eye disorders
Macular scar
Macular vasospasm
Eye disorders
Macular vasospasm
Maculopathy
Eye disorders
Maculopathy
Major depression
Psychiatric disorders
Major depression
Memory impairment
Nervous system
disorders
Memory impairment
Menopausal depression
Psychiatric disorders
Menopausal depression
Mental impairment
Nervous system
disorders
Mental impairment
Mental retardation
Nervous system
disorders
Intellectual disability
Metabolic acidosis
Metabolism and 
nutrition disorders
Metabolic acidosis
Metamorphopsia
Eye disorders
Metamorphopsia
Microlithiasis
General disorders and 
administration site
conditions
Lithiasis
Middle insomnia
Psychiatric disorders
Middle insomnia
Mikulicz's disease
Gastrointestinal 
disorders
Mikulicz's disease
Mikulicz's syndrome
Gastrointestinal
disorders
Mikulicz's syndrome
Mild mental retardation
Nervous system
disorders
Intellectual disability
Milia
Skin and 
subcutaneous tissue 
disorders
Milia


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
62
Heat rash
Skin and 
subcutaneous tissue 
disorders
Miliaria
Miosis
Eye disorders
Miosis
Mitochondrial aspartate
aminotransferase increased
Investigations
Mitochondrial aspartate
aminotransferase increased
Mixed hepatocellular
cholangiocarcinoma
Neoplasms benign,
malignant and
unspecified (incl cysts 
and polyps)
Mixed hepatocellular
cholangiocarcinoma
Mixed liver injury
Hepatobiliary 
disorders
Mixed liver injury
Moderate mental retardation
Nervous system
disorders
Intellectual disability
Molar ratio of total branched-
chain amino acid to tyrosine
Investigations
Molar ratio of total branched-
chain amino acid to tyrosine
Mood altered
Psychiatric disorders
Mood altered
Mood swings
Psychiatric disorders
Mood swings
Morose
Psychiatric disorders
Morose
Mouth ulceration
Gastrointestinal 
disorders
Mouth ulceration
Mucocutaneous ulceration
Skin and 
subcutaneous tissue 
disorders
Mucocutaneous ulceration
Mucosa vesicle
General disorders and 
administration site
conditions
Mucosa vesicle
Mucosal erosion
General disorders and 
administration site
conditions
Mucosal erosion
Mucosal exfoliation
General disorders and 
administration site
conditions
Mucosal exfoliation
Mucosal necrosis
General disorders and 
administration site
conditions
Mucosal necrosis
Mucosal ulceration
General disorders and 
administration site
conditions
Mucosal ulceration
Musculoskeletal chest pain
Musculoskeletal and 
connective tissue
disorders
Musculoskeletal chest pain
Musculoskeletal pain
Musculoskeletal and 
connective tissue
disorders
Musculoskeletal pain
Mutism
Psychiatric disorders
Mutism


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
63
Mydriasis
Eye disorders
Mydriasis
Myopia
Eye disorders
Myopia
Necrotising retinitis
Eye disorders
Necrotising retinitis
Negative cardiac inotropic 
effect
Cardiac disorders
Negative cardiac inotropic effect
Negative thoughts
Psychiatric disorders
Negative thoughts
Neglect of personal appearance
Psychiatric disorders
Neglect of personal appearance
Neologism
Psychiatric disorders
Neologism
Nephrocalcinosis
Renal and urinary 
disorders
Nephrocalcinosis
Nephrocalcinosis
Renal and urinary 
disorders
Nephrocalcinosis
Nephrolithiasis
Renal and urinary 
disorders
Nephrolithiasis
Nephrolithiasis
Renal and urinary 
disorders
Nephrolithiasis
Nervousness
Psychiatric disorders
Nervousness
Neurodevelopmental disorder
Psychiatric disorders
Neurodevelopmental disorder
Neuroleptic malignant
syndrome
Nervous system
disorders
Neuroleptic malignant
syndrome
Night blindness
Eye disorders
Night blindness
Night sweats
Skin and
subcutaneous tissue 
disorders
Night sweats
Nikolsky's sign
Skin and 
subcutaneous tissue 
disorders
Nikolsky's sign
Nitrite urine
Investigations
Nitrite urine
Nitrite urine present
Investigations
Nitrite urine present
Nodular regenerative
hyperplasia
Hepatobiliary 
disorders
Nodular regenerative
hyperplasia
Normal tension glaucoma
Eye disorders
Normal tension glaucoma
Obsessive rumination
Psychiatric disorders
Obsessive rumination
Ocular hypertension
Eye disorders
Ocular hypertension
Ocular icterus
Eye disorders
Ocular icterus
Oculomucocutaneous
syndrome
Skin and 
subcutaneous tissue 
disorders
Oculomucocutaneous syndrome
Oedema due to cardiac disease
General disorders and 
administration site
conditions
Oedema due to cardiac disease
Oedema due to hepatic disease
General disorders and 
administration site
conditions
Oedema due to hepatic disease
Oesophageal varices
haemorrhage
Gastrointestinal 
disorders
Oesophageal varices
haemorrhage


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
64
Open angle glaucoma
Eye disorders
Open angle glaucoma
Ophthalmoplegia
Eye disorders
Ophthalmoplegia
Optic atrophy
Eye disorders
Optic atrophy
Optic disc disorder
Eye disorders
Optic disc disorder
Optic disc drusen
Eye disorders
Optic disc drusen
Optic discs blurred
Eye disorders
Optic discs blurred
Optic ischaemic neuropathy
Eye disorders
Optic ischaemic neuropathy
Optic nerve cupping
Eye disorders
Optic nerve cupping
Optic nerve disorder
Eye disorders
Optic nerve disorder
Optic nerve infarction
Eye disorders
Optic nerve infarction
Optic neuritis
Nervous system
disorders
Optic neuritis
Optic neuropathy
Eye disorders
Optic neuropathy
Oral mucosal exfoliation
Gastrointestinal 
disorders
Oral mucosal exfoliation
Oropharyngeal blistering
Respiratory, thoracic
and mediastinal 
disorders
Oropharyngeal blistering
Oscillopsia
Eye disorders
Oscillopsia
Osteomalacia
Musculoskeletal and 
connective tissue
disorders
Osteomalacia
Osteoporosis
Musculoskeletal and 
connective tissue
disorders
Osteoporosis
Osteoporosis-pseudoglioma
syndrome
Congenital, familial
and genetic disorders
Osteoporosis-pseudoglioma
syndrome
Osteoporotic fracture
Musculoskeletal and 
connective tissue
disorders
Osteoporotic fracture
Papilloedema
Eye disorders
Papilloedema
Paracentesis eye
Investigations
Paracentesis eye
Paracentesis eye abnormal
Investigations
Paracentesis eye abnormal
Paralytic lagophthalmos
Eye disorders
Paralytic lagophthalmos
Paramnesia
Psychiatric disorders
Paramnesia
Pars plana cyst
Eye disorders
Pars plana cyst
Malignant myopia
Eye disorders
Pathologic myopia
Pathological fracture
Musculoskeletal and 
connective tissue
disorders
Pathological fracture
Pemphigoid
Skin and 
subcutaneous tissue 
disorders
Pemphigoid
Pemphigus
Skin and 
subcutaneous tissue 
disorders
Pemphigus


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
65
Penile exfoliation
Reproductive system
and breast disorders
Penile exfoliation
Perihepatic discomfort
Hepatobiliary 
disorders
Perihepatic discomfort
Perihepatitis gonococcal
Infections and 
infestations
Perihepatitis gonococcal
Perseveration
Psychiatric disorders
Perseveration
pH urine abnormal
Investigations
pH urine abnormal
pH urine decreased
Investigations
pH urine decreased
pH urine increased
Investigations
pH urine increased
Phonological disorder
Psychiatric disorders
Speech sound disorder
Photophobia
Eye disorders
Photophobia
Phosphenes
Eye disorders
Photopsia
Photopsia
Eye disorders
Photopsia
Poor quality sleep
Nervous system
disorders
Poor quality sleep
Poor weight gain neonatal
Pregnancy,
puerperium and
perinatal conditions
Poor weight gain neonatal
Porcelain gallbladder
Hepatobiliary 
disorders
Porcelain gallbladder
Portal hypertension
Hepatobiliary 
disorders
Portal hypertension
Portal triaditis
Hepatobiliary 
disorders
Portal tract inflammation
Portal vein flow decreased
Investigations
Portal vein flow decreased
Portal vein pressure increased
Investigations
Portal vein pressure increased
Portopulmonary hypertension
Respiratory, thoracic
and mediastinal 
disorders
Portopulmonary hypertension
Postpartum depression
Psychiatric disorders
Perinatal depression
Poverty of speech
Psychiatric disorders
Poverty of speech
Poverty of thought content
Psychiatric disorders
Poverty of thought content
Presbyopia
Eye disorders
Presbyopia
Pressure of speech
Psychiatric disorders
Pressure of speech
Profound mental retardation
Nervous system
disorders
Intellectual disability
Protein urine
Investigations
Protein urine
Protein urine present
Investigations
Protein urine present
Pseudarthrosis
Musculoskeletal and 
connective tissue
disorders
Pseudarthrosis
Pseudo-blepharoptosis
Eye disorders
Pseudo-blepharoptosis
Pseudopapilloedema
Eye disorders
Pseudopapilloedema
Psychomotor hyperactivity
Nervous system
disorders
Psychomotor hyperactivity


