A Phase 2, Prospective, Interventional, Open-Label, Multi-Site, Extension Study to Assess the Long-Term Safety and Tolerability of Soticlestat (TAK-935) as Adjunctive Therapy in Subjects With Developmental Epileptic Encephalopathies Including Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication Syndrome (ENDYMION 1)
Phase: PHASE2
Conditions: Epilepsy, Dravet Syndrome (DS), Lennox-Gastaut Syndrome (LGS)
Sponsor: Takeda

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TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 2, Prospective, Interventional, Open-Label, Multisite, Extension Study To Assess 
the Long-Term Safety and Tolerability of Soticlestat (TAK-935) as Adjunctive Therapy in 
Subjects With Developmental Epileptic Encephalopathies Including Dravet Syndrome, 
Lennox Gastaut Syndrome, CDKL5 Deficiency Disorder, and Chromosome 15 Duplication 
Syndrome (ENDYMION 1)
Open-Label Extension Study of Soticlestat in Developmental Epileptic Encephalopathies
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421 USA
Study Number:
TAK-935-18-001
IND Number:
133627
EudraCT Number:
2018-002485-39
Compound:
Soticlestat (TAK-935)
Date:
24 August 2021
Version/Amendment 
Number:
Amendment 4
Amendment History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
24 August 2021
Amendment 4
Substantial
Global
14 August 2020
Amendment 3
Substantial
Global
13 February 2020
Amendment 2
Substantial
Global
28 May 2019
Amendment 1 ES v1
Substantial
Spain
11 February 2019
Amendment 1
Substantial
Global
16 April 2018
Initial version
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.
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
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 are 
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, 
prescribing information 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, life, dignity, integrity, confidentiality of personal information, 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 Council for Harmonisation, E6(R2) 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 (SAEs) defined in Section 10.2
of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the Investigator. (Appendix D).
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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1.3
Protocol Amendment 4 Summary of Changes
Rationale for Amendment 4
This section describes the changes in reference to the protocol incorporating Amendment 4. The 
primary reasons for this amendment are to reflect change of sponsor, correct errors, and simplify 
the protocol to maximize subject retention.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only, 
and are not captured in the following table. The following table summarizes the changes.
Protocol Amendment 4
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
1.
Cover page.
Throughout text.
Change name of sponsor from 
Ovid Therapeutics Inc. to 
Takeda Development Center 
Americas, Inc.
Ovid is no longer involved in 
development of soticlestat.
2.
Cover page, page headers, 
Section 2.0, Study Summary
Remove (OV935) from study 
title and number.
Ovid is no longer involved in 
development of soticlestat.
3.
Cover page
Section 2.0, Study Summary
Section 9.1.2 Informed 
Consent Procedures
Rename ENDYMION to 
ENDYMION 1.
Change in recognition of the 
ENDYMION 2 study (TAK-935-
3003) planned for phase 3 subjects.
4.
Title and page headers.
Change throughout, except for 
study numbers.
Change TAK-935 to Soticlestat 
(TAK-935).
Replace TAK-935 with 
soticlestat in text.
Soticlestat has been approved as the 
International Nonproprietary Name 
for TAK-935.
5.
Section 1.2, Approval
Change signatories to Takeda.
Identify current sponsor.
6.
Section 2.0, Study Summary
Remove description of 
exploratory objectives and 
endpoints from synopsis.
To comply with the Takeda 
template.
7.
Section 2.0, Study Summary
Clarify that screening/baseline 
period of 4 weeks is the 
maximum.
Clarify maximum allowed gap 
between antecedent study and this 
study.
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Protocol Amendment 4
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
13.
Section 2.0, Study Summary
Remove reference to 
coronavirus disease 2019 
(COVID-19) procedures in 
synopsis.
This detail unnecessary for protocol 
synopsis.
14.
Section 2.0, Study Summary
Section 13.2, Determination of 
Sample Size
Reduce enrollment 
expectation.
Previously included rollover phase 
3 subjects in the estimate. Now 
phase 3 subjects who consent will 
be rolled over to planned 
ENDYMION 2 open-label 
extension study.
15.
Section 7.4.1, Criteria for 
Discontinuation or Withdrawal 
of a Subject
Expand criteria for 
discontinuation of subjects.
