A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in Pediatric and Young Adult Subjects With Dravet Syndrome (DS)
Phase: PHASE3
Conditions: Dravet Syndrome (DS)
Sponsor: Takeda

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TAKEDA PHARMACEUTICALS
PROTOCOL
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in 
Pediatric and Young Adult Subjects With Dravet Syndrome (DS)
Study of Soticlestat as Adjunctive Therapy in Pediatric and Young Adult Subjects With 
Dravet Syndrome
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
Study Number:
TAK-935-3001
IND Number:
133627
EudraCT Number:
2021-002480-22
Compound:
Soticlestat
Date:
22 April 2022
Version/Amendment 
Number:
Amendment 2
Amendment History:
Date
Amendment Number
Amendment Type
Region
22 April 2022
Amendment 2
Substantial
Global
03 November 2021
Amendment 1 FR-IT-RS v1
Substantial
France, Italy, Serbia
23 March 2021
Initial protocol
Not applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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Study No. TAK-935-3001
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided in the study manual.
Takeda Development Center (TDC)-sponsored investigators per individual country requirements 
will be provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study contact list.
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix D). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix F of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
30
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria No. 9
Allowed fenfluramine and 
cannabidiol (Epidiolex) as 
ASMs where available and 
counted as an ASM (formerly 
No. 8).
Some countries have these 
medications available as 
ASMs.
31
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria, No. 
13
Section 9.1.3 Seizure Identification 
and Diagnostic Review Forms 
(TESC)
Added that TESC review may 
include review of 
electroencephalogram and 
magnetic resonance imaging 
results (if available and 
permitted by local regulations), 
and that sponsor may be 
consulted if needed (formerly 
No. 12).
Makes additional information 
available to TESC.
32
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria No. 14
Clarified allowed contraceptive 
methods (formerly No. 13).
Clarifies that highly effective 
contraception is acceptable, 
in addition to effective 
contraception.
33
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria, No. 
3
Clarified the exclusion around 
participation in other clinical 
studies.
Clarifies that only trials 
related to treatment devices 
are excluded.
34
Section 7.2 Exclusion Criteria, No. 
11
Section 9.1.11.3 Procedures for 
Clinical Laboratory Samples, Table 
9.a
Clarified exclusion based on 
hepatitis history.
Added hepatitis screening to 
clinical laboratory tests.
Clarification.
Correction of omission.
35
Section 7.2 Exclusion Criteria, No. 
14.
Section 7.2 Exclusion Criteria, 
originally No. 15
Section 7.3 Excluded Medications
Section 7.4 Diet, Fluid, Activity 
Control
Appendix B Strong CYP3A
Inducers 
Removed inhibitors of CYP3A 
from the exclusion criteria, 
prohibited medications, and 
from the appendix. Allowed 
topical CYP3A inducers.
Deleted original criterion No. 
15, “Unwilling to withhold the 
fruit and juice of grapefruit, 
Seville oranges, and starfruit 
from their diet during the entire 
clinical trial.”
(Subsequent numbering of 
exclusion criteria shift by -1 
relative to Amendment 1 
FR-IT-RS v1.)
Deleted same prohibition from 
Section 7.4.
Per recent interim PK results 
from a phase 1 study, 
TAK-935-1007, the effect of 
a strong CYP3A4 inhibitor, 
itraconazole, on the PK 
exposure measures of 
soticlestat is small (<25% on 
maximum concentration and 
area under the plasma 
concentration-time curves). 
Therefore, strong CYP3A4 
inhibitors will be allowed in 
the study.
36
Section 8.4 Accountability and 
Allowed drug supplies to be 
destroyed at the site rather than 
Allows flexibility in 
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
throughout protocol.
52
Section 10.1.4 AEs of Special 
Interest
Removed instruction that an AE 
of special interest and clinical 
significance be recorded as a 
serious adverse event (SAE).
Correction.
53
Section 10.2.1.1 AE Collection 
Period
TEAE collection period was 
clarified.
Clarification.
54
Section 10.2.2 Collection and 
Reporting of SAEs
Indicated that contacts for SAE 
reporting are provided in the 
study manual.
Correction.
55
Section 13.2.1.2 mITT Analysis Set
Clarified that the mITT analysis 
set only includes subjects who 
have been assessed for seizures 
during the treatment period.
Clarification.
56
Section 2.0 STUDY SUMMARY
Section 13.2.4 Efficacy Analysis
Section 13.2.6
Exploratory/Additional Analyses
Corrected analysis description, 
including planned statistical 
tests.
Correction.
57
Section 13.3.3 Interim Analyses
Indicated that a blinded interim 
analysis may be performed to 
allow for sample size 
re-estimation.
Corrects inadvertent 
omission.
58
Section 14.1 Study-Site Monitoring 
Visits
With the exception of visits in 
China, monitoring visits can be 
virtual or on site, as indicated in 
the clinical monitoring plan.
Clarification.
59
Appendix H Protocol History
Added history of Amendment 1 
FR-IT-RS v1 to this new 
appendix.
Template requirement.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................19
3.0
STUDY REFERENCE INFORMATION ......................................................................27
3.1
Study-Related Responsibilities.................................................................................27
3.2
Coordinating Investigator.........................................................................................27
3.3
List of Abbreviations ...............................................................................................28
3.4
Corporate Identification...........................................................................................29
4.0
INTRODUCTION.........................................................................................................30
4.1
Background .............................................................................................................30
4.2
Rationale for the Proposed Study.............................................................................31
4.3
Benefit/Risk Profile .................................................................................................31
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................32
5.1
Objectives................................................................................................................32
5.1.1
Primary Objectives ..........................................................................................32
5.1.2
Secondary Objectives ......................................................................................32
5.1.3
Exploratory Objectives ....................................................................................33
5.1.4
Safety Objectives.............................................................................................33
5.2
Endpoints.................................................................................................................34
5.2.1
Primary Endpoints ...........................................................................................34
5.2.2
Secondary Endpoints .......................................................................................34
5.2.3
Exploratory Endpoints .....................................................................................34
5.2.4
Safety Endpoints..............................................................................................35
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................35
6.1
Study Design ...........................................................................................................35
6.1.1
Dose Titration Period (4 Weeks)......................................................................39
6.1.2
Maintenance Period (12 Weeks) ......................................................................39
6.1.3
Study Discontinuation/Completion ..................................................................39
6.1.4
End of Study for Individual Subject .................................................................40
6.1.5
End of Study Overall .......................................................................................40
6.2
Justification for Study Design, Dose, and Endpoints ................................................40
6.2.1
Study Design ...................................................................................................40
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6.2.2
Endpoints ........................................................................................................41
6.2.3
Dose ................................................................................................................41
6.3
Premature Termination or Suspension of Study or Study Site...................................43
6.3.1
Criteria for Premature Termination or Suspension of the Study........................43
6.3.2
Criteria for Premature Termination or Suspension of Study Sites.....................43
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...........................................................................43
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............43
7.1
Inclusion Criteria .....................................................................................................44
7.2
Exclusion Criteria ....................................................................................................47
7.3
Excluded Medications..............................................................................................48
7.4
Diet, Fluid, Activity Control ....................................................................................49
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................49
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................51
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................51
8.1
Study Drug and Materials ........................................................................................51
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................51
8.1.1.1
Study Drug ..............................................................................................51
8.1.1.2
Rescue Medication ..................................................................................52
8.1.2
Storage ............................................................................................................52
8.1.3
Dose and Regimen...........................................................................................52
8.1.4
Overdose .........................................................................................................54
8.2
Study Drug Assignment and Dispensing Procedures................................................54
8.3
Unblinding Procedures.............................................................................................54
8.4
Accountability and Destruction of Study Drugs .......................................................55
9.0
STUDY PLAN ..............................................................................................................56
9.1
Study Procedures.....................................................................................................56
9.1.1
Informed Consent Procedure............................................................................56
9.1.2
Historical Seizure Diary Review......................................................................56
9.1.3
Seizure Identification and Diagnostic Review Forms (TESC) ..........................56
9.1.4
Seizure Frequency ...........................................................................................57
9.1.5
Demographics, Medical History, and Medication History Procedure................58
9.1.6
Height and Weight...........................................................................................58
9.1.7
Concomitant Medications and Nonpharmacologic Therapies and Procedures...58
9.1.8
Vital Sign Procedure........................................................................................58
9.1.9
Physical Examination Procedure......................................................................59
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9.1.10
Neurological Examination Procedure...............................................................59
9.1.11
Safety Evaluations ...........................................................................................59
9.1.11.1
Ophthalmological Evaluation Procedure..................................................60
9.1.11.2
ECG Procedure........................................................................................60
9.1.11.3
Procedures for Clinical Laboratory Samples ............................................61
9.1.12
Documentation of Concomitant (Including ASM and Rescue) Medications .....63
9.1.13
Documentation of Concurrent Medical Conditions...........................................63
9.1.14
Clinical Assessment of Suicidal Ideation and Behavior....................................63
9.1.15
Health Outcome/Quality of Life Measures.......................................................64
9.1.15.1
CGI-I (Clinician) .....................................................................................64
9.1.15.2
Care GI-I (Caregiver) ..............................................................................64
9.1.15.3
CGI-I Seizure Intensity and Duration.......................................................64
9.1.15.4
CGI-I Nonseizure Symptoms...................................................................64
9.1.15.5
QI-Disability (Parent/Caregiver Version).................................................65
9.1.15.6
..............................................................65
9.1.16
Contraception and Pregnancy Avoidance Procedure ........................................65
9.1.16.1
Male Subjects and Their Female Partners ................................................65
9.1.16.2
Female Subjects and Their Male Partners ................................................65
9.1.16.3
General Guidance With Respect to the Avoidance of Pregnancy..............66
9.1.17
Pregnancy........................................................................................................67
9.1.18
Documentation of Screen Failure.....................................................................67
9.1.19
Documentation of Study Entrance....................................................................68
9.2
Monitoring Subject Treatment Compliance..............................................................68
9.3
Safety Monitoring....................................................................................................69
9.3.1
Reporting of Abnormal LFTs...........................................................................69
9.3.2
Reporting of QTcF Interval Increase................................................................69
9.3.3
Reporting of Perampanel Drug-Drug Interaction..............................................70
9.3.4
Reporting of Cataracts .....................................................................................70
9.3.5
...............................................................................70
9.3.5.1
....70
9.3.5.2
.......................................................71
9.3.5.3
.........................................................................................71
9.3.5.4
....................................................................................71
9.4
Biological Sample Retention and Destruction ..........................................................72
9.5
Schedule of Study Procedures..................................................................................72
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9.5.1
Unscheduled Visits..........................................................................................72
9.5.2
Poststudy Care.................................................................................................72
10.0
COLLECTION AND REPORTING OF ADVERSE EVENTS......................................73
10.1
Definitions...............................................................................................................73
10.1.1
AEs .................................................................................................................73
10.1.2
Additional Points to Consider for AEs .............................................................73
10.1.3
SAEs ...............................................................................................................75
10.1.4
AEs of Special Interest.....................................................................................75
10.1.5
Intensity of AEs...............................................................................................76
10.1.6
Causality of AEs..............................................................................................76
10.1.7
Relationship to Study Procedures.....................................................................76
10.1.8
Start Date.........................................................................................................77
10.1.9
Stop Date.........................................................................................................77
10.1.10 Frequency........................................................................................................77
10.1.11 Action Concerning Study Drug........................................................................77
10.1.12 Outcome..........................................................................................................77
10.2
Procedures...............................................................................................................78
10.2.1
Collection and Reporting of AEs .....................................................................78
10.2.1.1
AE Collection Period...............................................................................78
10.2.1.2
AE Reporting...........................................................................................78
10.2.2
Collection and Reporting of SAEs ...................................................................79
10.3
Follow-up of SAEs ..................................................................................................79
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...80
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................80
12.0
DATA HANDLING AND RECORDKEEPING............................................................80
12.1
eCRFs......................................................................................................................80
12.2
Record Retention .....................................................................................................81
13.0
STATISTICAL METHODS..........................................................................................82
13.1
Statistical and Analytical Plans ................................................................................82
13.2
Determination of Sample Size..................................................................................82
13.2.1
Analysis Sets ...................................................................................................82
13.2.1.1
ITT Analysis Set......................................................................................82
13.2.1.2
mITT Analysis Set...................................................................................83
13.2.1.3
Safety Analysis Set..................................................................................83
13.2.2
Analysis of Demographics and Baseline Characteristics...................................83
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13.2.3
Subject Disposition..........................................................................................83
13.2.4
Efficacy Analysis.............................................................................................83
13.2.5
Safety Analysis................................................................................................84
13.2.6
Exploratory/Additional Analyses .....................................................................84
13.3
Other Statistical Issues.............................................................................................85
13.3.1
Significance Levels..........................................................................................85
13.3.2
Missing or Invalid Data ...................................................................................85
13.3.3
Interim Analyses..............................................................................................85
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................85
14.1
Study-Site Monitoring Visits ...................................................................................85
14.2
Protocol Deviations..................................................................................................85
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................86
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................86
15.1
IRB and/or IEC Approval ........................................................................................87
15.2
Subject Information, Informed Consent, and Subject Authorization .........................87
15.3
Subject Confidentiality ............................................................................................88
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................89
15.4.1
Publication and Disclosure...............................................................................89
15.4.2
Clinical Trial Registration................................................................................89
15.4.3
Clinical Trial Results Disclosure......................................................................89
15.5
Insurance and Compensation for Injury....................................................................89
16.0
REFERENCES..............................................................................................................91
LIST OF IN-TEXT TABLES
Table 6.a
Dosing Schedules by Weight, 10 to <15 kg........................................................37
Table 6.b
Dosing Schedules by Weight, 15 to <30 kg........................................................37
Table 6.c
Dosing Schedules by Weight, 30 to <45 kg........................................................38
Table 6.d
Dosing Schedules by Weight, ≥45 kg.................................................................38
Table 9.a
Clinical Laboratory Tests...................................................................................62
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................36
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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................92
Appendix B
Strong CYP3A Inducers.....................................................................................98
Appendix C
Virtual Visits and Trial Management During COVID-19 Pandemic and Other 
Extenuating Circumstances ................................................................................99
Appendix D
Responsibilities of the Investigator...................................................................101
Appendix E
Elements of the Subject Informed Consent.......................................................103
Appendix F
Investigator Consent to Use of Personal Information........................................106
Appendix G 
Blood Volumes ................................................................................................107
Appendix H 
Protocol History...............................................................................................108
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
Soticlestat (also known as TAK-935)
Title of Protocol: A Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy, Safety, and Tolerability of Soticlestat 
as Adjunctive Therapy in Pediatric and Young Adult 
Subjects With Dravet Syndrome (DS) 
IND No.: 133627
EudraCT No.:
2021-002480-22
Study Number: TAK-935-3001 Amendment 2
Phase: 3
Study Design:
This is a phase 3, global, multicenter, 1:1 randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy, safety, and tolerability of soticlestat as an adjunctive therapy in pediatric and young adult 
subjects with DS. The treatment period is 16 weeks. The total duration of the study is approximately 25 weeks for 
subjects who complete the study and choose not to roll over to the open-label extension (OLE) study. For those who 
roll over to the OLE study, the study duration is 3 weeks shorter.
Approximately 142 male and female pediatric and young adult subjects will be randomized.
The study will consist of the following periods:

4- to 6-week screening/baseline period. The minimum visit window for screening is 28 days (ie, Visit 2/Day 0 
cannot occur earlier than 29 days after screening).