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
66
Psychomotor retardation
Psychiatric disorders
Psychomotor retardation
Psychomotor skills impaired
Nervous system
disorders
Psychomotor skills impaired
Psychosocial support
Surgical and medical 
procedures
Psychosocial support
Psychotherapy
Surgical and medical 
procedures
Psychotherapy
Pupil fixed
Eye disorders
Pupil fixed
Pupillary deformity
Eye disorders
Pupillary deformity
Pupillary disorder
Eye disorders
Pupillary disorder
Pupillary reflex impaired
Eye disorders
Pupillary reflex impaired
Pupillotonia
Eye disorders
Pupillotonia
Pupils unequal
Eye disorders
Pupils unequal
Pyrexia
General disorders and 
administration site
conditions
Pyrexia
Rash maculo-papular
Skin and 
subcutaneous tissue 
disorders
Rash maculo-papular
Rash pustular
Infections and 
infestations
Rash pustular
Reading disorder
Psychiatric disorders
Reading disorder
Red blood cells urine
Investigations
Red blood cells urine
Red blood cells urine positive
Investigations
Red blood cells urine positive
Refraction disorder
Eye disorders
Refraction disorder
Renal colic
Renal and urinary 
disorders
Renal colic
Renal failure
Renal and urinary 
disorders
Renal failure
Renal function test abnormal
Investigations
Renal function test abnormal
Renal pain
Renal and urinary 
disorders
Renal pain
Renal tubular acidosis
Renal and urinary 
disorders
Renal tubular acidosis
Repetitive speech
Nervous system
disorders
Repetitive speech
Residual urine volume
decreased
Investigations
Residual urine volume
decreased
Residual urine volume
increased
Investigations
Residual urine volume increased
Respiration abnormal
Respiratory, thoracic
and mediastinal 
disorders
Respiration abnormal
Retinal artery spasm
Eye disorders
Retinal artery spasm
Retinal artery stenosis
Eye disorders
Retinal artery stenosis
Retinal cyst
Eye disorders
Retinal cyst


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
67
Retinal degeneration
Eye disorders
Retinal degeneration
Retinal depigmentation
Eye disorders
Retinal depigmentation
Retinal deposits
Eye disorders
Retinal deposits
Retinal detachment
Eye disorders
Retinal detachment
Retinal disorder
Eye disorders
Retinal disorder
Retinal dystrophy
Eye disorders
Retinal dystrophy
Retinal haemorrhage
Eye disorders
Retinal haemorrhage
Retinal infarction
Eye disorders
Retinal infarction
Retinal infiltrates
Eye disorders
Retinal infiltrates
Retinal ischaemia
Eye disorders
Retinal ischaemia
Retinal oedema
Eye disorders
Retinal oedema
Retinal pallor
Eye disorders
Retinal pallor
Retinal pigment epitheliopathy
Eye disorders
Retinal pigment epitheliopathy
Retinal pigmentation
Eye disorders
Retinal pigmentation
Retinal scar
Eye disorders
Retinal scar
Retinal tear
Eye disorders
Retinal tear
Retinal toxicity
Eye disorders
Retinal toxicity
Retinal vascular occlusion
Eye disorders
Retinal vascular occlusion
Retinal vascular thrombosis
Eye disorders
Retinal vascular thrombosis
Retinal vasculitis
Eye disorders
Retinal vasculitis
Retinal vein occlusion
Eye disorders
Retinal vein occlusion
Retinal vein thrombosis
Eye disorders
Retinal vein thrombosis
Retinitis
Infections and 
infestations
Retinitis
Retinogram
Investigations
Retinogram
Retinogram abnormal
Investigations
Retinogram abnormal
Retinol binding protein
decreased
Investigations
Retinol binding protein
decreased
Retinoschisis
Eye disorders
Retinoschisis
Retinoschisis congenital
Congenital, familial 
and genetic disorders
Retinoschisis congenital
Retrograde amnesia
Nervous system
disorders
Retrograde amnesia
Retrograde portal vein flow
Hepatobiliary 
disorders
Retrograde portal vein flow
Reye's syndrome
Hepatobiliary 
disorders
Reye's syndrome
Scintillating scotoma
Eye disorders
Scintillating scotoma
Screaming
Psychiatric disorders
Screaming
Sedation
Nervous system
disorders
Sedation
Selective mutism
Psychiatric disorders
Selective mutism
Self esteem decreased
Psychiatric disorders
Self esteem decreased
Self injurious behaviour
Psychiatric disorders
Intentional self-injury
Self-injurious ideation
Psychiatric disorders
Self-injurious ideation


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
68
Severe mental retardation
Nervous system
disorders
Intellectual disability
Sicca syndrome
Musculoskeletal and 
connective tissue
disorders
Sjogren's syndrome
Sjogren's syndrome
Musculoskeletal and 
connective tissue
disorders
Sjogren's syndrome
Skin erosion
Skin and 
subcutaneous tissue 
disorders
Skin erosion
Skin exfoliation
Skin and 
subcutaneous tissue 
disorders
Skin exfoliation
Skin necrosis
Skin and 
subcutaneous tissue 
disorders
Skin necrosis
Somnolence
Nervous system
disorders
Somnolence
Speech disorder
Nervous system
disorders
Speech disorder
Speech disorder developmental
Nervous system
disorders
Speech disorder developmental
Spider naevus
Skin and 
subcutaneous tissue 
disorders
Spider naevus
Stag horn calculus
Renal and urinary 
disorders
Stag horn calculus
Stag horn calculus
Renal and urinary 
disorders
Stag horn calculus
Stevens-Johnson syndrome
Skin and 
subcutaneous tissue 
disorders
Stevens-Johnson syndrome
Stomatitis
Gastrointestinal 
disorders
Stomatitis
Strabismus
Eye disorders
Strabismus
Stupor
Nervous system
disorders
Stupor
Subacute hepatic failure
Hepatobiliary 
disorders
Subacute hepatic failure
Subacute myelo-
opticoneuropathy
Nervous system
disorders
Subacute myelo-
opticoneuropathy
Subretinal fibrosis
Eye disorders
Subretinal fibrosis
Sudden cardiac death
General disorders and 
administration site
conditions
Sudden cardiac death


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
69
Sudden visual loss
Eye disorders
Sudden visual loss
Suicidal behaviour
Psychiatric disorders
Suicidal behaviour
Suicidal ideation
Psychiatric disorders
Suicidal ideation
Suicide attempt
Psychiatric disorders
Suicide attempt
Sweat discolouration
Skin and 
subcutaneous tissue 
disorders
Sweat discolouration
Sweat gland disorder
Skin and 
subcutaneous tissue 
disorders
Sweat gland disorder
Synostosis
Musculoskeletal and 
connective tissue
disorders
Synostosis
Taciturnity
Psychiatric disorders
Taciturnity
Tangentiality
Psychiatric disorders
Tangentiality
Tear discolouration
Eye disorders
Tear discolouration
Tearfulness
Psychiatric disorders
Tearfulness
Temperature intolerance
General disorders and 
administration site
conditions
Temperature intolerance
Temperature regulation
disorder
General disorders and 
administration site
conditions
Temperature regulation 
disorder
Temperature regulation 
disorder
General disorders and 
administration site
conditions
Temperature regulation 
disorder
Terminal insomnia
Psychiatric disorders
Terminal insomnia
Thinking abnormal
Psychiatric disorders
Thinking abnormal
Thought blocking
Psychiatric disorders
Thought blocking
Thought withdrawal
Psychiatric disorders
Thought withdrawal
Tongue exfoliation
Gastrointestinal 
disorders
Tongue exfoliation
Total bile acids increased
Investigations
Total bile acids increased
Toxic epidermal necrolysis
Skin and 
subcutaneous tissue 
disorders
Toxic epidermal necrolysis
Toxic skin eruption
Skin and 
subcutaneous tissue 
disorders
Toxic skin eruption
Transaminases abnormal
Investigations
Transaminases abnormal
Transaminases increased
Investigations
Transaminases increased
Tunnel vision
Nervous system
disorders
Tunnel vision
Uhthoff's phenomenon
Nervous system
disorders
Uhthoff's phenomenon


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
70
Ultrasound biliary tract 
abnormal
Investigations
Ultrasound biliary tract 
abnormal
Ultrasound bladder abnormal
Investigations
Ultrasound bladder abnormal
Ultrasound eye abnormal
Investigations
Ultrasound eye abnormal
Ultrasound kidney abnormal
Investigations
Ultrasound kidney abnormal
Ultrasound liver abnormal
Investigations
Ultrasound liver abnormal
Underweight
Metabolism and 
nutrition disorders
Underweight
Urea urine abnormal
Investigations
Urea urine abnormal
Urea urine decreased
Investigations
Urea urine decreased
Urea urine increased
Investigations
Urea urine increased
Urine abnormality
Renal and urinary 
disorders
Urine abnormality
Urine albumin/creatinine ratio 
abnormal
Investigations
Urine albumin/creatinine ratio 
abnormal
Urine albumin/creatinine ratio 
decreased
Investigations
Urine albumin/creatinine ratio 
decreased
Urine albumin/creatinine ratio 
increased
Investigations
Urine albumin/creatinine ratio 
increased
Urine bilirubin increased
Investigations
Urine bilirubin increased
Urine calcium decreased
Investigations
Urine calcium decreased
Urine calcium increased
Investigations
Urine calcium increased
Urine calcium/creatinine ratio
decreased
Investigations
Urine calcium/creatinine ratio
decreased
Urine calcium/creatinine ratio
increased
Investigations
Urine calcium/creatinine ratio
increased
Urine flow decreased
Renal and urinary 
disorders
Urine flow decreased
Urine homocystine present
Investigations
Urine homocystine present
Urine ketone body
Investigations
Urine ketone body
Urine ketone body present
Investigations
Urine ketone body present
Urine lactic acid decreased
Investigations
Urine lactic acid decreased
Urine lactic acid increased
Investigations
Urine lactic acid increased
Urine nitrogen
Investigations
Urine nitrogen
Urine odour abnormal
Renal and urinary 
disorders
Urine odour abnormal
Urine osmolarity decreased
Investigations
Urine osmolarity decreased
Urine osmolarity increased
Investigations
Urine osmolarity increased
Urine output decreased
Investigations
Urine output decreased
Urine output increased
Investigations
Urine output increased
Urine oxalate decreased
Investigations
Urine oxalate decreased
Urine oxalate increased
Investigations
Urine oxalate increased
Urine phosphate abnormal
Investigations
Urine phosphorus abnormal
Urine phosphate decreased
Investigations
Urine phosphorus decreased
Urine phosphate increased
Investigations
Urine phosphorus increased