To comply with the Takeda 
template.
16.
Section 7.4.1, Criteria for 
Discontinuation or Withdrawal 
of a Subject
For subjects who do not 
undergo the Baseline Period in 
this study, only the seizure 
frequency from the Baseline 
Period of the antecedent study 
will be used as the baseline for 
determining increase in 28-day 
seizure frequency, not the 
historical baseline seizure 
frequency from the last 3 
months before entering the 
study.
Clarify the baseline for determining 
increase in 28-day seizure 
frequency.
17.
Section 8.1, Materials and 
Supplies
Section 8.1.1, Storage
Remove country-specific 
material.
Country-specific information will 
be included in site materials.
18.
Section 8.2.1, Subjects Who 
Complete Antecedent Studies 
>15 Days Before Screening in 
This Study
Remove seizure diary data 
collected during the antecedent 
study as baseline.
Clarify that the seizure diary data 
collected during the 4-week 
Baseline Period will be used as the 
baseline for endpoint analysis in 
this study.
19.
Section 9.1.1, COVID-19 
Pandemic Study Procedures
Appendix C, Study
Management During COVID-
19 Pandemic
Replace text of Appendix C, 
Study Management During 
COVID-19 Pandemic, with 
equivalent Takeda language
To comply with the Takeda 
template.
20.
Throughout Section 9.1, Study 
Procedures
Where remote assessments are 
permitted, clarify that these can 
be by video, phone, or 
telehealth/telemedicine.
Clarify allowable means of 
performing remote assessments.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 4 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................20
3.1
Study-Related Responsibilities.................................................................................20
3.2
Coordinating Investigator.........................................................................................20
3.3
List of Abbreviations ...............................................................................................21
4.0
INTRODUCTION.........................................................................................................23
4.1
Background .............................................................................................................23
4.2
Study Rationale .......................................................................................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Objectives................................................................................................................24
5.1.1
Primary Objective............................................................................................24
5.1.2
Secondary Objectives ......................................................................................24
5.1.3
Exploratory Objective......................................................................................25
5.2
Endpoints.................................................................................................................25
5.2.1
Primary Endpoints - Safety..............................................................................25
5.2.2
Secondary Endpoints .......................................................................................25
5.2.3
Exploratory Endpoints .....................................................................................26
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Summary of Study Design .......................................................................................26
6.2
End of Study Definition...........................................................................................27
6.3
Dosing Rationale .....................................................................................................27
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............28
7.1
Inclusion Criteria .....................................................................................................28
7.2
Exclusion Criteria ....................................................................................................30
7.3
Concomitant Medications ........................................................................................30
7.4
Discontinuations ......................................................................................................30
7.4.1
Criteria for Discontinuation or Withdrawal of a Subject...................................30
7.4.2
Discontinuation of Study Sites/Site Terminated by Sponsor.............................33
7.4.3
Discontinuation of the Study/Study Terminated by Sponsor.............................33
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................33
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8.1
Materials and Supplies.............................................................................................33
8.1.1
Storage ............................................................................................................33
8.2
Treatments Administered and Assignment to Treatment ..........................................33
8.2.1
Subjects Who Complete Antecedent Studies >15 Days Before Screening in 
This Study .......................................................................................................34
8.2.2
Subjects Who Complete Double-blind Antecedent Studies ≤15 Days Before 
Screening in This Study...................................................................................36
8.2.3
Subjects Who Complete the Open-Label Antecedent Study ≤15 Days Before 
Screening in This Study (Only)........................................................................37
8.2.4
Dose Tapering .................................................................................................38
8.2.5
Investigator Responsibilities for Drug Administration......................................38
8.3
Blinding...................................................................................................................38
8.4
Treatment Compliance.............................................................................................39
9.0
STUDY PLAN ..............................................................................................................39
9.1
Study Procedures.....................................................................................................39
9.1.1
COVID-19 Pandemic Study Procedures...........................................................39
9.1.2
Informed Consent Procedures ..........................................................................39
9.1.2.1
Materials and Supplies.............................................................................40
9.1.2.2
Screening/Baseline Visit..........................................................................40
9.1.3
Demographics, Medical History, and Medication History Procedures..............41
9.1.4
Physical Examination Procedure......................................................................41
9.1.5
Neurological Examination Procedure...............................................................41
9.1.6
Height and Weight...........................................................................................41
9.1.7
Vital Signs Measurements ...............................................................................42
9.1.8
Seizure and Dosing Diary Procedure................................................................42