16-week full treatment period:
–
4-week titration period.
–
12-week maintenance period.

1-week taper period for those discontinuing study drug, followed by a 2-week safety follow-up visit or a phone 
call.
This is a 2-arm study. All subjects will be randomized at a 1:1 ratio to receive standard of care (SOC) plus one of the 
following adjunctive therapies: soticlestat or placebo.
Soticlestat or matching placebo added to current antiseizure therapy will be administered orally twice daily (BID) with 
or without food or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY button). A jejunostomy tube 
(J-tube) may be considered following written approval by the medical monitor or sponsor. Note: Study drug will be 
administered only orally for subjects enrolled in sites in jurisdictions where alternative means are not permitted.
All doses will be blinded and will undergo the same titration scheme, with the same number and type of 
tablets/mini-tabs. Subjects randomized to placebo will undergo a mock titration to ensure the blind is maintained (see 
tables below).
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The total daily dose of study drug (either placebo or soticlestat) will be calculated based on body weight at Visit 1 
(screening visit) and given BID starting on the morning after Visit 2/Day 0 (ie, on study Day 1) (see tables below). The 
100 mg BID dose (or 100 mg BID equivalent weight-based dosing for weight <45 kg) is the minimum dose allowed 
during the study. Subjects who cannot tolerate the minimal dose will be discontinued from the study. Subjects 
weighing <45 kg will be dispensed 20 mg mini-tablets or matching placebo. Subjects weighing ≥45 kg may be 
dispensed 20 mg mini-tablets or 100 mg tablets or matching placebo.
Dosing Schedules by Weight, 10 to <15 kg
Treatment 
Arm
10 to <15 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
40 mg BID
2 mini tabs 
soticlestat BID
60 mg BID
3 mini tabs 
soticlestat BID
100 mg BID
5 mini tabs 
soticlestat BID
PBO
---
2 mini tabs 
PBO BID
---
3 mini tabs 
PBO BID
---
5 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Dosing Schedules by Weight, 15 to <30 kg
Treatment Arm
15 to <30 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
60 mg BID
3 mini tabs 
soticlestat BID
120 mg BID
6 mini tabs 
soticlestat BID
200 mg BID
10 mini tabs 
soticlestat BID
PBO
---
3 mini tabs 
PBO BID
---
6 mini tabs 
PBO BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Dosing Schedules by Weight, 30 to <45 kg
Treatment Arm
30 to <45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
80 mg BID
4 mini tabs 
soticlestat BID
140 mg BID
7 mini tabs 
soticlestat BID
200 mg BID
10 mini tabs 
soticlestat BID
PBO
---
4 mini tabs 
PBO BID
---
7 mini tabs 
PBO BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
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Dosing Schedules by Weight, ≥45 kg
Treatment Arm
≥45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
100 mg BID
1 tab soticlestat 
BID 
OR
5 mini tabs
soticlestat BID
200 mg BID
2 tabs 
soticlestat BID
OR
10 mini tabs 
soticlestat BID
300 mg BID
3 tabs 
soticlestat BID
OR
15 mini tabs 
soticlestat BID
PBO
---
1 tab PBO BID 
OR
5 mini tabs 
PBO BID
---
2 tabs PBO 
BID
OR
10 mini tabs 
PBO BID
---
3 tabs PBO 
BID
OR
15 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
The study design allows virtual visits if aligned with institutional or local guidelines, via phone or via any platforms 
approved by local regulations, in addition to the communication platform offered through the study. Screening (Visit 
1) and Visit 11 (Day 113)/early termination must be conducted in person; Visit 9 is to be conducted in person if 
possible but may be conducted virtually (via video or phone) in response to the coronavirus disease 2019 (COVID-19) 
pandemic and/or based on sponsor approval and if permitted by local regulations. In extenuating circumstances, the 
randomization visit (Visit 2) and Visit 11 (Day 113)/early termination can be virtual visits (only via video, not phone), 
with sponsor approval and if permitted by local regulations. In addition, any visit identified as a virtual visit in this 
protocol may be conducted in clinic and in person if requested by the subject/parent or guardian and/or at the 
investigator’s discretion.
Dose Titration Period (4 Weeks):
Subjects will take the first dose of study drug (Dose 1) the day after the study medication is received. Approximately 7 
days after initiating study medication, if there are no tolerability issues, study drug dose will be increased to Dose 2. 
After approximately 7 days on Dose 2, if there are no tolerability issues, study drug dose will be increased to Dose 3. 
If the subjects do not experience any tolerability issues, they will continue on Dose 3 for the remainder of the titration 
period. Subjects will only be allowed to increase their dose within the 4-week titration period before entering the 
12-week maintenance period. Decrease in dose level is allowed during the titration period if required for safety and 
tolerability. Subjects who cannot tolerate the minimum dose of 100 mg BID (or weight-based equivalent dosing <45 
kg) will be discontinued from treatment. The maximum allowed dose is 300 mg BID. The subjects/parents or 
caregivers will be contacted by phone within approximately 2 days following each dose escalation to assess safety and 
tolerability of the study drug. The final dose tolerated by the end of the 4-week titration period should be maintained 
until the end of the maintenance period, unless tolerability issues arise.
Maintenance Period (12 Weeks):
The dose level at the end of the titration period will be maintained until the end of the maintenance; period (dose 
increases are not permitted); however, during the maintenance period, the dose may be decreased by 1 dose level to the 
previous lower dose, for safety and tolerability issues. For example, Dose 3 may be reduced to Dose 2, and Dose 2 may 
be reduced to Dose 1. The minimum dose is Dose 1 (100 mg BID adult reference dose; or weight-based equivalent 
dosing for <45 kg); subjects who cannot tolerate the minimum dose of 100 mg BID will be discontinued from 
treatment. Dose changes during the maintenance period are allowed for safety or tolerability reasons as assessed by the 
investigator; however, if possible, dose changes will need to be discussed with the medical monitor and/or the sponsor.
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on an antiseizure therapy (eg, ASMs, vagus nerve stimulation, ketogenic/modified Atkins diet) or other treatment 
options considered as SOC. 
Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing 
regimen and manufacturer should remain constant throughout the study. (Artisanal cannabidiols will not be counted as 
ASMs.)
Currently taking 0 to 4 ASMs at stable doses for at least 4 weeks before the screening visit (Visit 1); benzodiazepines 
used chronically (daily) to treat seizures are considered ASMs. Fenfluramine and cannabidiol (Epidiolex) are allowed 
where available and should be counted as an ASM. ASM dosing regimen must remain constant throughout the study.
Female subjects of childbearing potential (defined as first menarche) must have a negative pregnancy test and agree to 
use an effective or highly effective method of birth control during the study and for 30 days following the last dose of 
study drug.
Main Criteria for Exclusion:
Currently enrolled in a clinical study involving an investigational product (ie, not approved in that country, other than 
soticlestat) or concurrently enrolled in any other type of medical research judged not to be scientifically or medically 
compatible with this study. Note: Compatibility will be determined based on consultation with the medical monitor or 
the sponsor.
Participated in a clinical study involving another study drug in the last 30 days (or 5 half-lives of the study drug, 
whichever is longer) before screening (Visit 1).
Received soticlestat in a previous clinical study.
Known hypersensitivity to any component of the soticlestat formulation.
Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months 
immediately before screening (Visit 1). For the purpose of this exclusion criterion, status epilepticus is defined as 
continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to baseline in between 
seizures.
Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, 
ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, 
endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to 
participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to 
assess the clinical significance; however, consultation with the medical monitor may be warranted.
Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition, within the 2 years immediately before screening (Visit 1).
Abnormal and clinically significant ECG abnormality at screening (Visit 1) or before randomization (Visit 2), 
including QT interval with Fridericia correction method (QTcF) >450 ms, confirmed with a repeat ECG using manual 
measurement of QTcF. Clinically significant ECG abnormalities should be discussed with the medical monitor.
Abnormal clinical laboratory test results at screening (Visit 1) that suggest a clinically significant underlying disease 
that would compromise the well-being of the subject. If the subject has a serum alanine aminotransferase and/or 
aspartate aminotransferase level >2.5 times the upper limit of normal (ULN), the medical monitor should be consulted.
Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the last dose of study drug.
Criteria for Evaluation and Analyses:
Primary Endpoint:

Percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as 
compared with placebo during the full treatment period.
For EMA registration:

Percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as 
compared with placebo during the maintenance period.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research 
as well as study participation. The Signatory Coordinating Investigator will be required to review 
and sign the clinical study report and by doing so agrees that it accurately describes the results of 
the study.
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3.3
List of Abbreviations
24HC
24S-hydroxycholesterol
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASM
antiseizure medication
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
area under the plasma concentration-time curve
BID
twice daily 
Care GI-C
Caregiver Global Impression of Change
Care GI-I
Caregiver Global Impression of Improvement
CGI-C
Clinical Global Impression of Change
CGI-I
Clinical Global Impression of Improvement
CH24H
cholesterol-24-hydroxylase
COVID-19
coronavirus disease 2019
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DEE
developmental epileptic encephalopathy
DMC
Data Monitoring Committee
DRF
diagnostic review form
DS
Dravet syndrome
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture 
EEG
electroencephalogram
EO
enzyme occupancy
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
G-tube
gastrostomy tube
hCG
human chorionic gonadotropin
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
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INR
international normalized ratio
IRB
institutional review board
ITT
intent-to-treat
IWRS
interactive web response system
J-tube
jejunostomy tube
LFT
liver function test
LGS
Lennox-Gastaut syndrome
MMD
major motor drop
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
OLE
open-label extension
PD
pharmacodynamic(s)
PK
pharmacokinetics
PTE
pretreatment event
QI-Disability
Quality of Life Inventory-Disability
QTc
corrected QT interval
QTcF
QT interval with Fridericia correction method
rSDV
remote Source Data Verification
SAE
serious adverse event
SAP
statistical analysis plan
SOC
standard of care
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TESC
The Epilepsy Study Consortium
ULN
upper limit of normal
US
United States
VNS
vagus nerve stimulation
WHO
World Health Organization
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
Dravet syndrome (DS) or severe myoclonic epilepsy in infancy is one of the most well-described 
disorders of epileptic encephalopathies. Clinically, DS is characterized at onset by frequent 
convulsive febrile seizures, followed later by frequent status epilepticus and nonfebrile seizures 
that are mainly clonic, unilateral, and of long duration (Dravet 2011).
Soticlestat is a first-in-class small molecule inhibitor of cholesterol-24-hydroxylase (CH24H) in 
the brain. It is hypothesized that soticlestat treatment will decrease the levels of 
24S-hydroxycholesterol (24HC) and improve convulsive seizure control in DS subjects. 
Nonclinical studies have demonstrated that soticlestat modulates the glutamatergic signaling and 
significantly reduces spontaneous seizure in a murine model of DS. Clinical Study TAK-935-2002 
(ELEKTRA) showed efficacy of soticlestat in subjects with DS or Lennox-Gastaut syndrome 
(LGS).
ELEKTRA was a phase 2, multicenter, randomized, double-blind, placebo-controlled study that 
evaluated the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) 
of soticlestat as adjunctive therapy in pediatric subjects aged ≥2 and ≤17 years with LGS or DS. A 
total of 141 subjects were enrolled (51 with DS and 90 with LGS), and 126 completed the study. 
Subjects were eligible for enrollment if they demonstrated ≥3 convulsive seizures (in the DS 
cohort) or ≥4 drop seizures (in the LGS cohort) during a minimum of 4 weeks during the 
prospective baseline period (based on the seizure diary records), and they were currently on a 
stable regimen of 1 to 4 concomitant antiseizure medications (ASMs). This study consisted of 
2 main periods, a 4- to 6-week screening/baseline period followed by a 20-week treatment period 
(8-week titration and dose optimization period and a 12-week maintenance period). Subjects who 
met the entry criteria were stratified by syndrome and randomized in a 1:1 ratio to soticlestat or 
matching placebo within each cohort. Subjects were dosed with oral 20 mg or 100 mg soticlestat 
tablets or matching placebo at 100 mg twice daily (BID) for 1 week, followed by 200 mg BID for 
another week, before titrating up to 300 mg BID, the maximum allowable dose. Subjects weighing
<60 kg were dosed by weight.
In the DS cohort (n = 51), subjects treated with soticlestat demonstrated a 33.8% median reduction 
in convulsive seizure frequency compared with a 7.0% median increase seen in subjects taking 
placebo during the 20-week treatment period (median placebo-adjusted reduction in convulsive 
seizure frequency was 46.0%; p = 0.0007). The responder rate (≥50% reduction in convulsive 
seizure frequency compared with baseline) for subjects taking soticlestat in the DS cohort was 
30.8% while for placebo was 0%. In the LGS cohort (n = 88), soticlestat decreased drop seizures 
by a median of 20.6% as compared with a median decrease of 6% in the placebo group (median 
placebo-adjusted reduction in drop seizure frequency was 14.8%; p = 0.1279) during the 20-week 
treatment period. Other secondary endpoints included the Clinical Global Impression of Change 
(CGI-C) and the Caregiver Global Impression of Change (Care GI-C). For the CGI-C, more 
soticlestat-treated DS and LGS subjects showed improvement than those receiving placebo 
(26.9% versus 8% and 27.9% versus 11.1%, respectively) as deemed by the investigator. 
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Caregivers also rated greater improvement in 57.7% and 51.2% of soticlestat-treated DS and LGS 
subjects compared with 32% and 28.9% of those receiving placebo, respectively, as assessed by 
the Care GI-C.
In ELEKTRA, soticlestat was generally well tolerated, and safety data were consistent with 
findings in previous studies. The incidence of treatment-emergent adverse events (TEAEs) was
similar in the treatment and placebo groups, with 57 (80.3%) of soticlestat subjects experiencing at 
least 1 TEAE compared with 52 (74.3%) of placebo subjects. The most common TEAEs in the 
soticlestat group were upper respiratory tract infection, pyrexia, seizure, nasopharyngitis, 
decreased appetite, and vomiting. The most frequent TEAEs reported in soticlestat-treated 
subjects with ≥5% difference from placebo were lethargy and constipation. The incidence of 
serious TEAEs was similar in both soticlestat and placebo groups, with 11 (15.5%) in the 
soticlestat group experiencing at least 1 serious TEAE compared with 13 (18.6%) in the placebo 
group. Four soticlestat (5.6%) subjects discontinued the study compared with 3 in the placebo 
group (4.3%) due to TEAEs.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of soticlestat may be found in the current edition of the Investigator’s 
Brochure (IB).
4.2
Rationale for the Proposed Study
Soticlestat has shown antiseizure efficacy in nonclinical studies, including models relevant to the 
rare developmental epileptic encephalopathies (DEEs) that are inadequately treated by current 
adjunctive antiepileptic drugs. In phase 1 studies in healthy adult subjects and in phase 1b/2a 
(TAK-935-2001) and phase 2 (ELEKTRA) studies in adult and pediatric subjects with DEEs, 
acceptable PK and safety characteristics have been observed.
Based on the efficacy, safety, and tolerability data collected in the phase 2 ELEKTRA study, 
combined with the safety and tolerability data from phase 1 and other completed or ongoing 
studies (please see the IB), soticlestat is being proposed as adjunctive therapy in pediatric and 
young adult subjects with DS, a highly impacted population with great unmet need. This phase 3 
study will evaluate the efficacy, safety, and tolerability of soticlestat in this population. The current 
study is designed to further characterize the effects of soticlestat on convulsive seizure frequency 
by using a seizure diary in subjects with DS. Additional aims are to assess efficacy by the 
investigator (characterized by Clinical Global Impression of Improvement [CGI-I]) as well as by 
the caregivers, CGI-I in nonseizure-related symptoms, impact on quality of life, and the safety, 
tolerability, 
of soticlestat administration in pediatric and young adult subjects 
with DS.
4.3
Benefit/Risk Profile
In the phase 1b/2a TAK-935-2001, phase 2 TAK-935-2002 (ELEKTRA), and open-label pilot 
TAK-935-18-002 (ARCADE) studies, the safety and tolerability data indicate that soticlestat was 
generally well tolerated in subjects with DEEs at doses up to 300 mg BID (weight-based dosing for 
<60 kg).
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The following have been identified as important potential risks and are being closely monitored 
during the clinical development program:

Neurological and psychiatric effects (clinical safety data and risks associated with compounds 
affecting glutamate excitotoxicity).

Cognitive effects (soticlestat inhibition of neuronal CH24H and clinical safety data).

Suicidal ideation or behaviors (class effect of ASMs).

Cataracts (nonclinical data).

Corrected QT interval (QTc) prolongation (nonclinical data).
More information about the known and expected benefits and reasonably anticipated AEs of 
soticlestat may be found in the current edition of the IB. This study will further examine risk and 
establish benefit in DS. This study will enroll subjects aged 2 to 21 years, inclusive.
DS is characterized by treatment-resistant seizures, presenting at a very young age. In addition, 
mortality is especially high in DS (up to 21%) (Shmuely et al. 2016), even compared with other 
chronic epilepsies, with a 30-fold higher rate of sudden unexpected death in epilepsy that accounts 
for up to 60% of deaths in these patients (Richards et al. 2018). Given the severe, profound, and 
chronic nature of DS and its associated signs and symptoms and their impact on quality of life, and 
considering the potential benefits that soticlestat treatment can confer to patients affected by DS, 
the benefit-risk profile is acceptable for this population.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives

To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy 
to standard of care (SOC) as compared with placebo during the full treatment period (titration 
+ maintenance).
For European Medicines Agency (EMA) registration:

To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy 
to SOC compared with placebo during the maintenance period only.
5.1.2
Secondary Objectives
To assess the following in subjects taking soticlestat as compared with placebo during the full 
treatment period, unless otherwise noted:

Proportion of treatment responders defined as those with ≥50% reduction in convulsive 
seizures from baseline during the maintenance period and the full treatment period. 
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This is a 2-arm study. All subjects meeting entry criteria will be randomized at a 1:1 ratio to 
receive SOC plus 1 of the following adjunctive therapies: soticlestat or placebo.
Soticlestat or matching placebo added to current antiseizure therapy will be administered orally 
BID with or without food or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY 
button). A jejunostomy tube (J-tube) may be considered following approval by the medical 
monitor or sponsor. Note: Study drug will be administered only orally for subjects enrolled in sites 
in jurisdictions where alternative means are not permitted.
A schematic of the study design is shown in Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
BID: twice daily; OLE: open-label extension.
All doses will be blinded; subjects on soticlestat or placebo will undergo the same titration scheme, 
with the same number and type of tablets (mini-tablets or tablets). Subjects randomized to placebo 
will undergo a mock titration to ensure the blind is maintained (see Table 6.a through Table 6.d).
The total daily dose of study drug (either placebo or soticlestat) will be calculated based on body 
weight at screening (Visit 1) and given BID starting on the morning after Visit 2/Day 0 (ie, on 
study Day 1) or on the day after receiving study medication. The dosing schedules by weight are 
shown in Table 6.a through Table 6.d. The minimum dose allowed during the study is 100 mg BID 
(weight-based dosing <45 kg). Subjects who cannot tolerate the minimum dose will be 
discontinued from the study. Subjects weighing <45 kg will be dispensed 20 mg mini-tablets or 
matching placebo. Subjects weighing ≥45 kg may be dispensed 20 mg mini-tablets or 100 mg 
tablets, or matching placebo.
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Table 6.a
Dosing Schedules by Weight, 10 to <15 kg
Treatment 
Arm
10 to <15 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
40 mg 
BID
2 mini tabs soticlestat 
BID
60 mg 
BID
3 mini tabs 
soticlestat BID
100 mg 
BID
5 mini tabs 
soticlestat 
BID
PBO
---
2 mini tabs PBO BID
---
3 mini tabs PBO 
BID
---
5 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Table 6.b
Dosing Schedules by Weight, 15 to <30 kg
Treatment Arm
15 to <30 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
60 mg BID
3 mini tabs 
soticlestat 
BID
120 mg 
BID
6 mini tabs 
soticlestat BID
200 mg 
BID
10 mini tabs 
soticlestat BID
PBO
---
3 mini tabs 
PBO BID
---
6 mini tabs PBO 
BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
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Table 6.c
Dosing Schedules by Weight, 30 to <45 kg
Treatment 
Arm
30 to <45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
80 mg BID
4 mini tabs 
soticlestat 
BID
140 mg 
BID
7 mini tabs 
soticlestat BID
200 mg 
BID
10 mini tabs 
soticlestat BID
PBO
---
4 mini tabs 
PBO BID
---
7 mini tabs PBO 
BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Table 6.d
Dosing Schedules by Weight, ≥45 kg
Treatment 
Arm
≥45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
100 mg 
BID
1 tab soticlestat 
BID 
OR
5 mini tabs 
soticlestat BID
200 mg 
BID
2 tabs soticlestat 
BID
OR
10 mini tabs 
soticlestat BID
300 mg 
BID
3 tabs soticlestat 
BID
OR
15 mini tabs 
soticlestat BID
PBO
---
1 tab PBO BID 
OR
5 mini tabs 
PBO BID
---
2 tabs PBO BID 
OR
10 mini tabs 
PBO BID
---
3 tabs PBO BID
OR
15 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
The study design allows virtual visits if aligned with institutional or local guidelines, via phone or 
via any platforms approved by local regulations, in addition to the communication platform 
offered through the study. Screening (Visit 1) and Visit 11/early termination must be conducted in 
person; Visit 9 is to be conducted in person if possible, but may be conducted virtually (via video 
or phone) in response to the coronavirus disease 2019 (COVID-19) pandemic and/or based on 
sponsor approval and if permitted by local regulations. In extenuating circumstances, the 
randomization visit (Visit 2), and Visit 11/early termination can be virtual visits (only via video, 
not phone), with sponsor approval and if permitted by local regulations. In addition, any visit 
identified as a virtual visit in this protocol may be conducted in clinic and in person if requested by 
the subject/parent or guardian and/or at the investigator’s discretion. Appendix C has additional 
information on virtual visits.
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In the event of rescreening, the subject may not need to repeat all assessments for the screening 
visit (Visit 1); this will need to be discussed with the medical monitor and/or sponsor.
6.1.1
Dose Titration Period (4 Weeks)
Subjects will take the first dose of study drug (Dose 1) the day after the study medication is 
received. Approximately 7 days after initiating study medication, if there are no tolerability issues, 
study drug dose will be increased to Dose 2. After approximately 7 days on Dose 2, if there are no 
tolerability issues, study drug dose will be increased to Dose 3. If the subjects do not experience 
any tolerability issues, they will continue on Dose 3 for the remainder of the titration period. 
Subjects will only be allowed to increase their dose within the 4-week titration period before 
entering the 12-week maintenance period. Decrease in dose level is allowed during the titration 
period if required for safety and tolerability. Subjects who cannot tolerate the minimum dose of 
100 mg BID (or weight-based equivalent dosing <45 kg) will be discontinued from treatment. The 
maximum allowed dose is 300 mg BID. The subjects/parents or caregivers will be contacted by 
phone within approximately 2 days following each dose escalation to assess safety and tolerability 
of the study drug. The final dose tolerated by the end of the 4-week titration period should be 
maintained until the end of the maintenance period, unless tolerability issues arise.
6.1.2
Maintenance Period (12 Weeks)
The dose level at the end of the titration period will be maintained until the end of the maintenance
period (dose increases are not permitted); however, during the maintenance period, the dose may 
be decreased by 1 dose level to the previous lower dose, for safety and tolerability issues. For 
example, Dose 3 may be reduced to Dose 2, and Dose 2 may be reduced to Dose 1. The minimum 
dose is Dose 1 (100 mg BID adult reference dose; or weight-based equivalent dosing for <45 kg); 
subjects who cannot tolerate the minimum dose of 100 mg BID will be discontinued from 
treatment. Dose changes during the maintenance period are allowed for safety or tolerability 
reasons as assessed by the investigator; however, if possible, dose changes will need to be 
discussed with the medical monitor and/or the sponsor.
6.1.3
Study Discontinuation/Completion
At Visit 11/early termination, subjects will have the option to enroll in the OLE study as per that 
study’s inclusion/exclusion criteria.
Subjects who enroll in the OLE study on the same day as Visit 11/early termination will take their 
final dose of double-blind study drug in the evening of the day of Visit 11/early termination and 
should continue to record seizures in the seizure diary until midnight of the day of Visit 11/early 
termination, at which time they will exit the study.
Subjects who do not roll over to the OLE study on the same day as Visit 11/early termination will 
take their final dose of double-blind study drug in the morning of Visit 11/early termination, 
followed by a taper period. The study drug dose will be tapered down to a lower dose (taper Dose 
3 to Dose 2, taper Dose 2 to Dose 1) approximately every 3 days until the study drug dose is 
discontinued. The subject/parent or caregiver should continue to record seizures in the seizure 
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diary until the safety follow-up phone call, which will occur approximately 14 days after the last 
dose of study drug. After completion of the safety follow-up phone call, the subject will exit the 
study.
Subjects/parents or caregivers who choose to enroll in the OLE study after Visit 11/early 
termination will continue the taper procedure until the investigator confirms eligibility for the OLE 
study; the subject will then exit the study and roll over to the OLE study.
6.1.4
End of Study for Individual Subject
The end of study for an individual subject who does not enroll in the OLE study on the same day as 
Visit 11/early termination is either:

The day of the scheduled safety follow-up phone call or visit.
OR

Midnight of the day after Visit 11/early termination but before the scheduled safety follow-up 
phone call, if, in agreement with the investigator, the subject/parent or caregiver decides on 
that day to enroll in the OLE study.
The end of study for an individual subject who enrolls in the OLE study on the same day as 
Visit 11/early termination is midnight of that same day.
6.1.5
End of Study Overall
The overall end of the study is defined as the date of the last individual subject’s end of study (as 
defined in Section 6.1.4). 
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group study to further evaluate 
the safety, tolerability, and efficacy of soticlestat as adjunctive therapy in pediatric and young 
adult subjects with DS.
Randomization of subjects in the study will be stratified by age group and country. The strata for 
stratification by age group will be: ≤6 years and >6 years; these age-group randomization strata 
will be included as a fixed effect factor in the statistical model for the analysis of the primary 
endpoint.
The strata for stratification by country will be: China, Japan, and the rest of the world. This country 
stratification is planned to be implemented for an administrative reason and therefore will not be 
included in the primary analysis model.
During this study, subjects will continue their current ASMs; therefore, placebo was chosen as the 
control group to provide maximum difference between the treatment and control arms.
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cholesterol 24-hydroxylase (CH24H) inhibitor, soticlestat, with liquid chromatography/tandem 
mass spectrometry. Report number:16354). In summary, these preclinical pharmacology studies 
suggest that high degree of target occupancy (≥65%) and 24HC reduction (≥60%) are considered 
to be related to the efficacy in the nonclinical animal model. 
The target dose of 300 mg BID (weight-based equivalent in pediatrics) will achieve the degree 
target occupancy and 24HC reduction required for efficacy. Based on a population PK/PD/EO 
model using data from 4 phase 1 studies in healthy subjects, the phase 1b/2a study in adult subjects 
with DEEs, and the TAK-935-2002 (ELEKTRA) study in pediatric subjects with DS or LGS, the 
300 mg BID dose (weight-based equivalent in pediatrics) is estimated to achieve approximately 
90% EO with approximately 82% decrease in 24HC level and potentially resulting in efficacy.
In addition, the same soticlestat target dose of 300 mg BID (adult reference dose; weight-based 
equivalent dosing for <60 kg) was administered in ELEKTRA and demonstrated clinically 
meaningful seizure reduction in DS subjects while maintaining a favorable safety and tolerability 
profile. Approximately 79% of subjects in the double-blind, randomized, placebo-controlled 
ELEKTRA study were able to be titrated up to and maintained on 300 mg BID (or adult 
weight-based equivalent) until the end of the maintenance period. Soticlestat-treated subjects with 
DS reported a 33.8% median reduction in convulsive seizures while those subjects receiving 
placebo experienced a median increase of 7.0% in convulsive seizures (median placebo-adjusted 
reduction in seizure frequency was 46.0%; p = 0.0007) over the 20-week treatment period. 
Responder rates (≥50% reduction in convulsive seizure frequency compared with baseline) for 
soticlestat-treated subjects with DS were 30.8% versus 0% in placebo, respectively. Soticlestat 
was generally safe and well tolerated at this dose in this study, and safety was consistent with 
previous studies with no new signals identified. The incidence of TEAEs was similar between the 
DS and LGS strata compared with placebo with 57 soticlestat subjects (80.3%) experiencing at 
least 1 TEAE compared with 52 placebo subjects (74.3%). The most frequent TEAEs reported in 
soticlestat-treated subjects with ≥5% difference from placebo were lethargy and constipation. The 
incidence of serious adverse events (SAEs) was similar in both soticlestat and placebo groups, 
with 11 (15.5%) in the soticlestat group experiencing at least 1 treatment-emergent SAE compared 
with 13 (18.6%) in the placebo group. There were no deaths reported. The combination of 
clinically meaningful convulsive seizure reduction and favorable tolerability and safety profile in 
ELEKTRA support the selection of 300 mg BID as the soticlestat target dose (adult reference dose; 
weight-based equivalent dosing for <45 kg BID).
Before reaching the target dose in the current study, subjects will receive the minimum soticlestat 
dose (ie, 100 mg BID adult equivalent dose for 1 week, followed by 200 mg BID adult equivalent 
dose for 1 week) in the titration phase. The goal of titration is to reach the target final dose of 300 
mg BID adult equivalent dose after a 14-day titration period; the same titration regimen was 
evaluated in study ELEKTRA and demonstrated a favorable safety and tolerability profile in 
addition to clinically meaningful and statistically significant efficacy.
The weight-based equivalent dosing in pediatrics was determined using the population PK model. 
Simulations were conducted using body weight intervals of 1 kg, dose strengths from 40 to 300 mg 
using 20 mg mini-tablets and 100 mg tablets, and a BID dosing regimen. A total of 10,000 
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simulations of steady-state exposure (median area under the plasma concentration-time curve 
[AUC]) were performed. A threshold for the fraction of subjects at or above the reference value 
was set to 35%. Setting the percentage threshold at “35%” ensures the safety of pediatric subjects 
as the reference AUC values are median steady-state AUC values in adults, ie, 50% of the adult 
population has AUCs above the reference AUC values while no more than 35% of pediatric 
population will have AUCs above the reference AUC values). Furthermore, an effort has been 
made to keep pediatric exposure from exceeding the 90th percentile of the adult exposure. The 
resulting weight-based equivalent dosing in pediatrics is provided in Table 6.a through Table 6.d.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known benefit-risk profile for soticlestat, such that the benefit-risk is 
no longer acceptable for subjects participating in the study.

The Data Monitoring Committee (DMC) recommends that the study should be suspended or 
terminated.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or is otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of termination 
or study suspension.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization or first dose. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, based on discussions and approval by the medical monitor and sponsor.
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5. Has had ≥12 convulsive seizures over 12 weeks before screening based on the historical 
information and has had ≥4 convulsive seizures per 28 days during the 4- to 6-week 
prospective baseline period. The seizure frequency will be calculated as:
(total number of seizures) / (total number of days seizures were assessed) × 28.
The total number of seizures includes only primary outcome seizure types with documentation 
TESC approval:

Hemi-clonic or focal clonic.

Focal to bilateral tonic-clonic.

Generalized tonic-clonic.

Bilateral clonic.

Convulsive status.
6. Weighs ≥10 kg at the screening visit (Visit 1).
7. Failure to control seizures despite appropriate trials of at least 1 ASM based on historical 
information and is currently on an antiseizure therapy (eg, ASMs, vagus nerve stimulation 
[VNS], ketogenic/modified Atkins diet) or other treatment options considered as SOC.
8. Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening 
visit (Visit 1); the dosing regimen and manufacturer should remain constant throughout the 
study. (Artisanal cannabidiols will not be counted as ASMs.)
9. Currently taking 0 to 4 ASMs at stable doses for at least 4 weeks before the screening visit 
(Visit 1); benzodiazepines used chronically (daily) to treat seizures are considered ASMs. 
Fenfluramine and cannabidiol (Epidiolex) are allowed where available and should be counted 
as an ASM. ASM dosing regimen must remain constant throughout the study.
10. If using a VNS, the subject must have had VNS placed at least 3 months before the screening 
visit (Visit 1) with stable settings for 4 weeks; VNS parameters must remain constant 
throughout the study (VNS will not be counted as an ASM).
11. If on ketogenic diet (or any other diet used for treatment of epilepsy, such as modified Atkins 
diet), the subject must have started the diet at least 3 months before the screening visit (Visit 1), 
and the subject’s diet should be stable for 4 weeks before the screening visit (Visit 1); the 
subject should continue this diet throughout the duration of the study (ketogenic diet, or any 
other diet for the treatment of epilepsy will not be counted as an ASM).
12. The use of felbamate is allowed provided that the subject does not meet the liver function test 
(LFT) exclusion criteria, the dose has been stable for at least 6 months before screening (Visit 
1), and the subject has had stable liver function (as determined by serum aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT] levels) and hematology 
laboratory tests during the course of treatment.
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13. Approved to participate by the sponsor’s designee (ie, TESC) based on the review of medical 
history and seizure classification, as well as review of electroencephalogram (EEG) and 
imaging results (if available and permitted by local regulations). The sponsor may be consulted 
if needed.
14. Female subjects of childbearing potential (defined as first menarche) must have a negative 
pregnancy test and agree to use an effective or highly effective method of birth control during 
the study and for 30 days following the last dose of study drug.
Effective contraceptive methods include the following:

Double-barrier method (contraceptive sponge, diaphragm, or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, PLUS condom with or without spermicide.
Highly effective contraceptive methods include the following:

Nonhormonal methods: 
–
Intrauterine device (IUD). 
–
Bilateral tubal occlusion. 
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success). 
–
Sexual abstinence:
Sexual abstinence may be considered as a method only if defined as refraining from 
heterosexual intercourse and determined to be the usual lifestyle before entering the 
study with reliability of abstinence for the duration of the study participation and for 30 
days after last dose of study drug.

Hormonal methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug OR 
combined with a barrier method (male condom, female condom or diaphragm) if for 
shorter duration until she has been on contraceptive for 3 months.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter until she has 
been on the contraceptive for 3 months.
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7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. Investigator site personnel directly affiliated with this study and/or their immediate family.
Note: Immediate family is defined as a spouse, parent, child, or sibling, whether biological or 
legally adopted.
2. Takeda employees or immediate family members.
3. Currently enrolled in a clinical study involving an investigational product or treatment device 
(ie, not approved in that country, other than soticlestat), or concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically compatible with this 
study. 
Note: Compatibility will be determined based on consultation with the medical monitor or the 
sponsor.
4. Participated in a clinical study involving another study drug in the last 30 days (or 5 half-lives 
of the study drug, whichever is longer) before screening (Visit 1).
5. Received soticlestat in a previous clinical study.
6. Known hypersensitivity to any component of the soticlestat formulation.
7. Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times 
in the 3 months immediately before screening (Visit 1). For the purpose of this exclusion 
criterion, status epilepticus is defined as continuous seizure activity lasting longer than 5 
minutes or repeated seizures without return to baseline in between seizures.
8. Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, 
cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, 
urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive 
tumors, or other abnormality that may impact the ability to participate in the study or that may 
potentially confound the study results. It is the responsibility of the investigator to assess the 
clinical significance; however, consultation with the medical monitor may be warranted.
9. Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-V), within the 2 years immediately before the 
screening visit (Visit 1).
10. Considered by the investigator to be at imminent risk of suicide or injury to self, others, or 
property, or the subject has attempted suicide within 12 months before the screening visit 
(Visit 1). Subjects who have positive answers on item numbers 4 or 5 on the C-SSRS before 
dosing (Visit 2) are excluded. This scale will only be administered to subjects aged ≥6 years.
11. The following medical histories:
a) History of HIV infection (subject who has tested positive for HIV-1/2 antibodies).
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b) History of hepatitis B infection or current active infection.
Note: Subjects who have been vaccinated against hepatitis B (hepatitis B surface 
antibody-positive) and who test negative for other markers of prior hepatitis B infection 
(eg, negative for hepatitis B core antibody) are eligible.
c) History of hepatitis C infection or current active infection.
Note: Subjects who test positive for hepatitis C antibody are eligible if they have a negative 
hepatitis C viral load by quantitative polymerase chain reaction.
12. Abnormal and clinically significant ECG abnormality at screening (Visit 1) or before dosing 
(Visit 2), including QT interval with Fridericia correction method (QTcF) >450 ms confirmed 
with a repeat ECG using manual measurement of QTcF. Clinically significant ECG 
abnormalities should be discussed with the medical monitor. 
13. Abnormal clinical laboratory test results at screening (Visit 1) that suggest a clinically 
significant underlying disease that would compromise the well-being of the subject. If the 
subject has serum ALT and/or AST level >2.5 times the upper limit of normal (ULN), the 
medical monitor should be consulted.
14. Unable to withhold the use of strong inducers of cytochrome P450 (CYP) 3A during the entire 
clinical trial, except for ASMs (eg, carbamazepine, phenobarbital, phenytoin) and topical 
preparations.
15. Use of herbal preparations (when used as an ASM) during the entire clinical trial.
16. Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the 
last dose of study drug.
7.3
Excluded Medications
Strong CYP3A inducers are excluded from screening (Visit 1) until the end of the follow-up visit, 
except for ASMs (eg, carbamazepine, phenobarbital, phenytoin) and topical preparations; refer to 
Appendix B for examples.
The use of herbal preparations (when used as an ASM) are not permitted.
Vaccinations are allowed; however, the medical monitor and sponsor should be informed about 
changes in the subject’s vaccination status and document it under the concomitant medication 
section of the electronic case report form (eCRF).
The use of felbamate is allowed provided that the subject meets the relevant inclusion and 
exclusion criteria.
If the subject is using VNS, the device must have been placed at least 3 months before the 
screening visit with stable settings for >1 month; VNS parameters must remain constant 
throughout the study (VNS will not be counted as an ASM).
All medications, including vitamin supplements and over-the-counter medications, will be 
documented throughout the study. 
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Subjects are instructed not to take any medications, including over-the-counter products, without 
first consulting with the investigator.
7.4
Diet, Fluid, Activity Control
If the subject is on a ketogenic diet (or other diet used as antiseizure therapy, such as modified 
Atkins diet), they must have started the ketogenic diet at least 3 months before the screening visit 
(Visit 1), and their diet should be stable for 1 month before the screening visit (Visit 1); the diet 
should be continued throughout the duration of the study.
As the effect of a strong CYP3A4 inhibitor on the PK of soticlestat is small (<25%), consumption 
of the fruit and juice of grapefruit, Seville oranges, and starfruit is permitted.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the eCRF using the categories detailed in this section. For screen failure subjects, refer 
to Section 9.1.18.
Study subjects will be withdrawn from the study/study drug for the following reasons:
1. Failure to meet continuation criteria: Enrollment in any other clinical study involving an 
investigational product or enrollment in any other type of clinical trial judged not to be 
scientifically or medically compatible with this study.
2. Withdrawal by investigator (Note: The specific reason for discontinuation must be recorded in 
the eCRF, and is only to be used if no other pertinent reason for discontinuation is applicable):
a) The investigator decides that the subject should be discontinued from the study.
b) If the subject, for any reason, requires treatment with another therapeutic agent, 
discontinuation from the study occurs before introduction of the new agent.
3. Withdrawal by subject/parent or legal guardian (Note: The specific reason for discontinuation 
should be recorded in the eCRF and is only to be used if no other pertinent reason for 
discontinuation is applicable). All attempts should be made to determine the underlying reason 
for the withdrawal and, where possible, the primary underlying reason should be recorded; ie, 
withdrawal due to a TEAE should not be recorded in this category. Similarly, lack of efficacy 
should not be recorded in this category.
4. Sponsor decision:
a) The sponsor or its designee discontinues the study.
b) The sponsor or its designee discontinues the subject’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP.
c) The sponsor or its designee stops the clinical study at a particular site.
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5. Discontinuation due to AE: The subject has experienced an AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health, or the 
subject is unwilling to continue because of the AE.
If the investigator decides that the subject should be withdrawn because of an AE or a 
clinically significant laboratory value, the study drug is to be discontinued and appropriate 
measures are to be taken. The sponsor or its designee is to be alerted immediately.
a) LFT abnormalities: Study drug should be discontinued immediately (withdrawal of the 
subject from the study should be discussed with the sponsor/medical monitor) with 
appropriate clinical follow-up, including repeat laboratory tests, until a subject’s laboratory 
profile has returned to normal/baseline status (see Section 9.3.1) if the following 
circumstances occur at any time during study drug treatment:
i. Serum ALT or AST >8 times the ULN, or
ii. Serum ALT or AST persistently >5 times the ULN that persists for more than 
2 weeks, or
iii. Serum ALT or AST >3 times the ULN in conjunction with elevated total bilirubin >2 
times the ULN or international normalized ratio (INR) >1.5, or
iv. Serum ALT or AST >3 times the ULN with appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
b) QTcF >500 ms or an increase of QTcF >60 msec above baseline.
Note: Study drug should be discontinued immediately (withdrawal of the subject from the 
study should be discussed with the sponsor/medical monitor) with appropriate clinical 
follow-up and confirmation by repeat ECG with manual measurement of the QTcF interval 
if the QTcF is >500 ms or if there is an increase of QTcF >60 msec above baseline.
c) Greater than a 100% increase in 28-day seizure frequency from the 4- to 6-week 
prospective baseline period and considered by the investigator to be clinically significant 
worsening of the seizure frequency that is related to the study drug.
d) Not tolerating the lowest dose of the study drug.
e) Suicidal ideation: Subjects who experience suicidal ideation or who attempt suicide will be 
immediately withdrawn from the study.
6. Lost to follow-up: The subject did not attend visits, and multiple attempts to contact the 
subjects were unsuccessful. Attempts to contact the subject must be documented in the 
subject’s source documents.
7. Pregnancy: Female subject of childbearing potential is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.17.
8. Other: The specific reason should be recorded in the eCRF.
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9. COVID-19/pandemic: If, in the opinion of the investigator, the safety of a trial subject is at risk 
because the subject cannot complete key evaluations or adhere to critical mitigation steps, then 
the investigator should consider discontinuing that subject. In addition, for any such subject 
with COVID-19 diagnosis or in a pandemic circumstance, GCP for AE reporting processes 
will apply.
10. Noncompliance with study drug.
11. Significant protocol deviation: The discovery following randomization that the subject failed 
to meet protocol entry criteria or did not adhere to protocol requirements, and/or continued 
participation poses an unacceptable risk to the subject’s health.
Subjects who discontinue the study drug and/or study early will have end-of-study 
procedures/early termination visit performed as shown in the schedule of assessments 
(Appendix A). Precise reason for discontinuation will be recorded in the eCRF; for example, 
instead of “withdrawal by the subject/parent or legal guardian” or “withdrawal by the 
investigator,” a more accurate reason will need to be recorded in the eCRF if applicable 
(eg, discontinuation due to AEs, discontinuation due to lack of efficacy).
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to a TEAE 
should not be recorded in the “withdrawal by subject/parent or legal guardian” category).
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term “study drug” refers to all or any of the drugs defined below.
8.1.1.1
Study Drug
The sponsor will supply the study sites with soticlestat 20 mg mini-tablets, soticlestat 100 mg 
tablets, matching placebo mini-tablets, and matching placebo tablets. Study drug will be supplied 
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in high-density polyethylene bottles with induction seal and child-resistant caps. Each bottle will 
contain a label that includes pertinent study information and caution statements.
Clinical study materials will be labeled according to the country’s regulatory requirements.
All subjects will continue on SOC antiseizure therapies throughout the study.
8.1.1.2
Rescue Medication
Rescue ASMs as per SOC will be allowed throughout the study and their use recorded in the daily 
electronic seizure and medication diary. Rescue medication will not be supplied by the sponsor.
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is dispensed or 
returned to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every day.
Please refer to the pharmacy manual for additional information related to the study drug. In 
instances where the protocol and pharmacy manual text conflict, the pharmacy manual text shall 
supersede the text in the protocol.
8.1.3
Dose and Regimen
This study involves a comparison of soticlestat to matching placebo.
The investigator or his/her designee is responsible for the following:

Explaining the correct use of the study drug to the subject/parent or caregiver.

Verifying that instructions are followed properly.

Maintaining accurate records of study drug dispensing and collection.

Returning or destroying all unused study drugs to the sponsor or its designee at the end of the 
study after the monitor completes final accountability and reconciliation.
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical study materials. Clinical supply manager review and approval are 
required before proceeding.
Subject/parent or caregiver will be instructed to contact the investigator as soon as possible if he or 
she has a complaint or problem with the study drug so that the situation can be assessed.
All study drug provided to the investigator will be stored in a secure place and allocated and 
dispensed by appropriately trained persons. The allocation and dispensing of the study drug will be 
fully documented and verified by a second person. Detailed records of the amounts of the study 
drug received, dispensed, and remaining at the end of the study will be maintained.
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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at doses above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated TEAEs) will be documented on an Overdose 
page of the eCRF to capture this important safety information consistently in the database. Cases 
of overdose without manifested signs or symptoms are not considered TEAEs. TEAEs associated 
with an overdose will be documented on TEAE eCRFs according to Section 10.2.1. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically, as determined by the 
investigator.
8.2
Study Drug Assignment and Dispensing Procedures
Sites should refer to the interactive web response system (IWRS) manual for specific instructions. 
The subjects will be assigned to receive their treatment according to the randomization schedule. 
The investigator or investigator’s designee will access the IWRS at the Visit 1 (screening/baseline) 
to obtain the subject number. At Visit 2 (randomization), the investigator or the investigator’s 
designee will use the IWRS to randomize eligible subjects into the study. During this visit, the 
investigator or designee will provide the necessary subject identifying information, including the 
subject number assigned at screening. The medication identification number of the study drug to 
be dispensed will then be provided by the IWRS. If study drug supplied is lost or damaged, the site 
can request a replacement from IWRS (refer to the IWRS manual provided separately). At 
subsequent drug-dispensing visits, the investigator or designee will again access the IWRS to 
request additional study drug for a subject. The medication identification number of the study drug 
to be dispensed will be provided by the IWRS.
8.3
Unblinding Procedures
Unblinding should only be considered for the safety of the subject. The study drug blind shall not 
be broken by the investigator unless information concerning the study drug is necessary for the 
medical treatment of the subject. All study assessments and causality assessment should be 
performed, if possible, prior to unblinding. In the event of a medical emergency, if possible, the 
medical monitor or sponsor should be contacted before the study drug blind is broken to discuss 
the need for unblinding. If unblinding is deemed necessary by the investigator, the investigator can 
unblind the subject’s treatment allocation using IWRS. The investigator must note the date, time, 
and reason for unblinding in subject’s source documents.
If an investigator, site personnel performing assessments, or subject is unblinded, the subject must 
be discontinued from the study. The investigator should inform the sponsor that the subject was 
unblinded; however, they are not required to reveal to the sponsor the subject’s treatment 
allocation.
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In cases where there are ethical reasons to have the subject remain in the study, the investigator 
must obtain specific approval from the sponsor’s medical monitor for the subject to continue in the 
study.
When a TEAE is an unexpected, related SAE, the blind will be broken by the sponsor only for that 
specific subject for reporting purposes and to adhere to regional regulatory requirements for 
unblinding investigators. The blind will be maintained for persons responsible for the ongoing 
conduct of the study (such as the monitors, investigators, etc.) and those responsible for data 
analysis and interpretation of results at the conclusion of the study, such as biometrics personnel. 
Unblinded information will only be accessible to those who need to be involved in the safety 
reporting to health authorities, ethics committees, and/or IRBs.
Investigators will receive only blinded information unless unblinded information is judged 
necessary for regulatory requirements or safety reasons.
8.4
Accountability and Destruction of Study Drugs
Drug supplies, including the number of returned tablets to sites, will be counted and reconciled at 
the site before being returned to the sponsor or designee or destroyed at the site.
The investigator or designee must ensure that the study drug is used in accordance with the 
protocol and is dispensed only to subjects enrolled in the study. The investigator or designee is 
responsible for ensuring that the study drug provided to the subject and returned from the subject is 
accounted for and noted in source documents. To document appropriate use of study drug, the 
investigator or designee must maintain records of all study drug delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee. If any dispensing 
errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
Periodically, throughout and at the conclusion of the study, the monitor or a sponsor representative 
will conduct an inventory of unused study drug. At the completion of the study, a final study drug 
accountability review will be conducted before the unused study drugs are returned to the sponsor 
or its designee for destruction. All study drug not returned to the site by a subject must be 
investigated by the site and appropriately documented. 
Destruction at the site, where applicable, must be in accordance with local standard practice with 
prior approval from the sponsor/CRO. 
Please refer to the pharmacy manual for additional information related to the study drug. In 
instances where the protocol and pharmacy manual text conflict, the pharmacy manual text shall 
supersede the text in the protocol.
The site must have destruction procedures in place and be able to supply a Certificate of 
Destruction (COD) or similar document once destruction is completed. Sites shall also document 
the event in the IWRS.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
schedule of study procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
The investigational site is responsible for the consenting process. The requirements of informed 
consent are described in Section 15.2.
9.1.2
Historical Seizure Diary Review
Per inclusion criteria, historical seizure information will be used to support study entry. It is very 
common for caregivers of subjects with DS to maintain daily seizure diaries that capture both 
seizure type and frequency and days when no seizures occur as part of their SOC treatment 
regimen. A 3-month (12-week) daily historical seizure diary will be reviewed at screening 
(Visit 1) to determine eligibility. In the event that daily seizure diaries are not routinely maintained 
as part of the SOC, the investigator will be asked to review in detail with the subject/caregiver the 
number of seizures over the last 3 months for each seizure type and attest eligibility to the study at 
screening (Visit 1).
9.1.3
Seizure Identification and Diagnostic Review Forms (TESC)
Per inclusion criteria, enrollment into the study is based on a subject having ≥12 convulsive 
seizures during the 12 weeks preceding screening based on the historical information and having 
≥4 convulsive seizures per 28 days during the 4- to 6-week prospective baseline period (Day -42 to 
Day -1). To confirm diagnosis, standardize seizure identification and classification, and approve 
seizures that will be recorded by the parent or caregiver in the electronic daily seizure and 
medication diary, a Seizure Identification Form (SIF)/Diagnostic Review Form (DRF) will be 
submitted to, reviewed by, and approved by TESC. In addition, previously prepared documents 
(including, but not limited to, EEG and imaging results and summary reports) may be sent to 
TESC as part of the SIF/DRF for diagnosis evaluation, if allowed by local regulations. Submission 
of these materials is expected shortly after the screening visit and needs to be approved before 
randomization. 
All new reports of seizures (parent or caregiver descriptions) identified by the parent or caregiver 
after screening (Visit 1) must also be reviewed by the investigator and approved by TESC to 
confirm seizure classification. A new DRF must be submitted to TESC for review and approval for 
all new seizures and/or recurrence of past (>1 year) identified seizures throughout the course of the 
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study. Only seizure classification/descriptions approved by TESC will be collected in the 
electronic seizure and medication diary for this study.
9.1.4
Seizure Frequency
The primary efficacy measure is the percent change from baseline in convulsive seizure frequency 
per 28 days in subjects on soticlestat as compared with placebo during the treatment period (or 
during the 12-week maintenance period only for EMA registration regions). Secondary efficacy 
measures include the proportion of responders defined as those with a ≥50% reduction in 
convulsive seizures from baseline.
Seizure frequency will be collected via an electronic daily seizure and medication diary. The 
electronic diary will allow a 7-day window for data entry/correction by the subject/parent or 
caregiver. In the event of a device malfunction, the subject/parent or caregiver should contact the 
site as soon as possible for the back-up solution (access to web back-up) to record daily seizures 
and medications. The backup paper daily seizure and medication diary will be utilized to ensure 
compliance and reduce the incidence of missed entries only in cases when the web backup is not 
available. The electronic daily seizure and medication diary is an observer-reported clinical 
outcome assessment measure that captures seizures noted as occurring as individual seizures and 
seizures occurring in a cluster. Countable and uncountable seizures occurring within a cluster will 
be captured. Subject/parent or caregiver will be the observers and reporters in the current study.
Subject/parent or caregiver will be educated on the importance to record seizures throughout the 
day to ensure that the daily diary assessment is completed each evening, even if no seizures 
occurred.
Convulsive seizures include hemi-clonic or focal clonic, focal to bilateral tonic-clonic, generalized 
tonic-clonic, bilateral clonic seizures, and convulsive status epilepticus.
At the screening visit (Visit 1), the subject/parent or caregiver will be provided with the electronic 
daily seizure and medication diary and specific instructions to ensure compliance with the seizure 
recording. In addition, a corresponding web backup solution and paper daily seizure and 
medication diary will be provided in the case of an electronic diary device malfunction. All seizure 
events will be recorded starting at the screening/baseline period up until the follow-up visit. At 
each visit, the electronic diary will be reviewed, and paper diary collected, if applicable. All entries 
will be reviewed by the investigator with the subject/parent or caregiver at the time of each visit to 
ensure proper recording. Any new seizures that may have occurred since the last visit must be 
reviewed by the investigator and approved by TESC via submission of a DRF. Only seizure 
classification/descriptions approved by TESC will be collected in the electronic daily seizure and 
medication diary for this study.
For the prospective baseline period, the seizure frequency will be calculated as:
(total number of seizures) / (total number of days seizures were assessed) × 28.
Seizure frequency calculated through this method will be used to confirm the eligibility.
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9.1.5
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic ethnicity, 
and race as described by the subject at screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.13).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 6 months before signing of informed 
consent. 
All ASMs stopped prior to signing of informed consent should be recorded.
9.1.6
Height and Weight
Weight and height are to be measured while the subject is wearing indoor clothing and with shoes 
off. If unable to obtain height or weight, data that was obtained ≤30 days before the screening visit 
may be collected from other sources (eg, medical records or the subject’s caregiver). The 
investigator must record in the source document the reason for not obtaining height or weight (eg, 
the subject is in a wheelchair). These data may be used to determine the weight-based starting 
dose.
9.1.7
Concomitant Medications and Nonpharmacologic Therapies and Procedures
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. A by-subject listing of concomitant medications will include all medications 
(including vaccinations) taken during the study regardless of the timing for the start of the 
medication. All medications started before the administration of the study drug will be included in 
the data but will be identified as “prior” in the listing. Only the concomitant medication use will be 
summarized.
The number and percentage of subjects who took at least 1 medication during the double-blind 
period as well as the number and percentage of subjects who took each type of medication will be 
presented for each treatment group. Medications will be listed according to their WHO Drug 
Dictionary Anatomic Therapeutic Chemical (ATC) class level 4 and preferred drug name within 
ATC class level 4 by decreasing frequency of incidence for all active treatment groups combined. 
The list of excluded medications is provided in Appendix B.
9.1.8
Vital Sign Procedure
The following vital signs will be recorded at the times specified in Appendix A: height (cm), 
weight (kg), systolic and diastolic blood pressure (mm Hg), heart rate (beats/min), respiratory rate 
(breaths/min), and temperature (°C or °F). If clinically significant vital sign changes from 
screening/baseline are noted, the changes will be documented as TEAEs in the TEAE eCRF. 
Screening/baseline events will be documented in the Medical History eCRF. Clinical significance 
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is defined as any variation in vital signs that has medical relevance and may result in an alteration 
in medical care. The investigator will continue to monitor the subject until the parameter returns to 
baseline or until the investigator determines that follow-up is no longer medically necessary.
9.1.9
Physical Examination Procedure
A physical examination will be performed at the times specified in Appendix A. Each examination 
will include the following assessments: eyes; ears; nose; throat; cardiovascular system; respiratory 
system; gastrointestinal system; dermatologic system; musculoskeletal system; extremities; 
nervous system; lymph nodes; and other.
If clinically significant changes from screening/baseline are noted, the changes will be 
documented as TEAEs in the TEAE eCRF. Screening/baseline events will be documented in the 
medical history eCRF. Clinical significance is defined as any variation in physical findings that 
has medical relevance and may result in an alteration in medical care. The investigator will 
continue to monitor the subject until the parameter returns to baseline or until the investigator 
determines that follow-up is no longer medically necessary.
9.1.10
Neurological Examination Procedure
A separate neurological examination will be performed and results collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, motor function (including 
strength and reflexes), and sensation.
9.1.11
Safety Evaluations
Investigators are responsible for monitoring the safety of subjects who have entered this study and 
for alerting the sponsor or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
TEAEs that are serious, considered related to the study treatment or the study, or that caused the 
subject to discontinue before completing the study. The subject should be followed until the event 
is resolved or explained. Frequency of follow-up evaluation is left to the discretion of the 
investigator.
The following additional clinical safety monitoring and expanded evaluation by the previously 
established DMC for soticlestat phase 3 clinical studies to utilize the following:

Electronic data capture (EDC) will have a specific flag that will be checked at enrollment for
subjects on concomitant perampanel.

Electronic daily seizure and medication diary will be used for the phase 3 studies. This will 
enable review of blinded seizure count data for subjects on concomitant perampanel (and all 
subjects included in phase 3).
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
The contract research organization (CRO) and sponsor medical monitors will closely monitor 
the seizure frequency counts entered in the electronic daily seizure and medication diary for 
subjects on concomitant perampanel and will have a standing agenda item to review data for 
subjects on perampanel in the medical monitor review meetings.

If there is a significant increase in seizure frequency rate noted for the subjects on concomitant 
perampanel (blinded review), an ad hoc DMC meeting will be called for an unblinded review 
and recommendation by the independent DMC members.

There will be a standing agenda item for review of seizure frequency rate and safety data for all 
subjects on concomitant perampanel in the DMC meetings.
9.1.11.1
Ophthalmological Evaluation Procedure
An ophthalmologic evaluation will be conducted by a pediatric ophthalmologist or 
neuro-ophthalmologist preferably, although an adult ophthalmologist or an optometrist 
experienced with examining children may be allowed following discussion with the medical
monitor. The ophthalmologic evaluation may include:
1. Age and developmentally appropriate quantitative visual acuity.
a) If the subject is unable to perform quantitative visual acuity assessment due to age or 
developmental ability, a qualitative assessment should be attempted.
2. Bilateral red reflex test (also known as Bruckner transillumination test), to assess for lens 
abnormalities.
3. Postinstillation of mydriatic eye drop (cyclopentylate is contraindicated in this population with 
epilepsy), slit lamp (portable acceptable) examination for anterior or posterior lens opacities 
concerning for cataracts after adequate pupil dilation. For subjects unable to cooperate with slit 
lamp examination due to age or developmental ability, use of a 20-D double aspheric binocular 
indirect ophthalmoscopy lens or penlight is acceptable.
4. Indirect and or direct ophthalmoscopy of the optic nerve and retina after adequate pupillary 
dilation, preferably with a picture of the fundus.
These evaluations are to be collected at baseline (between the screening and randomization visits) 
and end of the study (before the last visit) for subjects who complete the 16 weeks of double-blind 
treatment or at the early termination visit for those subjects who do not complete (please see 
Appendix A).
9.1.11.2
ECG Procedure
For each subject, 12-lead digital electrocardiograms (ECGs) will be collected according to the 
schedule of study procedures (Appendix A). Subjects must be supine for approximately 5 to 
10 minutes before ECG collection and remain supine but awake during ECG collection.
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ECGs may be obtained at additional times, when deemed clinically necessary. Collection of more 
ECGs (more replicates) than expected at a particular time point is allowed when needed to ensure 
high-quality recordings.
ECGs will initially be interpreted by a qualified physician (the investigator or qualified designee) 
at the site as soon after the time of ECG collection as possible, and ideally while the subject is still 
present at the site, to determine whether the subject meets entry criteria at the relevant visit(s) and 
for immediate subject management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the subject will be assessed by the investigator for symptoms (eg, palpitations, near 
syncope, syncope) and to determine whether the subject can continue in the study, and the medical 
monitor or the sponsor should be contacted. The investigator or qualified designee is responsible 
for determining if any change in subject’s management is needed and must document his/her 
review of the ECG printed at the time of evaluation from at least 1 of the replicate ECGs from each 
time point.
Any clinically significant finding that was not present at screening/baseline will be reported and 
discussed with the medical monitor or the sponsor. When there are differences in ECG 
interpretation between the investigator (or qualified designee) and the site/local cardiologist, the 
investigator (or qualified designee’s) interpretation will be used for study entry and immediate 
subject management. The investigator (or qualified designee) must document his/her review of the 
ECGs printed at the time of collection.
9.1.11.3
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of these 
procedures and specimen handling will be given in the laboratory manual. 
The details for amounts of blood collected per visit and for the study are provided in Appendix G. 
The volumes do not exceed 3 mL/kg of body weight during any 8-week period or at any visit.
Table 9.a lists the tests that will be obtained for each laboratory specimen.
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis a
Erythrocytes
Hemoglobin
Hematocrit
Red blood cell indices
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Red cell distribution width
White blood cell count and 
differential
Neutrophils, segmented
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Mean platelet volume
Sodium
Potassium
Total bilirubin
Direct bilirubin
Indirect bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma glutamyl transferase (GGT)
Blood urea nitrogen (BUN)
Creatinine
Urea
Calcium
Phosphate
Glucose
Albumin
Protein
Carbon dioxide
Magnesium
Chloride
pH a
Protein a
Glucose a
Ketones a
Bilirubin a
Nitrite a
Urobilinogen a
Erythrocytes
Leukocyte esterase
Microscopy
Other Serum
Hepatitis B virus surface antigen
Hepatitis B core antibody
Hepatitis C virus antibody
Parathyroid hormone, intact
Vitamin D
Pregnancy test (female subjects only)—choriogonadotropin beta
a Urinalysis is the primary method. Urine dipstick may be used as a backup only. If sufficient volume of urine cannot 
be obtained for either central urinalysis testing or dipstick testing in clinic, per investigator’s discretion, dipstick tests 
can be provided to parents/caregivers for home urine testing and results reported to the site for interpretation.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results. Local laboratories are allowed before randomization only if a 
screening laboratory value is missing, and after randomization only for emergent reasons, 
including pregnancy tests.
It is anticipated that some laboratory values may be outside of the normal value range due to the 
underlying disease. As in routine practice, the investigators should use their medical judgment 
when assessing clinical significance. Clinical significance is defined as any variation in laboratory 
measurements which has medical relevance, and which results in a change in medical care. If 
clinically significant laboratory changes from baseline are noted, the changes will be documented 
as TEAEs in the eCRF. The investigator will also assess the relationship to study treatment for all 
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clinically significant out of range values. The investigator will continue to monitor the subject with 
additional laboratory assessments until (1) values have reached normal range and/or baseline, or 
(2) in the judgment of the investigator, out of range values are not related to the administration of 
study drug or other protocol-specific procedures.
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase [GGT], and 
INR) should be performed within a maximum of 7 days and preferably within 48 to 72 hours after 
the abnormality was noted. (Refer to Section 7.5 and Section 9.3.1 for the appropriate guidance on 
reporting abnormal liver function tests.)
If ALT or AST remains elevated >3 times the ULN on these 2 consecutive occasions the 
investigator must contact the medical monitor for consideration of additional testing, close 
monitoring, possible discontinuation of study drug, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as a TEAE (please refer to 
Section 9.3.1).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
9.1.12
Documentation of Concomitant (Including ASM and Rescue) Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject/parent or caregiver over the counter. Concomitant 
medication is not provided by the sponsor. At each study visit, the subject/parent or caregiver will 
be asked whether they have taken any medication other than the study drug (used from signing of 
informed consent through the end of the study), and all medications including vitamin 
supplements, over-the-counter medications, and oral herbal preparations must be recorded in the 
eCRF. Documentation will include generic or trade medication name, dose, unit, frequency, route 
of administration, start and end dates, and reason for use.
ASMs treatments, artisanal cannabidiol use, VNS settings, and ketogenic diet should not be altered 
during the study.
9.1.13
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. These include clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening (Visit 1), according to the judgment of the 
investigator. The condition (ie, diagnosis) should be described and recorded in the eCRF.
9.1.14
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed in children aged ≥6 years by use of the C-SSRS. 
The C-SSRS is a 3-part scale that measures suicidal ideation (eg, subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency), and suicidal 
behavior (actually, interrupted, and aborted attempts at suicide) (Posner et al. 2011).
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Two versions of the C-SSRS will be used in this study for all subjects ages 6 through 21 years: the 
C-SSRS Children’s Screening/Baseline (recall period lifetime/12 months) and the C-SSRS 
Children’s Since-Last-Visit.
Children who are <6 years old at the start of the study will have an unscheduled visit after turning 
age 6, at which time the C-SSRS Children’s Screening/Baseline version will be completed. The 
C-SSRS Children’s Since-Last-Visit version will be completed at the end of the study.
Study staff trained in the administration of the C-SSRS will assess subject suicidality using the 
C-SSRS, eliciting answers from the subject/parent or caregiver. Ultimately, the determination of 
the presence of suicidal ideation or behavior depends on the clinical judgment of the investigator.
If a subject exhibits signs of suicidal ideation or behavior, the subject will be withdrawn as 
described in Section 7.5.
9.1.15
Health Outcome/Quality of Life Measures
9.1.15.1
CGI-I (Clinician)
The CGI-I Clinician) is a 7-point Likert scale that the investigator uses to rate a subject’s change 
(improvement) in overall seizure control, behavior, safety and tolerability, after the initiation of 
study drug relative to baseline (before treatment with the study drug). The subject will be rated as 
follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 
(minimally worse), 6 (much worse), and 7 (very much worse). The investigator or designee will 
complete the CGI-I at the timepoints specified in Appendix A.
9.1.15.2
Care GI-I (Caregiver)
The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall 
seizure control, behavior, safety and tolerability after the initiation of study drug relative to 
baseline (before treatment with the study drug). The subject will be rated as follows: 1 (very much 
improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 
(much worse), and 7 (very much worse). The parent/caregiver will complete the Care GI-I via 
interview at the timepoints specified in Appendix A.
9.1.15.3
CGI-I Seizure Intensity and Duration
The CGI-I Seizure Intensity and Duration instrument is used by the parent/caregiver to rate 
changes in intensity and/or duration of the most impactful seizures from the first assessment. The 
subject’s symptoms will be rated as follows: 1 (very much improved), 2 (much improved), 
3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much 
worse). The parent/caregiver will complete the CGI-I seizure intensity and duration at the 
timepoints specified in Appendix A.
9.1.15.4
CGI-I Nonseizure Symptoms
The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the 
investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains 
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The following definitions apply for contraception and pregnancy avoidance procedures.

A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in 
younger women (eg, those <45 years old) or women who are not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.
For sterilized male partners, at least 1 year should have passed since bilateral vasectomy, and they 
must confirm they have obtained documentation of the absence of sperm in the ejaculate or have 
had bilateral orchidectomy. Subjects and parents/legal guardians will be provided with 
information regarding acceptable methods of contraception as part of the informed consent 
process and will be asked to sign a consent form stating that there is clear understanding (including 
by the parents/legal guardian) of the requirements for avoidance of pregnancy and donation of ova 
during the course of the study and for 30 days after the last dose of study drug. This consent may be 
signed by the legally authorized representative of the subject. 
Female subjects of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at screening (Visit 1). A pregnancy test at randomization 
(Visit 2) is not required for eligibility if performed and confirmed negative at Visit 1 and if the 
investigator does not deem it necessary to repeat pregnancy test at Visit 2. 
During the course of the study, subjects will receive continued guidance with respect to the 
avoidance of pregnancy and ova donation as part of the study procedures. A serum or urine hCG 
pregnancy test will also be performed at Visit 11 (Day 113)/early termination. Additional 
pregnancy tests (serum or urine) may be performed throughout the study at the investigator’s 
discretion.
9.1.16.3
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Assessment of subject compliance through such questions as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late? (Even in women with irregular or infrequent menstrual cycles, a 
pregnancy test must be performed if the answer is “yes.”)
–
Is there a chance you could be pregnant?
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9.1.17
Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn immediately, and 
the study drug should be immediately discontinued. 
For female subjects, if the pregnancy occurs during administration of active study drug, eg, after 
Visit 2 or within 30 days of the last dose of active study drug, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.1. For partners 
of male subjects, if the pregnancy occurs during the study or within 90 days after the last dose, it 
should be reported following authorization from the subject’s partner.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted.
9.1.18
Documentation of Screen Failure
Investigators must account for all subjects with a signed informed consent. If the subject is found 
to be ineligible for the study before randomization, the investigator should record the primary 
reason for screen failure in the eCRF. The IWRS should be contacted as a notification of screen 
failure.
The primary reason for screen failure is to be recorded in the IWRS. Subjects may be rescreened 
after consultation with the medical monitor or sponsor.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Pretreatment event (PTE).