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
71
Urine protein/creatinine ratio
abnormal
Investigations
Urine protein/creatinine ratio
abnormal
Urine protein/creatinine ratio
decreased
Investigations
Urine protein/creatinine ratio
decreased
Urine protein/creatinine ratio
increased
Investigations
Urine protein/creatinine ratio
increased
Urine sodium abnormal
Investigations
Urine sodium abnormal
Urine sodium decreased
Investigations
Urine sodium decreased
Urine sodium increased
Investigations
Urine sodium increased
Urine transitional cells present
Investigations
Urine transitional cells present
Urine uric acid abnormal
Investigations
Urine uric acid abnormal
Urine uric acid decreased
Investigations
Urine uric acid decreased
Urine uric acid increased
Investigations
Urine uric acid increased
Urine viscosity abnormal
Investigations
Urine viscosity abnormal
Urine viscosity decreased
Investigations
Urine viscosity decreased
Urine viscosity increased
Investigations
Urine viscosity increased
Urobilin urine present
Investigations
Urobilinogen urine increased
Uveitis
Eye disorders
Uveitis
Vaginal exfoliation
Reproductive system
and breast disorders
Vaginal exfoliation
Vaginal ulceration
Reproductive system
and breast disorders
Vaginal ulceration
Varices oesophageal
Gastrointestinal 
disorders
Varices oesophageal
Caput medusae
Gastrointestinal 
disorders
Varicose veins of abdominal
wall
Vasodilatation
Vascular disorders
Vasodilatation
Venoocclusive liver disease
Hepatobiliary 
disorders
Venoocclusive liver disease
Venous stasis retinopathy
Eye disorders
Venous stasis retinopathy
Verbigeration
Psychiatric disorders
Verbigeration
Vision abnormal neonatal
Eye disorders
Vision abnormal neonatal
Vision blurred
Eye disorders
Vision blurred
Visual acuity reduced
Eye disorders
Visual acuity reduced
Visual brightness
Eye disorders
Visual brightness
Visual evoked potentials
Investigations
Visual evoked potentials
Visual evoked potentials 
abnormal
Investigations
Visual evoked potentials 
abnormal
Scotoma
Nervous system
disorders
Visual field defect
Visual field defect
Nervous system
disorders
Visual field defect
Visual field tests
Investigations
Visual field tests
Visual field tests abnormal
Investigations
Visual field tests abnormal
Visual impairment
Eye disorders
Visual impairment


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
72
Visual pathway disorder
Nervous system
disorders
Visual pathway disorder
Vitreous abscess
Infections and 
infestations
Vitreous abscess
Vitreous detachment
Eye disorders
Vitreous detachment
Vitritis
Eye disorders
Vitritis
Vulval ulceration
Reproductive system
and breast disorders
Vulval ulceration
Vulvovaginal ulceration
Reproductive system
and breast disorders
Vulvovaginal ulceration
Weight abnormal
Investigations
Weight abnormal
Weight decrease neonatal
Pregnancy,
puerperium and
perinatal conditions
Weight decrease neonatal
Weight decreased
Investigations
Weight decreased
Weight fluctuation
Metabolism and 
nutrition disorders
Weight fluctuation
Weight gain poor
Metabolism and 
nutrition disorders
Weight gain poor
White blood cells urine
Investigations
White blood cells urine
White blood cells urine positive
Investigations
White blood cells urine positive
X-ray hepatobiliary abnormal
Investigations
X-ray hepatobiliary abnormal
X-ray hepatobiliary abnormal
Investigations
X-ray hepatobiliary abnormal
Yellow skin
Skin and 
subcutaneous tissue 
disorders
Yellow skin


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
73
Appendix4:Vinelandscores
OVERVIEW
The Vineland Adaptive Behavior Scale is a composite of four Vineland domains:
Communications (Receptive, Expressive, Written)
Daily Living Skills (Personal, Domestic, Community)
Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills)
Motor Skills (Gross, Fine)
Reference: Vineland Adaptive Behavior Scales, Interview Edition, Survey Form Manual,
S. Sparrow et al, 1984.
The KVINLAND.XPT dataset includes standard scores, age-equivalences, the adaptive
levels for subdomains, domains, and adaptive Behavior Composite, and percentile ranks
for domains and adaptive behavior composite. These variables are based on the 1984 
Vineland scale analyses from the Vineland Interview Edition.
Standard scores (mean 100, SD=15) were analyzed for each of the four adaptive behavior
domains and the Adaptive Behavior composite. The standard score is “based on the
performance of a representative national standardization sampleof3000 individualsbetween birth and age
18-11-30”(p. 116).
STANDARD SCORES
As stated in the Vineland manual (p. 116), “standard scores express in standard deviation units
the extent to which the individual's score exceeds or falls below the mean score of persons the same age
with whomthe instrumentwas standardized. Adaptive BehaviorCompositeand adaptivebehaviordomain
standard scores range from 20 to 160, or 5.5 SD below the mean to 4 SD above the meanStandard
scores have the advantage of being equal units across the full range of scores The difference in
performance between standard scores of 100 and 115 is the same as that between 130 and 145. Because
they are of equal units, standard scores can easily be manipulated statistically.”
PERCENTILE RANKS
As stated in Vineland manual (p. 117), “although standard scores are superior to percentile ranks
in a psychometric sense, they are not easily understood by many people. Percentile ranks aid in giving
meaning to standard scores. Percentile ranks range from 0.1 to 99.9. A percentile rank of50 indicates
median performanceThe chief advantageof percentile ranks is that they are easily understood. A major
limitation is that unlike standard score units, percentile rank units are unequalThe difference between
percentile ranks of 50 and 55 is much smaller than the difference of percentile ranks of 90 and 95. This
occurs because percentile ranksare compressed near the center of the distribution and less heavily
concentratedattheextremes.”
ADAPTIVE LEVELS
Adaptive levels are a categorical representation of the standard scores (p. 118):
AdaptiveLevelStandardScorePercentileRank
High 131 98


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
74
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
ModeratelyHigh116-13085-97
Adequate85-11516-84
ModeratelyLow70-84 3-15
Low 69 2
AGE EQUIVALENTS
As described on page 119, the age equivalent represents the raw score that was the 
average of individuals of a given chronological age in the national standardization 
sample. They are not used for statistical analysis because the scale units are unequal. In
the communication domain, for example, performance increases more between the ages of
2 and 3 than between 10 and 11, for example.
VARIABLES IN KVINLAND.XPT


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
75
12.
VARIABLE DESCRIPTION
VNSS Standard score. Standard scores of '<20' are set to 19. Standard scores of
'Above 160' are set to 161.
VNSS_PRORATED Standard score - prorated. For adaptive behavior composite scores,
VNSS_PRORATED not equal to VNSS means that the
standard score was prorated. VNSS_PRORATED equal to VNSS
means the score was not prorated. VNSS_PRORATED is missing
(not applicable) for the adaptive behavior composite. The Vineland
manual describes the rules for prorating on pages 89 and 107.
VNP Percentile rank
VN_AL Adaptive level
VN_AE Age equivalent. VN_AE is computed using methods given on p. 101 of 
the Vineland manual (median used only if one or more
subdomain age equivalents are below 0-1 and above 18-11).
VNSCORE Raw score. For domain totals (VNEXAMC=100) VNSCORE is the
raw score total for that domain. The raw score total is
undefined for adaptive behavior composite
Records for domain and ADAPTIVE BEHAVIOR COMPOSITE results are derived.
These records are identified as follows:
VNEXAMC=100: domain scores
VNEXAMC=101: adaptive behavior composite scores
Composite score
The composite score will be the sum of 4 standardized domain scores. If a subject has only 3 
domains, then the standardized score for the missing domain will be prorated and the composite
score will be calculated as sum of 4 domains. If a subject has less than 3 domains, then the composite
score will not be calculated.
SAS code:
/* Program: vineland.sas
Author:
Dr.
, University of Texas
Date:
18-S
Purpose: The program implements the 1984 Vineland scale analyses from the
Vineland Interview Edition) to calculate standard score,
age-equivalence, the Adaptive Levels for Subdomains and Domains and
Adaptive Behavior Composite, and percentile ranks
for Domains and Adaptive Behavior Composite to Johnson & Johnson
Pharmaceutical Research & Development, L.L.C. (J&J PRD)
for use in analyzing Vineland data in any J&JPRD study.
Vineland variables:
PPD
PPD


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
76
The output dataset contains all variables in the input dataset.
In
addition, the following variables are created:
- VNSS:
standard score
- VN_AL:
adaptive level
- VN_AE:
age equivalent.
- VNSS_PRORATED:
standard score - prorated.
For adaptive behavior
composite scores, VNSS_PRORATED ^= VNSS means the score was
prorated, and VNSS_PRORATED = VNSS means the score was
not prorated.
VNSS_PRORATED is missing (not applicable) for
the adaptive behavior composite.
- VNP:
percentile rank
- VNSCORE:
raw score.
For domain totals (VNEXAMC=100) VNSCORE is
the raw score total for that domain. The raw score total is
undefined for adaptive behavior composite
Records Created:
The program adds records for domain and ADAPTIVE BEHAVIOR COMPOSITE
results.
The records are identified as follows:
- VNEXAMC=100:
domain scores
- VNEXAMC=101:
adaptive behavior composite scores
Supporting Data Files:
The program expects the seven lookup data sets to be associated with a SAS
libname of "NORMDATA".
These datasets are:
- vineland_table1.sas7bdat
- vineland_table2.sas7bdat
- vineland_table5_2.sas7bdat
- vineland_table6.sas7bdat
- vineland_table8.sas7bdat
- vineland_table10.sas7bdat
- vineland_table11.sas7bdat
Notes:
- Standard scores of '<20' are set to 19.
- Standard scores of 'Above 160' are set to 161.
- The program assumes that the combination of SUBJECT and VNDT uniquely
identify each record.
- VN_AE is computed using methods given on p. 101 of the Vineland manual
(median used only if one or more subdomain age
equivalents are below 0-1 and above 18-11).
Modified: M. Todd 21-Sep-2007 - added header block and macro parameters
(INDATA and OUTDATA).
*/
%macro vineland(indata=,
outdata=);
%let sortby=SUBJECT VNDT VNMAINC VNSEQ;
datavineland_1(index=(complex=(&sortby))); length
vnmain $40; set
&indata(rename=(vnscore=_vnscore));
length vnscore 3; vnscore=left(_vnscore);
drop _vnscore; run;
proc means data=vineland_1 noprint nway;