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Withdrawal by subject/parent or legal guardian (specify reason).

Study terminated by sponsor.
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
Other (specify reason).
Subjects may be rescreened after consultation with the medical monitor or sponsor.
9.1.19
Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the study.
If the subject is found to be ineligible, the investigator should record the primary reason for failure 
on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
The subject/parent or caregiver will record the study drug taken by subject daily, in the morning 
and evening. This module in the electronic daily seizure and medication diary is only available to 
the subject/parent or caregiver for entry each day, and retroactive entries are not allowed using the 
handheld device or web portal.
Confirmation of study drug intake and dosing will be recorded in the electronic daily seizure and 
medication diary on a daily basis. Any missed doses will be recorded in the electronic daily seizure 
and medication diary by the subject/parent or caregiver and reviewed by the site personnel. The 
subject/parent or caregiver will be required to bring used/unused study drug and the electronic 
daily seizure and medication diary device to each site visit. All subject/parent or caregiver should 
be re-instructed about the dosing requirements during study contacts. The authorized site 
personnel conducting the re-education must document the process in the subject’s source records.
Missed or discrepant entries must be reconciled at the site level and must be accurately reflected in 
the eCRF. Sites will be asked to submit data correction request forms to correct any discrepancies 
regarding study medication that may pose a potential safety concern for the participant. This 
includes potential typographical and/or data entry errors indicating study drug overdose or 
underdose, etc. Sites must ensure the eCRF accurately reflects study drug administration in 
accordance with eCRF completion guidelines.
Subject compliance with study drug will be assessed at each visit.
Compliance will be tracked through the subject electronic daily seizure and medication diary and 
all entries will be reviewed by site personnel, reconciled against returned study medication with 
queries, as necessary.
Subjects who are significantly noncompliant will be discontinued from the study. A subject will be 
considered significantly noncompliant if he or she misses more than 20% of study medication 
during the study duration unless there is a valid reason for interruption in the study medication 
such as hospitalization. These cases should be discussed with the study monitor. Similarly, a 
subject will be considered significantly noncompliant if he or she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.
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9.3
Safety Monitoring
The sponsor’s medical monitor and/or pharmacovigilance physician will monitor safety data 
throughout the course of the study.
9.3.1
Reporting of Abnormal LFTs
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed 
within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Refer to Section 7.5 and Section 10.2.1 for the appropriate guidance on reporting abnormal liver 
function tests.)
If a subject is noted to have elevated ALT or AST >3 times the ULN on 2 consecutive occasions, 
the abnormality should be recorded as a TEAE or SAE. In addition, eCRFs must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed. The investigator must contact 
the medical monitor for discussion of the relevant subject details. and possible alternative 
etiologies. The abnormality should be recorded as a TEAE (please refer to Section 10.2.1).
If a subject is noted to have ALT or AST >3 times the ULN and total bilirubin >2 times the ULN 
for which an alternative etiology has not been identified, a CRF must be completed and transmitted 
with the SAE Report form (as per Section 10.2.2). The investigator must contact the medical 
monitor for discussion of the relevant subject details, possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions, 
and continued participation in the study. Follow-up laboratory tests as described in Table 9.a must 
also be performed.
A consultation with a hepatologist may be considered as per investigator judgement or 
consultation with the medical monitor/sponsor.
9.3.2
Reporting of QTcF Interval Increase
As noted in Section 7.5, if the QTcF is >500 ms or if there is an increase of QTcF >60 msec above 
baseline, study drug should be discontinued immediately, and the subject should be provided with 
appropriate clinical follow-up. The subject’s ECG findings should be confirmed by repeat ECG 
with manual measurement of the QTcF interval.
The investigator must contact the medical monitor for discussion of the relevant subject details, 
possible alternative etiologies, such as medical history/concurrent medical conditions, and 
continued participation in the study.
In addition, the eCRF must be completed and transmitted with the SAE Report form (as per 
Section 10.2.2).
If safety monitoring uncovers an issue that needs to be addressed by unblinding at the group level, 
only members of the DMC (see Section 11.0) can conduct additional analyses of the safety data.
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10.0
COLLECTION AND REPORTING OF ADVERSE EVENTS
10.1
Definitions
In this study, AE refers to both PTEs and TEAEs. PTEs are AEs that started after the signing of 
informed consent but before receiving any study drug. TEAEs are AEs that started after the first 
dose of study drug.
10.1.1
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
been administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.2
Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as
additional AEs. If a diagnosis is unknown, signs or symptoms should be recorded 
appropriately as AEs.
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be AEs if they are judged 
to be clinically significant (ie, if some action or intervention is required, or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory or 
ECG re-test and/or continued monitoring of an abnormal value or finding are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.
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
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased serum creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations (eg, 
laboratory tests, ECG, radiographs) should NOT be recorded as PTEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded appropriately 
as a PTE (worsening or complication occurs before start of study drug) or a TEAE (worsening 
or complication occurs after start of study drug). Investigators should ensure that the event 
term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy), 
any occurrence of an episode should only be captured as an AE if the condition becomes more 
frequent, serious or severe in nature. Investigators should ensure that the event term recorded 
captures the change in the condition from baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a AE if occurring to a greater 
extent to that which would be expected. Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as a TEAE. Investigators should ensure that 
the event term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of a TEAE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in intensity of AEs:

If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be recorded as an AE. Complications resulting from any planned surgery should be 
reported as AEs.
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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded as an 
AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
AEs but instead will be documented on an Overdose page of the (e)CRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF.
10.1.3
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which 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.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
10.1.4
AEs of Special Interest
An AE of special interest (serious or nonserious) is one of scientific and medical concern specific 
to the compound or program for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda.

Potential drug-drug interaction between soticlestat and perampanel leading to increased 
seizure frequency:
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A potential drug-drug interaction with perampanel and soticlestat resulting in increased seizure 
frequency was noted in 3 subjects in the TAK-935-2001 study of adult subjects with DEEs. To 
assess this potential interaction, the following clinical safety monitoring and expanded 
evaluation will be performed to closely monitor seizure frequency in these subjects. (Please 
see Section 9.3.3.)

Cataracts:
During nonclinical studies, incipient posterior cortical, subcapsular lenticular cataracts of 
moderate grade were seen in 1 male rat at 300 mg/kg/d and in 1 female rat at 100 mg/kg/d. To 
assess these potential changes, a detailed ophthalmological monitoring and evaluation will be 
performed. (Please see Section 9.1.11.1 and Section 9.3.4.)

Psychosis:
During the phase 1 multiple rising dose study in healthy subjects, episodes of confusion, 
euphoria, and psychosis were seen at the highest dose of 600 mg/d. However, in this study 
subjects were not up-titrated to the target dose. Psychiatric AEs should be monitored closely by 
the investigator and reported based on AE/SAE criteria described in Section 10.1.3.
AEs of special interest must be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor.
10.1.5
Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6
Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments.
10.1.7
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
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10.1.8
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.1.9
Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.10
Frequency
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.1.11
Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE (eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE).

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Dose interrupted – the dose was interrupted due to the particular AE.
10.1.12
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
sign/symptom has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, sign/symptom, or laboratory value on the last day of the observed 
study period is worse than when it started; is an irreversible congenital anomaly; the subject 
died from another cause with the particular AE state remaining “not recovered/not resolved.”

Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).
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
Fatal – the AE is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
AE Collection Period
Collection of PTEs will commence from the time the subject/parent or legal guardian signs the 
informed consent to participate in the study and will continue until the subject is first administered 
study drug (Day 1) or until screen failure. For subjects who discontinue before study drug 
administration, PTEs are collected until the subject discontinues study participation.
Collection of TEAEs will commence from the time that the subject is first administered study drug 
(Day 1). Routine collection of TEAEs will continue until Visit 12 for those who do not roll over to 
the OLE study. For those who do roll over, routine collection of TEAEs will continue to midnight 
on the day of Visit 11.
10.2.1.2
AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing TEAEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until a satisfactory explanation for the changes is 
observed. All AEs will be documented in the AE page of the eCRF, whether or not the investigator 
concludes that the event is related to the drug treatment. The following information will be 
documented for each event:
1. Event term.
2. Start and stop date and time.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not applicable for PTEs).
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6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
Subject diary and/or health outcome/quality of life measures will not be used as a primary means 
to collect AEs. However, should the investigator become aware of a potential AE through the 
information collected with this instrument, proper follow-up with the subject for medical 
evaluation should be undertaken. Through this follow-up, if it is determined that an AE not 
previously reported has been identified, normal reporting requirements should be applied.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure:

A sponsor SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event.