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
77
class SUBJECT VNDT VNMAIN VNMAINC agevisit; var
vnscore;
output out=vineland_2 n=n_within_domain sum=vnscore;
where vnexam ne "DON'T KNOW" and VNSCORE NE . and agevisit ne .; run;
proc sort data=vineland_1 out=vineland_dk_too_high(keep=subject vndt vnmain);
by subject vndt vnmain;
where vnexam="DON'T KNOW" and VNSCORE>=5;
run;
data vineland_3; merge
vineland_2
vineland_dk_too_high(in=indk);
by subject vndt vnmain;
if indk then delete;
if (vnmain in ('COMMUNICATION' 'DAILY LIVING SKILLS' 'SOCIALIZATION') and
n_within_domain=3) or
(vnmain='MOTOR SKILLS' and n_within_domain=2);
drop _:;
run;
proc sql noprint;
create table vineland_4 as
select a.*,b.standscore as vnss
from vineland_3 a left join
normdata.vineland_table1 b
on b.agemin<=agevisit<=b.agemax and a.vnscore=b.raw and a.vnmain=b.domain
order by subject,vndt,vnmainc;
quit;
proc means data=vineland_4 noprint nway;
class subject vndt agevisit;
var vnss;
output out=vineland_5(drop=_:) n=n_domains sum=sum_ss_across_domains;
run;
data vineland_5a; set
vineland_5;
if (n_domains=3 and 0<=agevisit<=71) or (n_domains=2 and agevisit>71) and
sum_ss_across_domains ne . then
prorated_flag='X';
run;
proc sql noprint;
create table vineland_5b as
select a.*,case when prorated_flag='X' and n_domains=3 then
prorated_sum_for_4_domains
when prorated_flag='X' and n_domains=2 then
prorated_sum_for_3_domains
else . end as prorated_sum from
vineland_5a a left join
normdata.vineland_table5_2b
on
a.sum_ss_across_domains=b.actual;
quit;
data vineland_5c; set
vineland_5b;
if prorated_sum ne . then do;
sum_ss_across_domains=prorated_sum;
n_domains=n_domains+1;
end;
drop prorated_sum; run;


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
78
proc sql noprint;
create table vineland_6 as
select a.*,b.domain as vnmain,b.ss as vnss
from vineland_5c a left join
normdata.vineland_table2 b
on b.ndomain=a.n_domains and b.minsum<=a.sum_ss_across_domains<=b.maxSUM
where (n_domains=4 and 0<=agevisit<=71) or (n_domains=3 and agevisit>71)
order by subject,vndt; quit;
proc sort data=vineland_1 out=vnunique nodupkey; by
subject vndt;
run;
data combined1;
merge vineland_4(in=ins keep=subject vndt vnmain vnmainc vnss vnscore)
vnunique(drop=vnmain vnmainc vnscore);
by subject vndt; if
ins; vnexamc=100;
vnseq=vnmainc+1-.001;
vnexam=vnmain;
run;
data combined2;
merge vineland_6(in=ins keep=subject vndt vnmain vnss prorated_flag)
vnunique(drop=vnmain);
by subject vndt; if
ins; vnexam=vnmain;
vnmainc=5;
vnexamc=101;
vnseq=5.1;
vnscore=.;
run;
data combined3;
set vineland_1
combined1
combined2;
run;
proc sql noprint;
create table vineland_7 as
select a.*,b.adaptive_level as vn_al,c.adaptive_level as vn_al2,d.ae as
vn_ae,e.ae as vn_ae2
from combined3 a left
join
normdata.vineland_table6 b
on b.domain=a.vnmain and b.subdomain=a.vnexam and
b.agemin<=a.agevisit<=b.agemax
and
b.minraw<=a.vnss<=b.maxraw
left join normdata.vineland_table8
c
on c.domain=a.vnmain and c.subdomain=a.vnexam and
c.agemin<=a.agevisit<=c.agemax
and
c.minraw<=a.vnscore<=c.maxraw
left join normdata.vineland_table10
d
on a.vnmain=d.domain and a.vnexam=d.domain and a.vnscore=d.raw left
join
normdata.vineland_table11e
on a.vnmain=e.domain and a.vnexam=e.subdomain and a.vnscore=e.raw
order by subject,vndt,vnmainc,vnseq;


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
79
quit;
data &outdata;
set vineland_7; by
subject vndt;
length _avg_method $6;
retain _ae1 _ae2 _ae3 _ae4 _avg_method;
if first.vndt then do;
_ae1=.; _ae2=.; _ae3=.; _ae4=.; _avg_method='MEAN'; _count=1;
end;
array ae(4) _ae1 _ae2 _ae3 _ae4;
length vnss_prorated 3 ;
if vn_ae2 ne '' then vn_ae=vn_ae2;
if vn_al2 ne '' then vn_al=vn_al2;
if vnmain=vnexam and vnmain ne 'ADAPTIVE BEHAVIOR COMPOSITE' then do;
if vn_ae ne '' then do;
if index(vn_ae,'>') or index(vn_ae,'<') then do;
_avg_method='MEDIAN';
if index(vn_ae,'>') then ae(_count)=228;
else ae(_count)=.1;
end;
else do;
ae(_count)=12*scan(vn_ae,1,'-')+scan(vn_ae,2,'-');
end;
_count+1;
end;
end;
if vnmain='ADAPTIVE BEHAVIOR COMPOSITE' then do;
vnss_prorated=vnss;
if prorated_flag='X' then vnss=.;
if _avg_method='MEAN' then _ae_avg=round(mean(of _ae1-_ae4));
else _ae_avg=median(of _ae1-_ae4);
if _ae_avg=.1 then vn_ae='<0-1';
else
vn_ae=cats(int(_ae_avg/12),'-',int(mod(_ae_avg,12)));
end;
_ss=vnss;
if vnss=. then _ss=vnss_prorated;
if _ss ne . then vnp=probnorm((_ss-100)/15);
if
52<=_ss<=61 or 139<=_ss<=148 then vnp=round(vnp,.001);
else if 62<=_ss<=138 then vnp=round(vnp,.01);
format vnp percent7.1;
label vnss='VINELAND Standard Score'
vnss_prorated='VINELAND Standard Score - Prorated'
vn_ae='VINELAND Age Equivalent'
vnp
='VINELAND Percentile'
vn_al='VINELAND Adaptive Level';
drop vn_ae2 vn_al2 prorated_flag _:;
run;
proc sql noprint;
drop table
COMBINED1, COMBINED2, COMBINED3, VINELAND_1, VINELAND_2,
VINELAND_3, VINELAND_4, VINELAND_5,


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
80
VINELAND_5A, VINELAND_5B, VINELAND_5C, VINELAND_6, VINELAND_7,
VINELAND_DK_TOO_HIGH,
VNUNIQUE;
quit;
%mend vineland;


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Applyin U.S.
81
Status: Approved, Date: 08 June 2020
Appendix 5: CBCL scoring instruction


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
82
Status: Approved, Date: 08 June 2020
IV-B..Mean job quality. Compute as specified in 1-B.
Total score for Activities Scale. Sum the 6 scores just entered for the items of the Activities scale. If
missing data prevent computation of 1 score, substitute the mean of the other 5 scores for the missing score
in computing the total. Ifitem I-B, II-B, or IV-B is missing and the mean of the other 5 scores exceeds 2.0,
round it down to 2.0. Round off total to nearest .5.
SOCIAL
SCALE
Do not score if data.are missing for more than 1 of the 6 scores.
III-A. # of organizations.
If respondent checked box for None-enter 0 below profile
If respondent reported: 1-enter 1below profile
2-enter 2 below profile
3 or more--enter 3 below profile
IIl-B. Mean of participation in organizations. Compute as specified in I-B.
V-1.#offriends.
If respondent checked box for None-enter 0 below profile
I-enter 1below profile
2 or 3-enter 2 below profile
4 or more-enter 3 below profile
V-2. Contacts with friends. (Item V-2 can be scored 1or 2 even if no close friends were reported in
item V-1.)
·
If respondent checked less than I-enter 0 below profile
Ior2-enter 1below profile
3 or more-enter 2 below profile
VI-A. Behavior with others (items a,.b, & c).
If the respondent checked worse-score 0
. average-score I
better-score 2
Excluding any items for which the respondent did not check a box, compute the mean of these scores and
enter-itbelow the profile.
VI-B. Does things alone (item d).
If the respondent checked worse-enter 0 below profile
. <1verage---enter 1below profile .
better-enter 2 below profile


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
83
Status: Approved, Date: 08 June 2020
Total score.for Social Scale. Sum the 6 scoresjust entered for the items of the Social scale. Ifinissing data
prevent computation of 1 score, substitute the mean of the other 5 scores for the missing score in comput-
ing the total. If item 111-B, V-2, VI-A, or VI-B is missing and the mean of the other 5 scores.exceeds 2.0,
round it down to 2.0. Round off total to nearest .5.
CBCL SCHOOL SCALE
Do not score if the child does not attend school or if data are missing for any of the 4 scores indicated
below for items VII-1 through VII-4, which appear on Page 2 of the CBCL and on the School scale of the
profile scoring form.
VII-1. Academic performance. For each academic subject checked by respondent:
failing- score 0
below average-score 1
average-score 2
above average-score 3
Enter the mean of these scores on the profile. (Academic subjects include reading, writing, arithmetic,
spelling, science, English, foreign language, history, social stl1dies, and similar subjects. Do not count
physical education, a1i,music, home economics, driver education, industrial arts, typing, or the like.)
VII-2. Special services, special class, or special school.
For any type of remedial special services, class, or school (for retarded, emotionally disturbed,
learning
diability, perceptual-motor handicapped, reading
readiness,
resource
room,
behavior
problems, etc):
-enter 0 below profile
.
not in re1nedial class-enter 1below profile
VII-3. Repeated grade.
If any grades were repeated- enter 0 below profile
no grades repeated- enter 1below profile
VII-4. School problems.
If the respondent entered any school problem that was present in the last 6 mouths but was not
already scored above:
-enter 0 below profile
no problem beside those scored above---enter 1below profile
Total score for School Scale. Sum the 4 scoresjust entered on the School scale of the profile, unless any
score is missing. After computing the total, round off to the nearest .5.
CBCL TOTAL COMPETENCE SCORE
Compute the Total Competence score by summing the total scores for the Activities, Social, and School
scales. Do not compute a Total Competence score if any of these 3 scale scores is inissing. T scores for
Total Competence scores are listed in the box to the right of the profile. Circle the child's Total Competence
score in the column for the child's age. After you circle the child's raw score, look to the right to find the T
score.
YSR ACADEMIC  PERFORMANCE
Compute in the same way·as specified in VII- I for CBCL Academic Performance .
YSR TOTAL COMPETENCE SCORE
Sum the total scores for Activities, Social, and Academic Performance. Do 11oi- ompute a Total Compe-
tence score if any of these 3 scores is missing. ·T scores for Total Competence scores are in the box to the
right of the profile. Circle the youth's Total Competence raw score in the column for the youth's
gender.
After you circle the youth's raw score, look to the right to find the T score.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
84
Status: Approved, Date: 08 June 2020
ScoringtheTRFAcademicPerformance midAdaptiveFunctioning
Item VII. For each academic subject, score the teacher's ratings as follows:
Far below grade = 1
·
Somewhat below grade = 2
At grade level = 3
Somewhat above grade = 4
Far above grade = 5
If a teacher checked two boxes for one subject, use the mean of the two scores assigned to these boxes.
Enter the mean of the teacher 's ratings for all academic subjects beneath the heading Academic Perfor-
mance on the profile. (Academic subjects include reading, writing, aritlnnetic, spelling, science, English,
foreign language, history, social studies, computer programming, etc. Do not count physical education, art,
music, home economics, driver education, industrial art.s,typing, or the like.)
Iten1VIII. For each of the questions 1-4, score the teacher's ratings as follows:
Much less = 1
.S Somewhat less =
2 Slightly less = 3
About ave1·age= 4
Slightly more = 5
Somevhat more = 6
Much more = 7
Enter the score for each rating beneath the appropriate heading on the profile.
Sum of Items VIII. 1-4. Sum the scores for.Items VIII. 1,2, 3, and 4. Enter this sum beneath the appropri-
ate heading on the profile. Do not compute this sum if any of the 4 items is missing.
Scoring the CBCL/6-18,YSR, and TRF Problem Scales
Do not score the problem scales if data are missing for more than 8 items, not counting open-ended items
56h and 113, or YSR socially desirable items 6, 15, 49, 59, 60, 73, 80, 88, 92, 98, 106, 107, 108, 109. If
TRF items 56a-56g were left blank, score them 0.
TRANSFERRING PROBLEM ITEM SCORES TO THE PROFILES
Templates. Templates are available to aid in transferring data from the school-age fonns to the profiles.
Different templates are needed for the CBCL/6-18, YSR, and TRF. To transfer problem item scores onto
the profile, place the Page 3 template on Page 3 of the form. For each problem item, the template indicates
whether the item's score is to be entered on a syndrome scale or on the OT.HER PROBLEMS list of the
profile of empirically based syndromes. The template also indicates the DSMcoriented scale on which to
score each item. Repeat using the Page 4 template pn Page 4 of the form.
Item Seo.res. For each problem item, print the respondent's 0, 1, or 2 response in the appropriate space
beside the item on the profile form. If the respondent circled two numbers for an item, print 1 beside the
item on the profile form. Comments written by the respondent should be used in judging whether items
deserve to be scored, with the following guidelines:
1.
For each problem reported by the respondent , only the item that most specifically de-
scribes the problem should be scored. If the respondent 's comments show that more than


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
85
Status: Approved, Date: 08 June 2020
RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
one item has been scored for a particular problem, or if the respondent wrote in a problem
for item 56h or 113 that is specifically covered elsewhere, score only the most specific
item.
2.
For items on which the respondent noted "used to do this,"score as the respondent scored
it, unless it clearly occurred earlier than the 6 months specified in the instructions for the
CBCL and YSR, or 2 months for the TRF.
3.
When in doubt, score the item the way the respondent scored it, except on the following
items:
CBCL &TRF9.-0bsessions--exclude anything that is clearly 11ot obsessional; e.g., do not score "won't
take no for an answer."
YSR 9. Can't get mind off certain thoughts-On the YSR, this item is 11ot restricted to obsessions. Itcan
include almost anything the youth lists here except problems that are specifically listed elsewhere. Ifthe
youth wrote "sex" for this item, for example, it would be more appropriately scored on Item 96, I think
about sex too much. Ifnot covered by another item, responses that might be considered normal for the
youth's age should be scored the way the youth scored them; e.g., "cars,""girls,""boys."
YSR 40. Hears sounds and 70. Sees things core experiences such as "ringing in ears" and "spots
befo1·eeyes"the waytheyouth scoredthem; donotscoreexperiences while undertheinfluenceofdrugs
or alcohol.
46. Nervous movements-if "can't sit still" or anything entirely covered by item 10 is entered here, score
only item 10.
.
56d. Problems with eyes-do not score "wears glasses," "near-sighted," and other visual problems hav-
ingan organic basis.
·
CBCL &TRF 66. Compulsions--Oo not score noncompulsive behavior; e.g., "keeps hitting brother."
YSR 66. Repeats actions-On the YSR, this item is not restricted to compulsions . It can include almost
anything the youth lists here except problems that are specifically listed elsewhere. Speech repetitions or
stammers, forexample, would bemore appropriately scored on Item 79.Speechproblem.
CBCL 72. Sets fires-score playing with matches or lighter if parent reported it.
77. Sleeps more than most--Oo not s.core "wants to stay in bed,"but score difficulties in waking child.
83. Stores up too many things-do not Score hobby collections, such as stamps, dolls.
84. Strangebehavior and 85. Strange ideas-if what the respondent describes is specifically covered by
anotheritern,scorethen1orespecificiteminstead.
CBCL & YSR 105. Drugs-if alcohol or tobacco are entered here, score item 2 or 99, if they are not
already.scored.
TRF 105. Drugs-if tobacco is entered here, score item 99, if it is not already scored.
113. Additional problems-score only if not specifically covered by another item; if respondent listed
inore than 1"other" item, count only highest toward total problem score. For example, if a respondent


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
scored one additional problem "2" and another additional problem "l,"add 2 to the total problem score.
Syndrome and DSM-Oriented  Scale Scores. To obtain the total raw score for each scale, sum the 1s and
2s you have entered for the scale. The OTHER PROBLEMS do not form a scale, but should be summed to
help in computing the Total Problems score, as described later.
GRAPHIC DISPLAY AND T SCORES
To complete the graphic displays
for
the
syndrome
and
DSM-oriented scales,
circle
the
number
above
each scale that equals the total score obtained for that scale. Be sure to circle the 11umber i11 the co/um11
approp1;iatefor the child's age a11d gende1: Then draw a line to connect the circled numbers. Percentiles
based on the normative sample can be read from the left side of the graphic display. Tscores can be read
from the right side.
INTERNALIZING, EXTERNALIZING,
TOTAL PROBLEMS
Computatio11 of Scores. On the profile of syndrome scales, look to the right of the graphic
display. You
will see a column headed Computatio11s. Under Computatio11s, enter the raw scores that
you
have
ob-
tained for each of the syndrome scales and for the OTHER PROBLEMS as follows:
1.
Enter the scores for the 3leftmost syndrome scales inthe spaces provided .
2   Enter their sum in the box marked I11ter11al (a).
3.
Enter the scores for the 2 rightmost syndrome scales in the spaces provided.
4.
Enter their sum in the box marked External (b).
5.
Enter the total score for the 3 middle syndrome scales and OTHER PROBLEMS in the
spacesprovided.
6.
Ente1·the sum of scores from # 5 in the box marked (c).
7.
Enter the sum of scores from boxes (tt), (b), and (c) in the box marked Totttl.
T Scores. Obtain Tscores for Internalizing, Externalizing, and Total Problems as follows:
1. Look in the appropriate columns of the large box on the right side of the profile forn1.
2.
Inthe appropriate column under the heading Internalizing, circle the raw score that
corresponds to the score you have entered in the box beside Internal.
3.
Look to the right in the I11ternalizi11g column headed Tand circle the Tscore that corre-
sponds to the Internalizing raw score that you have obtained.
4.
Enter this Tscore in the box marked Internal Tunder the Computtttio11s heading.
5.
Look under the Exter11alizi11g and Total Problems headings to obtain T scores-in the
same way as was done for Internalizing; enter the Externalizing  and Totttl Problems T
scores in the appropriate boxes.
Status: Approved, Date: 08 June 2020
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
86