Regardless of causality, SAEs must be reported to the sponsor Global Pharmacovigilance 
department or designee, to the attention of the individual identified in the contact information 
list, which will be provided in the study manual, within 24 hours of becoming aware of the 
event. This will be done by transmitting an EDC SAE report. If transmission of an EDC SAE 
report is not feasible within 24 hours, then a facsimile of the completed paper-based SAE form 
should be sent. If SAEs are reported via fax or by email, EDC must be updated as soon as 
possible with the appropriate information.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of serious PTEs will follow the procedure described for SAEs.
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
transmit it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
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10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA, 
investigators, and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor-supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB or IEC.
11.0
STUDY-SPECIFIC COMMITTEES
Details of the DMC are captured in a DMC charter written before the start of the study.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO Drug 
Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent form.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
After submission of the CRFs to the sponsor, any change of, modification of or addition to the data 
on eCRFs should be made by the investigator with use of change and modification records of 
eCRFs (data clarification form) provided by the sponsor. The principal investigator must review 
the data clarification form for completeness and accuracy and must sign and date the form.
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After the lock of the study database, any change of, modification of, or addition to the data on the 
eCRFs should be made by the investigator with the approval from the sponsor. The principal 
investigator must review the data change for completeness and accuracy and must sign and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The following procedure is applicable for all countries except Japan.
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, ICFs, subject authorization 
forms regarding the use of personal health information (if separate from the ICFs), including 
consent to use digital tools and applications, if applicable, electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long term legibility. Furthermore, International Conference on Harmonisation (ICH) E6 
Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the study site agreement between the 
investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The following procedure is applicable for Japanese sites only.
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), and detailed records of drug disposition to enable evaluations or audits 
from regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
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the subject’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator and the head of the study site to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the study site agreement between the 
investigator and/or the head of the study site and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted before unblinding of subject’s treatment assignment. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods.
13.2
Determination of Sample Size
The study will randomize a total of approximately142 subjects at a 1:1 ratio to receive soticlestat 
or placebo, resulting in approximately 71 subjects per arm. A minimum of 20 pediatric subjects 
aged 2 through 6 years will be enrolled. The sample size calculation is based on the results from 
the ELEKTRA study and other studies on seizure frequency reduction in subjects with DS and 
under the assumption of using the Wilcoxon rank-sum test. The pooled SD of the percent change 
from baseline in convulsive seizure frequency is 55%. It is assumed that subjects in the placebo 
group will experience a mean reduction from baseline in convulsive seizure frequency of 5%. A 
sample size of 71 subjects per treatment arm will provide at least 80% power at a 2-tailed 
significance level of 5% to detect a 27% difference in mean percent reduction in convulsive 
seizure frequency per 28 days during the 16-week treatment period between treatments (assuming 
subjects receiving soticlestat will experience at least a 32% mean reduction in convulsive seizure 
frequency).
13.2.1
Analysis Sets
13.2.1.1
ITT Analysis Set
All randomized subjects will be included in the intent-to-treat (ITT) analysis set. All ITT analyses 
will be based on each subject’s randomized treatment assignment.
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13.3
Other Statistical Issues
13.3.1
Significance Levels
All statistical analyses will be 2-sided and will be tested at the 0.05 level of significance.
13.3.2
Missing or Invalid Data
Techniques for handling missing information with respect to reporting of seizures in the treatment 
period and with respect to subjects who discontinue early will be specified in detail in the SAP.
13.3.3
Interim Analyses
A blinded interim analysis may be performed to allow for sample re-estimation based on the 
pooled standard deviation of the percent change from baseline in convulsive seizure frequency per 
28 days. Details will be provided in the SAP.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
With the exception of visits in China, monitoring visits can be virtual or on site, as indicated in the 
clinical monitoring plan. The investigator guarantees access to source documents by the sponsor or 
its designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process.
In case of prolonged access restrictions to external visits (study monitors) to an investigative site 
due to COVID-19 pandemic and wherever possible by local regulations, remote Source Data 
Verification (rSDV) may be considered for critical data related to subject’s safety and any key 
variables to ensure data accuracy and integrity.
If rSDV is required, full details of the process will be included the Clinical Monitoring Plan 
following any applicable local guidance for secure access to remote source documents and data 
security provisions to protect personal data.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
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deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A protocol deviation form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
The following procedure applies to Japanese sites only: 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the study site of the deviation or change as 
well as its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the study site as soon as possible and an approval from IRB should be obtained.
The investigator should document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States [US] Food and Drug Administration [FDA], 
the United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and study site (or in 
Japan, the head of the study site) guarantee access for quality assurance auditors to all study 
documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual subjects (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix D. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
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15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the US Department of Health and Human 
Services (for studies including TDC Americas).
The sponsor or designee will supply relevant documents for submission to the respective IRB 
or IEC for the protocol’s review and approval. This protocol, the IB, the informed consent form, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB or IEC 
for approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study. 
The IRB or IEC approval must refer to the study by exact protocol title, number, and version date; 
identify versions of other documents (eg, informed consent form) reviewed; and state the approval 
date. The sponsor will notify the site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the study.
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or 
IEC. All IRB and IEC approvals and relevant documentation for these items must be provided to 
the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written and electronic consent documents will embody the elements of informed consent as 
described in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study, including the use of electronic devices and associated technologies (if 
applicable). The informed consent form and the subject information sheet (if applicable) further 
explain the nature of the study, its objectives, and potential risks and benefits, as well as the date 
informed consent is given. The informed consent form will detail the requirements of the subject 
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and the fact that he or she is free to withdraw at any time without giving a reason and without 
prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ballpoint ink in the case of written consent. The 
investigator must also sign and date the informed consent form and subject authorization (if 
applicable) at the time of consent or after the receipt of subject signature (in the case of consent) 
and prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable.
Once signed, the original informed consent form or certified copy (if applicable), subject 
authorization form (if applicable), and subject information sheet (if applicable) will be maintained 
by the study site. The investigator must document the date the subject signs the informed consent 
in the subject’s medical record. Copies of the signed informed consent form, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be provided 
to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
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permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials, may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 9.1.1).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
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designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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Appendix A
Schedule of Study Procedures
Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
Informed consent and assent (if 
applicable)
X
Historical seizure calendar 
review
X
Inclusion/exclusion criteria
X
X
Randomization
X
Demographics, medical history, 
medication history
X
Seizure identification and 
diagnostic review form (TESC)
X
Height, weight
X
Weight 
only
X
Serum/urine pregnancy test m
X
X
X
Vital signs
X
X
X
X
Physical examination
X
X
X
X
Neurological examination
X
X
X
X
Ophthalmological examination n
X
X n
12-lead ECG j
X
X
X
X
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Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
Clinical laboratory tests 
(chemistry, hematology, and 
urinalysis)
X
X
X
X
Hepatitis B virus surface antigen
Hepatitis B core antibody 
Hepatitis C virus antibody
X
Concomitant medications review
o
X
X
X
X
X
X
X
X
X
X
X
X
Prior ASM review
X
X
Concomitant ASM and rescue 
medications
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS p
X
X
X
X
Electronic daily seizure and 
medication diary review 
X
X
X
X
X
X
X
X
X
X
X
X
CGI-I (clinician)
X
X
X
Care GI-I
X
X
X
CGI-I Nonseizure Symptoms
X
X
X
CGI-I Seizure Intensity and 
Duration
X
X
X
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Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
QI-Disability
X
X
X
Contact IWRS to obtain subject 
ID/medication
ID/subject status s
X
X
X
X
Dispense study drug
X
X
X k
At-home administration of first 
dose of study drug (Dose 1) in 
the morning (continue Dose 1 
through morning dose of Day 8)
X
At-home dose adjustment to 
Dose 2 (continue Dose 2 through 
morning dose of Day 15)
X t
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a VVs are allowed if aligned with institutional or local guidelines, via phone or via any platforms approved by local regulations, in addition to the communication 
platform offered through the study. V1 (screening) and V11 (Day 113)/ET must be conducted in person; V9 (Day 57) is to be conducted in person if possible, but 
may be conducted virtually (via video or phone) in response to the COVID-19 pandemic and/or based on sponsor approval and if permitted by local regulations. In 
extenuating circumstances, V2 (Day 0/randomization) and V11 (Day 113)/ET can be virtual visits (only via video, not phone), with sponsor approval and if 
permitted by local regulations. In addition, any visit identified as VV in this table may be conducted in clinic and in person if requested by the subject/parent or 
guardian and/or at the investigator’s discretion.
b The minimum duration for screening is 28 days (ie, V2 [Day 0/randomization] cannot occur earlier than 29 days after V1 [screening]). All efforts shall be made to 
complete all procedures at randomization visit (V2 [Day 0/randomization]). If unable to complete, reason should be captured and subject can proceed to 
randomization if there are no clinically significant abnormalities in screening procedures and it is thought appropriate, in the investigator’s judgment. For female 
subjects of childbearing potential, pregnancy test at V2 (Day 0/randomization) is not required for eligibility if performed and confirmed negative at V1 (screening) 
and if the investigator does not deem it necessary to repeat pregnancy test at V2 (Day 0/randomization).
c Dose 1 is started the morning after V2 (Day 0/randomization) or the day after study medication is received. Dose 2 and Dose 3 are started the evening of dose 
titration (V4 [Day 8] and V6 [Day 15], respectively).
d Approximately 2 days after starting Dose 1 and after each dose escalation or taper and before the next visit, subjects will be contacted by phone to monitor study 
drug compliance, to assess the tolerability and safety of the study drug, and to monitor concomitant medication use and treatment-emergent AEs. These safety 
checks at V3 (Day 3), V5 (Day 10), and V7 (Day 17) are calculated as approximately 2 days after starting Dose 1, Dose 2, and Dose 3, respectively.
e Dates of V4 [Day 8] and V6 [Day 15] are calculated from the date of the first dose (Day 1) and the date of titration to Dose 2 (V6 [Day 15]), respectively.
f Dates calculated from V2 (Day 0/randomization).
g Subjects who do not continue into the OLE study will undergo the dose taper procedures and will then proceed to the follow-up period.
h Subjects who withdraw early from the study should complete all final visit procedures at V11 (Day 113)/ET.
(For legibility considerations, footnote i is not used.)
j A 12-lead ECG will be recorded at V1 (Day -42 to -1/screening), V2 (Day 0/randomization), V9 (Day 57), and V11 (Day 113)/ET and will be read locally. ECG at 
V1 needs to be recorded before randomization to evaluate subject’s eligibility.
k At V11 (Day 113)/ET, subjects who do not enroll in the OLE study that day will be dispensed study drug to taper down. Subjects who enroll in the OLE study that 
day should take their final dose of double-blind study drug in the evening of the day of V11 (Day 113)/ET.
l The timing of the follow-up phone call, follow-up period, or follow-up visit will depend on the dose taper procedures followed. Visit will be eliminated for subjects 
enrolled in OLE.
m For female subjects of childbearing potential, pregnancy test at V2 (Day 0/randomization) is not required for eligibility if performed and confirmed negative at V1 
(screening) and if the investigator does not deem it necessary to repeat pregnancy test at V2 (Day 0/randomization). A serum or urine hCG pregnancy test will also 
be performed at V11 (Day 113)/ET. Additional pregnancy tests (serum or urine) may be performed throughout the study at the investigator’s discretion.
n Ophthalmological examination at V11 (Day 113)/ET may be conducted within a 14-day window (-14 days) before V11 (Day 113)/ET.
o Subjects on concomitant perampanel will undergo additional safety monitoring as per Section 9.3.3.
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Appendix B
Strong CYP3A Inducers 
Strong inducers of CYP3A are prohibited, except antiseizure medication. Examples of prohibited 
inducers are listed below. (Source: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-ta
ble-substrates-inhibitors-and-inducers, Table 3-3 [inducers], accessed 06 March 2022.)
Strong CYP3A Inducers (examples)
Apalutamide
Enzalutamide
Mitotane
Rifampin
St. John’s wort
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Appendix C
Virtual Visits and Trial Management During COVID-19 Pandemic and Other 
Extenuating Circumstances
The purpose of this section is to safeguard the safety of study subjects, ensure continuation of 
study conduct and uninterrupted maintenance of treatment, and preserve the integrity of the study, 
in case of a general public health crisis or pandemic, such as COVID-19, or other extenuating 
circumstances, such as war or natural disaster. This section addresses situations in which 
scheduled in-person clinic visits are not feasible due to local, regional, or national restrictions.
COVID-19 vaccination of subjects is allowed during the study.
The principal investigator holds the ultimate responsibility for the safety and well-being of study 
subjects and shall maintain compliance with the current local and health authority guidelines and 
recommendations pertaining to the pandemic. The study procedures outlined in this protocol may 
be modified subsequently according to any emerging or revised health authority guidelines during 
conduct of the trial due to the ongoing COVID-19 pandemic.
Due to the COVID-19 pandemic or other extenuating circumstances, such as war or natural 
disaster, study subjects may not be able to attend scheduled in-person clinic visits as per protocol. 
All investigational sites should follow local and country health and government authorities’ 
restrictions and recommendations on conduct of clinical trials during the event. Sites are 
encouraged to discuss subjects and their continued virtual participation with the medical monitor.
In the event an in-person visit is not possible for the planned clinic visits and in alignment with 
institutional or local guidelines, comfort level of site staff, and caregiver/family willingness to 
travel, virtual visits are allowed to monitor subject safety. Additional details around such virtual 
visits are provided in Appendix A.
The virtual visits identified in Appendix A, if aligned with institutional or local guidelines, to 
ensure a point of contact between subjects/parents/caregivers and site staff, can be conducted via 
phone or via any platforms approved by local regulations, besides the communication platform 
offered through the study. This flexibility of communication is not expected to negatively affect 
subject safety or study data integrity.
In addition, the virtual visits included in the study, if aligned with institutional or local guidelines, 
can be converted into clinic visits at the request of subjects or parents/caregivers or at 
investigators’ discretion to lessen the burden of the study and support investigators, subjects, and 
parents/caregivers, particularly during the COVID-19 pandemic or other extenuating 
circumstances, such as war or natural disaster. This conversion is not expected to negatively affect 
subjects’ safety or study data integrity.
A decentralized clinical trial platform may be used to conduct the virtual visits, if permitted by 
local regulations. The site will ensure that any related subject data privacy aspects are 
appropriately managed and will obtain subjects’ consent for the use of the platform for virtual 
visits. 
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If necessary and in alignment with institutional or local guidelines and as allowed by local 
regulations, a virtual visit can be conducted as a phone visit instead. Likewise, if necessary, the site 
can use the site’s own platform or phone/tablet social media apps in place of virtual visits. 
In case subjects are not able to attend the planned clinic visits, Direct to Patient (DTP) study drug 
shipment may be considered using a specialized courier vendor, if in alignment with institutional 
or local guidelines and as allowed by local regulations. A process has been put in place to ensure 
shipment traceability, proper temperature control conditions, study drug return and accountability 
should be properly managed to ensure that any related subject data privacy aspects are 
appropriately covered. The investigator will obtain subject’s consent to DTP study drug shipment 
and the use of their personal data to that effect.
Any protocol deviations, missing visits, or missing assessments related to COVID-19 restrictions 
will be recorded and reported in the clinical study report.
In case of prolonged access restrictions to external visits (study monitors) to an investigative site 
due to COVID-19 pandemic and wherever possible by local regulations, remote Source Data 
Verification (rSDV) may be considered for critical data related to subject’s safety and any key 
variables to ensure data accuracy / integrity.
If rSDV is required, full details of the process will be included the Clinical Monitoring Plan 
following any applicable local guidance for secure access to remote source documents and data 
security provisions to protect personal data.
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Appendix D
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each consent form should contain a subject authorization 
section that describes the uses and disclosures of a subject’s personal information (including 
personal health information) that will take place in connection with the study. If a consent form 
does not include such a subject authorization, then the investigator must obtain a separate 
subject authorization form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix E
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written ICF, the subject or the subject’s 
legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative (parent or legal guardian) may discontinue participation at 
any time without penalty or loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative (parent or legal 
guardian) will be informed in a timely manner if information becomes available that may be 
relevant to the subject’s willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for subjects, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use effective or highly effective contraception (as defined in the 
informed consent) from screening throughout the duration of the study, and for 30 days 
following the last dose of study drug. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. If a subject is found to be pregnant 
during study, study drug will be discontinued, and the investigator will offer the subject the 
choice to receive unblinded treatment information.
26. Male partners of female subjects must use effective or highly effective contraception (as 
defined in the informed consent) if required as part of the method (eg, double-barrier, 
vasectomized partner) from signing the informed consent throughout the duration of the study, 
and for a minimum of 30 days following the last dose of study drug. If the partner or wife of the 
subject is found to be pregnant during the study, the investigator will offer the subject the 
choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix F
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix G
Blood Volumes
The amount of blood collected from subjects at any single visit and at all scheduled visits during 
the study (including screening and post randomization treatment period) will be the volumes as 
shown in the table for the respective weight categories. Additional blood may be drawn for retests 
or unscheduled visits, if any, and will not exceed the volume indicated for each weight group. 
Additional blood may be drawn for retests or unscheduled visits, if any, and will not exceed 30 mL 
per visit.
Blood Sample Volumes (mL) by Visit and Subject Weight
Subject 
Weight
Screening, 
Visit 1 a
Randomization,
Day 0, 
Visit 2
Day 57, 
Visit 9 a
ET, Visit 11 
(Day 113) a
Total, 
Scheduled 
Visits
Unscheduled/ 
Retest b
10-15 kg
21.5
5.3
14.6
14.6
56.0
21.5
>15-45 kg
26.1
7.0
18.3
20.0
71.4
26.1
>45 kg
30.0 
9.0
22.0
23.5
84.5
30.0
See the laboratory manual for details.
ET = early termination.
a Blood volumes may vary slightly if performed by a local laboratory or by central antiseizure medication testing 
laboratory in China.
b Unscheduled retests are allowed at investigator discretion. Scheduled and unscheduled blood sample volumes must 
not exceed 3 mL/kg of body weight during any 8-week period or in any single day.
Weight is measured to 1 decimal place for determining dosing bands. Thus, 44.9 kg would be in the 30 to <45 mg 
band.
These volumes represent the approximate maximum for visit and weight. 
 
 These volumes do not 
exceed 3 mL/kg of body weight during any 8-week period or in any single day.
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Protocol Amendment FR-IT-RS v1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
7
Appendix C Trial Management 
During COVID-19 Pandemic
Revised language regarding 
conditions under which virtual 
visits are allowed.
Clarification.
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