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
c:
30
30
-90
42-43
14-12
12
17
21
21
10
15
19
19
t- --
..i
Gl
7
11
11
CBCL/6-18 PROFILE FOR BOYS -SYNDROME SCALES
Internal/zing
External/zing
ID#
Age: 6-11     12·18
6-11  12-18
6-11   12-18
6-11  12-18
6·11   12-18
6-11  12-18
6·11   12-18
6-11  12-18
T
Age.
lnternalizln11 Externallzina Total Score
6-11 12-18 T 6·11 12-18 T  6-11  12-18 T
_
i::.t     tN   7n
70
1""" 238-240 2·u.?4nff>i
roe
_
662
61   0
1'181:1  i:i::a:o     iA::A
o    9a9a 22'2\?6.-?2 7 22J0·.22
26
26
16
16
22
22
22
22
30
30
29
29
34
34
33
33
36
36
100
DateCBCL filledout:
t:rii::t  1 1::n        ' 07    fi7
R7
7 221-22  2  • 22   7
2S
2S
IS
21
21
21
21
28
28
32
31
32
JS
JS
34
34
<O
°"' 96 AA
AA   •& 1&-22
I    0•
58
•7    95    6S     ••    95 210.•1  20·2    9
20
20
26
26
19
33
33
-95
1'7   55-56  °'
64   · 04 204.'V   tn 2     94
Cll
24
24
23
23
IS
20
20
19
19
19
19
27
27
19
30
31
29
30
32
32
CBCLfilledoutby:
""
"'   93
6'  ' 01 198-203 189-1951 •1
54-55 152-!'i.1. 92 2
?       92 19'Lf07 1
lo2
22
14
18
25
2S
28
29
Cl
22
21
13
18
17
18
ca
2243
24
18
2276
28
31
31
S3      51    9
I
61      91 18 ·192 1fo'.iA2 9i
21
17
18
22
23
18
2S
27
52    4g.50  90      n      60    90 1•1.181; 15•.175 90
0::
20
13
16
22
2243
26
29
29
Computations
40SI."1 446A-478•9••,<.9.•7·5<89888195917.1<71480lm16.135-12688889
i:
is
i
20
12
16
19
IS
17
17
21
21
17
20
22
2S
28
28
ScaleI
47-4R   4.i;,   R7       ci:.  cc c.i:.     7
168 154-1C'7 IA7
19
IS
18
11
12
14
16
19
20
17
16
19
21
24
20
23
27
27
26
26
II
444R-45 424-44'\ J8l.r.: 11''1'L.'>542 "2Y·5 351l11561.11"C7\-I1!R; 12441-41n4.18513•58
18
17
"
13
IS
IS
18
18
17
16
19
22
2S
2S
+Ill
T
42-43  41   .. 49-""  51   .. 14&-150 130.14,1 ..
u
17
16
10
13
12
14
16
17
16
16
18
17
21
,.
24
-80
Internal (a)DD
41      4n    83   47-4"' A04,17'1\-4813 8121'\103.134-14"113"5"--113364rA832
16
12
14
IS
IS
16
20
1Q-40 '"on  R2  4&-46
IS
11
13
14
IS
IS
19
23
23
'1·"'  '7    8f  4344     46     •t 1'7-132 12&-1?0 81
IS
14
10
II
10
13
12
13
14
12
13
14
13
18
22
22
Scale VII
O<"
>A  Rn 41-4? 44-45 80 121·12 121-124 80
'\4      •u ,.,;   79  39-4n
79
11'-1?n 79
14
13
10
12
11
IS
II
12
14
20
20
-75
+VIII
T
2-1.3    1.1.     78 1 1.] 'lA    .41    1R 108-11  111-115 1
o/oile
13
12
12
II
II
10
10
II
9
10
11
16
9
18
18
External (b) D
3-0.31   1·32 71 3&-36 '0-40 77 fn2.101 111   7
29
"" '" JJ.34 37·"' 16 gs.jn1 102-105 7•
8
9
13
14
8
"
ro
21-28  29    7 '"·2
36   " 9().95 97-fiil
15
98
-M- -.J9_ _ i;._ _ _a_ _ _ L_ _A. _
9
5
7
6
-L -
..J--}- --12--13-
-
--H----1t--f.--=
11
15
15
ScaleIV
v
2r;._?J::: 27-'H:I  7' 29-  I'tA.'\5 4 A.A3l9 92-96 7'
" 2•   13 21·
" 
3  7
87-91 7'
9
s
1
6
11
12
6
910
14g
"
22-23   2S   72 2&-2• 'I·" 72  72-77   8
12
93
_ 8_ _ .J8. _ _ 4_  6
_ _ _ _ _ _
6
5
10
---.----lt---=
I ?fi.21 23-24  11 2'.\.'. 4  -30 1 71 i:i::.71    7tu 2  7
VI
18-fQ    0-22 70     22
2R   I 10   i:v::c     7 .7     .,,
7
4
4
_7_ ------------ _JI_
5
9
10
18-••   g   21   2&-27  69  S9.AA    68-7    6
Cl
6
10
+ Other
16·17    17    f;fl          ?ll      23-24  68  57.58   CC:' ]     68
84
9
<cJO
14  -:1r
<-
4
66
18  '""·21  66   54:<5    tfU'J  66
9
10
-60
P1obs
15
1•   67    1•     22     67      S6      64-65   67
0::
.JZ,·p.
17
65  50-53   58-60  6•
iii
E... 69
0
50
2
G-1
2
G-1
s
4
3
G-2
4
3
G-2
-55
-50
Sum (a) +(b)+(c):
T
Tota/ DD
1
17  ' 1
1_'!-r
- 4
· S4
37  58
OTHER
7     55     Q
11  57 ---;y-
I.ANXIOUS/
If. WITHDRAWN!
Ill.SOMATIC
IV. SOCIAL
VII. RULE-BREAKING
VIII.AGGRESSIVE
PROBLEMS
6
R    I " 8
1"   56   32·33     30-32 '6
DEPRESSED
DEPRESSED
COMPLAINTS
PROBLEMS
BEHAVIOR
BEHAVIOR
•
•    52     7
9    1<5  30-31    28·29   55
14.Crlesa lot
29.Fears
30. Fears school
_ 31.Fearsdoing
bad
_ 5.Enjoyslittle
42.Ratherbe
alone
65. Won'ttalk
69. Secretive
_ 417.Nightmares _11.Dependent
_49.Constipated _12.Lonely
_ 51. Feelsdizzy _25. Doesn'tget
54.Overtired
along
_56a.Aches
_27. Jealous
_40.Hearsthings
_46.Twitching
8.Can't
concentrate
_10. Can't sit sllll
2. Drinksalcohol
_ 26.Lacksguilt
28. Breaks rules
39. Bad friends
43. lies, cheats
_ 3.Arguesalot
16.Mean
19. Demands attenllon
_ 20.Destroysownthings
_ 21. Destroysothers'things
6.BM out of toilet
_ 7.Brags
15.Cruel to animals
24.Doesn't eat well
44. Biles nails
44
4    48  jO.?n
3    46   17-18
26-27  S4
24·25   53
22·23   52
20.21   5'
19   <o
11·18  49
Status: Approved, Date: 08 June 2020
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
87
-85
D


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
,.
32. Mustbe
perfect
_7S.Shy,timid
_102.Lacks
_56b. Headaches,
_56e. Nausea
:W.Others outto
- gethlm
58.Picksskin
_ 59.Sexpartspubllc
_13. Confused
_17.Daydreams
63. Prefers older kids
_67.Runsaway
22. Disobedient at home
23. Disobedient at.school
_ 53.Overeating
_55.Overweight
n
n   34
43     1"
14-15   '7
13     46
_ 33.Feelsunloved
energy
_36.Accldent1>rone _ 60.Sexpartstoo
_41. lmpulslve
_ 56h.Otherphysical
34    12-13    11·12  45
35. Feels
_103.Sad
_56d.  Eyeprobs.
_38. Gels teased
much
72. Sets fires
Sax problems
_ 37. GetsInfights
_57.Attackspeople
problems
33  II
9I"   ',-,'
_45.NelwVoOrtUhlSess
_111.Withdrawn
_56e. Skinprobs.
_56f. Stomach
_48. Not liked
_ 66. Repeatsacts
schoolwork
_73.
81. Stealsat home
68. Screams a lot
74.Shows off
10
8      42
50.Fearful
_52.Feelstoo
guilty
71. Self·
conscious
Tolaf
_56g. Vomiting
Totaf
_62. Clumsy
_ 70. Seesthings
_64.Prefers
_76.Sleepslass
younger kids
_ 83.Storesthings
_79.Speechprob. _84.Strangebehavior
Total
_ 85. StrangeIdeas
_78. lnaHenllve
_80.Stares
Total
82. Steals outside horn•
_ 90.Swearing
96.Thinks of sax
loomuch
99.Uses tobacco
_ 86.Stubborn,sullen
_ 87. Moodchanges
88.Sulks
_ 89.Suspicious
94.Teasesalot
_ 77.Sleepsmore
93.Talks too much
_ 98.Thumbsucklng
_107. Wets salf (day)
_108.Wetsthebad
1"
19
s   -,.
4
37
36
, 34
_91.Tatksof
suicide
_112.Worries
Total
Copyright 2001 T. Achenbach
ASEBA,University of Vermont
1 South Prospect St..Bur1ington, VT 05401-3456
Web: www.ASEBA.org
UNAUTHORIZEDCOPYINGISILLEGAL
_ 92. Sleeptalks/walks
_100.Troublesleeping
Total
Brokenlines=borderlineclinicalrange
_101.Truant
_105.Uses drugs
_106.Vandalism
Total
_ 95.Temper
97.Threatensothers
104. oud
Total
_109.Whining
110.Wishes to be
- os)posllesex
_113.Other problems
Tolal
6·1-01 Edition-202
2
JI
I 27
26
n
n
24
Status: Approved, Date: 08 June 2020
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
88
_61.Poor
I
40
44
16


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
89
Appendix 6:Method for computing height velocity values and z-scores for individual subjects
For each subject, a height velocity value will be assigned to each calendar year according to
the following algorithm:
Notations:
AB = age at baseline height measurement (Months)
A1 = age at measurements assigned to years 1 (months)
HB = height at baseline (cm)
H1 = height at measurements assigned to years 1 (cm)
HV1 = height velocityat measurements assigned to years 1 (cm/year); computed only if
the corresponding year was assigned a non-missing height.
Note: HB and AB are required to be non-missing for all subjects included in the height
velocity analysis
Year
Time Interval
(months)
Assigned height value
(cm)
Assigned height velocity value
(cm/year)
1
[AB, AB+12
)
H1 = height value closest
to the upper limit of the 
time interval
If H1 is non-missing,
HV1=12*(H1-HB)/(A1-AB)
If H1 is missing then HV1 is 
missing
For each non-missing height velocity value assigned to a year, the z-score will be computed as
Year
Z-score
1
If HV1 is non-missing,
Z1 = (HV1 – Mean at mid-point age in years MA1)/Standard deviation at age
MA1) , where
the mid-point age in years MA1 = ( (A1+AB)/2)/12 = (A1+AB)/24 (rounded to
closest first decimal)
and
the mean (same as 50th percentile) and standard deviation (SD) will be read
from the following tables with height velocitynormative data for the
corresponding gender and mid-point age in years MA1
If HV1 is missing then Z1 is missing
Height Velocity Normative Data Based on Tanner et al[6]
Notes:
The 3rd, 50th and 97th percentiles are interpolated from the height velocity charts from Tanner et


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
90
al[6] for the average maturing children. These percentiles were provided by Dr. Paul Boepple,
who used them in his previous research.
Mean and standard deviation (SD) derived based on the normal (and therefore symmetrical)
distribution assumption:
Mean = 50th percentile
SD = [(50th percentile – 3rd percentile) + (97th percentile – 50th percentile)]/2*1.88
The 2.5 years mean and SD is applied for all subjects with age 2 - 2.5 years. For girls, the 15.5
years mean is applied for subjects with age >15.5 years, the 14.5 years SD is applied for subjects
age >14.5 years; For boys, the 17.5 years mean and SD is applied for all subjects with age > 17.5
years. The values carried forward have been filled up to age 18.5 years for both boys and girls.


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
91
Girls:
AGE 
(YEARS)
50th
percentile
/ Mean
3rd 
percentile
97th
percentile
Derived
SD
2.5
8.6
5.9
11.3
1.4
2.6
8.5
5.8
11.2
1.4
2.7
8.4
5.7
11.0
1.4
2.8
8.3
5.7
10.9
1.4
2.9
8.2
5.6
10.7
1.4
3.0
8.1
5.5
10.6
1.4
3.1
8.0
5.4
10.5
1.3
3.2
7.9
5.4
10.3
1.3
3.3
7.8
5.3
10.2
1.3
3.4
7.7
5.3
10.0
1.3
3.5
7.6
5.2
9.9
1.3
3.6
7.5
5.1
9.8
1.2
3.7
7.4
5.1
9.7
1.2
3.8
7.4
5.0
9.5
1.2
3.9
7.3
5.0
9.4
1.2
4.0
7.2
4.9
9.3
1.2
4.1
7.1
4.9
9.2
1.2
4.2
7.0
4.8
9.2
1.2
4.3
7.0
4.8
9.1
1.2
4.4
6.9
4.7
9.1
1.1
4.5
6.8
4.7
9.0
1.1
4.6
6.8
4.7
8.9
1.1
4.7
6.7
4.7
8.8
1.1
4.8
6.7
4.6
8.8
1.1
4.9
6.6
4.6
8.7
1.1
5.0
6.6
4.6
8.6
1.1
5.1
6.6
4.6
8.5
1.1
5.2
6.5
4.6
8.5
1.0
5.3
6.5
4.5
8.4
1.0
5.4
6.4
4.5
8.4
1.0
5.5
6.4
4.5
8.3
1.0
5.6
6.4
4.5
8.2
1.0
5.7
6.3
4.5
8.2
1.0
5.8
6.3
4.4
8.1
1.0
5.9
6.2
4.4
8.1
1.0
6.0
6.2
4.4
8.0
1.0
6.1
6.2
4.4
8.0
1.0
6.2
6.2
4.4
7.9
0.9
6.3
6.1
4.3
7.9
0.9
6.4
6.1
4.3
7.8
0.9
6.5
6.1
4.3
7.8
0.9


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
92
AGE 
(YEARS)
50th
percentile
/ Mean
3rd 
percentile
97th
percentile
Derived
SD
6.6
6.1
4.3
7.8
0.9
6.7
6.1
4.3
7.7
0.9
6.8
6.0
4.3
7.7
0.9
6.9
6.0
4.3
7.6
0.9
7.0
6.0
4.3
7.6
0.9
7.1
6.0
4.3
7.6
0.9
7.2
6.0
4.3
7.6
0.9
7.3
5.9
4.3
7.5
0.9
7.4
5.9
4.3
7.5
0.9
7.5
5.9
4.3
7.5
0.9
7.6
5.9
4.3
7.5
0.9
7.7
5.9
4.3
7.5
0.9
7.8
5.8
4.2
7.4
0.9
7.9
5.8
4.2
7.4
0.9
8.0
5.8
4.2
7.4
0.9
8.1
5.8
4.2
7.4
0.8
8.2
5.8
4.2
7.4
0.8
8.3
5.7
4.2
7.3
0.8
8.4
5.7
4.2
7.3
0.8
8.5
5.7
4.2
7.3
0.8
8.6
5.7
4.2
7.3
0.8
8.7
5.7
4.2
7.3
0.8
8.8
5.7
4.2
7.3
0.8
8.9
5.7
4.2
7.3
0.8
9.0
5.7
4.2
7.3
0.8
9.1
5.7
4.2
7.3
0.8
9.2
5.7
4.2
7.3
0.8
9.3
5.8
4.3
7.4
0.8
9.4
5.8
4.3
7.4
0.8
9.5
5.8
4.3
7.4
0.8
9.6
5.9
4.3
7.5
0.9
9.7
6.0
4.3
7.6
0.9
9.8
6.0
4.4
7.8
0.9
9.9
6.1
4.4
7.9
0.9
10.0
6.2
4.4
8.0
1.0
10.1
6.3
4.5
8.1
1.0
10.2
6.4
4.5
8.3
1.0
10.3
6.5
4.6
8.4
1.0
10.4
6.6
4.6
8.6
1.0
10.5
6.7
4.7
8.7
1.1
10.6
6.9
4.9
8.9
1.1
10.7
7.1
5.1
9.1
1.1
10.8
7.4
5.3
9.3
1.1
10.9
7.6
5.5
9.5
1.1
11.0
7.8
5.7
9.7
1.1


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
93
AGE 
(YEARS)
50th
percentile
/ Mean
3rd 
percentile
97th
percentile
Derived
SD
11.1
7.9
5.8
9.8
1.1
11.2
8.0
5.9
10.0
1.1
11.3
8.1
5.9
10.1
1.1
11.4
8.2
6.0
10.3
1.1
11.5
8.3
6.1
10.4
1.1
11.6
8.1
5.9
10.2
1.2
11.7
7.9
5.7
10.1
1.2
11.8
7.7
5.5
9.9
1.2
11.9
7.5
5.3
9.8
1.2
12.0
7.3
5.1
9.6
1.2
12.1
7.0
4.8
9.3
1.2
12.2
6.7
4.5
9.0
1.2
12.3
6.5
4.2
8.6
1.2
12.4
6.2
3.9
8.3
1.2
12.5
5.9
3.6
8.0
1.2
12.6
5.6
3.3
7.7
1.1
12.7
5.3
3.1
7.3
1.1
12.8
4.9
2.8
7.0
1.1
12.9
4.6
2.6
6.6
1.1
13.0
4.3
2.3
6.3
1.1
13.1
4.0
2.1
6.0
1.0
13.2
3.8
1.9
5.7
1.0
13.3
3.5
1.6
5.4
1.0
13.4
3.3
1.4
5.1
1.0
13.5
3.0
1.2
4.8
1.0
13.6
2.8
1.0
4.5
0.9
13.7
2.5
0.9
4.2
0.9
13.8
2.3
0.7
3.8
0.8
13.9
2.0
0.6
3.5
0.8
14.0
1.8
0.4
3.2
0.7
14.1
1.6
2.9
0.7
14.2
1.4
2.6
0.6
14.3
1.3
2.4
0.6
14.4
1.1
2.1
0.5
14.5
0.9
1.8
0.5
14.6
0.8
0.5
14.7
0.7
0.5
14.8
0.6
0.5
14.9
0.5
0.5
15.0
0.4
0.5
15.1
0.3
0.5
15.2
0.3
0.5
15.3
0.2
0.5
15.4
0.2
0.5
15.5
0.1
0.5


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
94
AGE
50th
3rd 
percentile
97th
percentile
Derived
SD
percentile
(YEARS)
/ Mean
15.6
0.1
0.5
15.7
0.1
0.5
15.8
0.1
0.5
15.9
0.1
0.5
16.0
0.1
0.5
16.1
0.1
0.5
16.2
0.1
0.5
16.3
0.1
0.5
16.4
0.1
0.5
16.5
0.1
0.5
16.6
0.1
0.5
16.7
0.1
0.5
16.8
0.1
0.5
16.9
0.1
0.5
17.0
0.1
0.5
17.1
0.1
0.5
17.2
0.1
0.5
17.3
0.1
0.5
17.4
0.1
0.5
17.5
0.1
0.5
17.6
0.1
0.5
17.7
0.1
0.5
17.8
0.1
0.5
17.9
0.1
0.5
18.0
0.1
0.5
18.1
0.1
0.5
18.2
0.1
0.5
18.3
0.1
0.5
18.4
0.1
0.5
18.5
0.1
0.5
Boys:
AGE
50th
3rd 
percentile
97th
percentile
Derived
SD
percentile
(YEARS)
/ Mean
2.5
8.3
5.7
10.9
1.4
2.6
8.2
5.6
10.8
1.4
2.7
8.1
5.6
10.6
1.3


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
95
AGE 
(YEARS)
50th
percentile
/ Mean
3rd 
percentile
97th
percentile
Derived
SD
2.8
8.0
5.5
10.5
1.3
2.9
7.9
5.5
10.3
1.3
3.0
7.8
5.4
10.2
1.3
3.1
7.7
5.3
10.1
1.3
3.2
7.6
5.3
10.0
1.2
3.3
7.6
5.2
9.8
1.2
3.4
7.5
5.2
9.7
1.2
3.5
7.4
5.1
9.6
1.2
3.6
7.3
5.1
9.5
1.2
3.7
7.3
5.0
9.4
1.2
3.8
7.2
5.0
9.4
1.2
3.9
7.2
4.9
9.3
1.2
4.0
7.1
4.9
9.2
1.1
4.1
7.0
4.9
9.1
1.1
4.2
7.0
4.8
9.0
1.1
4.3
6.9
4.8
9.0
1.1
4.4
6.9
4.7
8.9
1.1
4.5
6.8
4.7
8.8
1.1
4.6
6.8
4.7
8.8
1.1
4.7
6.7
4.7
8.7
1.1
4.8
6.7
4.6
8.7
1.1
4.9
6.6
4.6
8.6
1.1
5.0
6.6
4.6
8.6
1.1
5.1
6.6
4.6
8.5
1.1
5.2
6.5
4.6
8.5
1.0
5.3
6.5
4.5
8.4
1.0
5.4
6.4
4.5
8.4
1.0
5.5
6.4
4.5
8.3
1.0
5.6
6.4
4.5
8.3
1.0
5.7
6.3
4.4
8.2
1.0
5.8
6.3
4.4
8.2
1.0
5.9
6.2
4.3
8.1
1.0
6.0
6.2
4.3
8.1
1.0
6.1
6.2
4.3
8.0
1.0
6.2
6.1
4.3
8.0
1.0
6.3
6.1
4.2
7.9
1.0
6.4
6.0
4.2
7.9
1.0
6.5
6.0
4.2
7.8
1.0
6.6
6.0
4.2
7.8
1.0
6.7
6.0
4.2
7.8
0.9
6.8
5.9
4.2
7.7
0.9
6.9
5.9
4.2
7.7
0.9
7.0
5.9
4.2
7.7
0.9
7.1
5.9
4.2
7.7
0.9
7.2
5.9
4.2
7.6
0.9


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
96
AGE 
(YEARS)
50th
percentile
/ Mean
3rd 
percentile
97th
percentile
Derived
SD
7.3
5.8
4.1
7.6
0.9
7.4
5.8
4.1
7.5
0.9
7.5
5.8
4.1
7.5
0.9
7.6
5.8
4.1
7.4
0.9
7.7
5.7
4.0
7.4
0.9
7.8
5.7
4.0
7.3
0.9
7.9
5.6
3.9
7.3
0.9
8.0
5.6
3.9
7.2
0.9
8.1
5.6
3.9
7.2
0.9
8.2
5.5
3.9
7.1
0.9
8.3
5.5
3.8
7.1
0.9
8.4
5.4
3.8
7.0
0.9
8.5
5.4
3.8
7.0
0.9
8.6
5.4
3.8
7.0
0.8
8.7
5.4
3.8
6.9
0.8
8.8
5.3
3.8
6.9
0.8
8.9
5.3
3.8
6.8
0.8
9.0
5.3
3.8
6.8
0.8
9.1
5.3
3.8
6.8
0.8
9.2
5.3
3.8
6.8
0.8
9.3
5.2
3.7
6.7
0.8
9.4
5.2
3.7
6.7
0.8
9.5
5.2
3.7
6.7
0.8
9.6
5.2
3.7
6.7
0.8
9.7
5.2
3.7
6.6
0.8
9.8
5.1
3.7
6.6
0.8
9.9
5.1
3.7
6.5
0.8
10.0
5.1
3.7
6.5
0.7
10.1
5.1
3.7
6.5
0.7
10.2
5.1
3.7
6.5
0.7
10.3
5.1
3.7
6.5
0.7
10.4
5.1
3.7
6.5
0.7
10.5
5.1
3.7
6.5
0.7
10.6
5.1
3.7
6.5
0.8
10.7
5.1
3.7
6.5
0.8
10.8
5.2
3.7
6.6
0.8
10.9
5.2
3.7
6.6
0.8
11.0
5.2
3.7
6.6
0.8
11.1
5.2
3.7
6.6
0.8
11.2
5.2
3.7
6.6
0.8
11.3
5.3
3.8
6.7
0.8
11.4
5.3
3.8
6.7
0.8
11.5
5.3
3.8
6.7
0.8
11.6
5.4
3.8
6.8
0.8
11.7
5.5
3.9
6.9
0.8


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
97
AGE 
(YEARS)
50th
percentile
/ Mean
3rd 
percentile
97th
percentile
Derived
SD
11.8
5.5
3.9
7.1
0.8
11.9
5.6
4.0
7.2
0.9
12.0
5.7
4.0
7.3
0.9
12.1
5.9
4.2
7.6
0.9
12.2
6.1
4.3
8.0
1.0
12.3
6.4
4.5
8.3
1.0
12.4
6.6
4.6
8.7
1.1
12.5
6.8
4.8
9.0
1.1
12.6
7.2
5.1
9.4
1.2
12.7
7.6
5.3
9.9
1.2
12.8
7.9
5.6
10.3
1.3
12.9
8.3
5.8
10.8
1.3
13.0
8.7
6.1
11.2
1.4
13.1
8.9
6.3
11.3
1.3
13.2
9.0
6.5
11.5
1.3
13.3
9.2
6.7
11.6
1.3
13.4
9.3
6.9
11.8
1.3
13.5
9.5
7.1
11.9
1.3
13.6
9.3
6.9
11.7
1.3
13.7
9.0
6.7
11.5
1.3
13.8
8.8
6.4
11.2
1.3
13.9
8.5
6.2
11.0
1.3
14.0
8.3
6.0
10.8
1.3
14.1
7.9
5.6
10.4
1.3
14.2
7.6
5.2
10.0
1.3
14.3
7.2
4.9
9.6
1.3
14.4
6.9
4.5
9.2
1.3
14.5
6.5
4.1
8.8
1.3
14.6
6.1
3.7
8.4
1.3
14.7
5.8
3.4
8.1
1.3
14.8
5.4
3.0
7.7
1.3
14.9
5.1
2.7
7.4
1.3
15.0
4.7
2.3
7.0
1.3
15.1
4.4
2.1
6.7
1.2
15.2
4.1
1.9
6.4
1.2
15.3
3.9
1.6
6.1
1.2
15.4
3.6
1.4
5.8
1.2
15.5
3.3
1.2
5.5
1.1
15.6
3.1
1.0
5.2
1.1
15.7
2.9
0.9
4.9
1.1
15.8
2.6
0.7
4.7
1.0
15.9
2.4
0.6
4.4
1.0
16.0
2.2
0.4
4.1
1.0
16.1
2.1
3.9
1.0
16.2
1.9
3.7
0.9


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
98
AGE
50th
3rd 
percentile
97th
percentile
Derived
SD
percentile
(YEARS)
/ Mean
16.3
1.8
3.4
0.9
16.4
1.6
3.2
0.8
16.5
1.5
3.0
0.8
16.6
1.4
2.8
0.8
16.7
1.3
2.7
0.8
16.8
1.1
2.5
0.7
16.9
1.0
2.4
0.7
17.0
0.9
2.2
0.7
17.1
0.8
2.1
0.7
17.2
0.7
2.0
0.6
17.3
0.7
1.8
0.6
17.4
0.6
1.7
0.6
17.5
0.5
1.6
0.6
17.6
0.5
0.6
17.7
0.5
0.6
17.8
0.5
0.6
17.9
0.5
0.6
18.0
0.5
0.6
18.1
0.5
0.6
18.2
0.5
0.6
18.3
0.5
0.6
18.4
0.5
0.6
18.5
0.5
0.6


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
99
Appendix 7: List of generic and brand names of AED medications
Generic names
Acetazolamide
Cannabidiol
Carbamazepine
Clobazam
Clonazepam
Diazepam
Eslicarbazepine
acetate Ethosuximide
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Nitrazepam
Oxcarbazepine
Perampanel
Piracetam
Phenobarbital
Phenytoin
Pregabalin
Primidone
Retigabine
Rufinamide
Sodium 
valproate
Stiripentol
Tiagabine
Topiramate
Valproic acid
Vigabatrin
Zonisamide
Brand names (available as):
Carbogen modified release
Convulex
Desitrend
Diacomit


RWJ-17021-000 (topiramate)
StatisticalAnalysisPlanTOPMATEPY4067
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
Status: Approved, Date: 08 June 2020
100
Diamox SR
Emeside
Epanutin
Epidiolex
Epilim
Epilim Chrono
Epilim Chronosphere
Episenta (prolonged
release) Epival
Frisium
Fycompa
Gabitril
Inovelon 
Keppra
Lamictal
Lyrica
Neurontin
Nootropil
Phenytoin Sodium Flynn
Rivotril
Sabril
Tapclob 
Tegretol
Tegretol Prolonged Release
Topamax
Trileptal 
Trobalt 
Valium
Vimpat
Zarontin 
Zebinix
Zonegran