9.1.9
Documentation of Concomitant Medications ...................................................42
9.1.10
Documentation of Concurrent Medical Conditions...........................................43
9.1.11
Procedures for Clinical Laboratory Samples ....................................................43
9.1.12
Contraception and Pregnancy Avoidance Procedure ........................................44
9.1.13
ECG Procedure................................................................................................45
9.1.14
Clinical Assessment of Suicidal Ideation and Behavior....................................45
9.1.15
Aberrant Behavior Checklist............................................................................45
9.1.16
Vineland Adaptive Behavior Scale...................................................................46
9.1.17
Quality of Life in Childhood Epilepsy .............................................................46
9.1.18
Sleep Disruption Numerical Rating Scale ........................................................47
9.1.19
Clinician’s Clinical Global Impression of Severity...........................................47
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9.1.20
..............................................47
9.2
Documentation of Screen Failure.............................................................................48
9.3
Documentation of Study Entrance............................................................................48
9.4
Laboratory Sample Collection..................................................................................48
9.5
..........................................48
9.6
.............................48
10.0
SAFETY EVALUATIONS ...........................................................................................49
10.1
AEs..........................................................................................................................49
10.1.1
Severity Assessment ........................................................................................51
10.1.2
Causality Assessment ......................................................................................51
10.1.3
SAEs ...............................................................................................................51
10.1.4
Suspected Unexpected Serious Adverse Reactions...........................................52
10.2
Reporting AEs .........................................................................................................52
10.2.1
Sponsor Reporting Requirements.....................................................................53
10.2.2
Investigator Reporting Requirements...............................................................53
10.3
Exposure During Pregnancy and/or Lactation ..........................................................54
10.4
Safety Monitoring....................................................................................................54
10.4.1
Reporting of Abnormal Liver Function Tests...................................................54
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................55
12.0
DATA QUALITY ASSURANCE .................................................................................55
12.1
Data Collection and Storage.....................................................................................56
13.0
STATISTICAL METHODS AND PLANNED ANALYSES.........................................56
13.1
General Considerations............................................................................................56
13.2
Determination of Sample Size..................................................................................57
13.3
Definition of Baseline..............................................................................................57
13.4
Analysis Sets ...........................................................................................................57
13.4.1
Safety Analysis Set..........................................................................................57
13.4.2
Intent-to-Treat Analysis Set .............................................................................57
13.4.3
Modified Intent-to-Treat Analysis Set..............................................................57
13.5
Demographics and Baseline Characteristics .............................................................57
13.6
Subject Disposition..................................................................................................57
13.7
Concomitant Medications and Non-Pharmacologic Therapies and Procedures .........58
13.8
Treatment Compliance.............................................................................................58
13.9
Safety Analyses .......................................................................................................58
13.10 Efficacy Analyses....................................................................................................59
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13.11 Exploratory Analyses...............................................................................................59
13.12 Other Statistical Issues.............................................................................................60
13.12.1 Significance Levels..........................................................................................60
13.12.2 Missing or Invalid Data ...................................................................................60
13.13 Ad hoc/Interim Analyses .........................................................................................60
14.0
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS.....................................................................................................60
14.1
Informed Consent ....................................................................................................60
14.2
Ethical Review.........................................................................................................60
14.3
Regulatory Considerations.......................................................................................61
14.4
Confidentiality.........................................................................................................61
14.5
Investigator Information ..........................................................................................62
14.6
Protocol Signatures..................................................................................................62
14.7
Final Report Signature.............................................................................................62
14.8
Publication Policy....................................................................................................62
15.0
LIST OF REFERENCES...............................................................................................62
LIST OF IN-TEXT TABLES
Table 8.a
Dosing Schedule by Weight for Subjects Who Complete the Antecedent Study 
>15 Days Before the Screening Visit of This Study............................................35
Table 8.b
Dosing Schedule by Weight for Subjects Who Complete the Double-blind 
Antecedent Study ≤15 Days Before the Screening Visit of This Study ...............37
Table 9.a
Clinical Laboratory Tests...................................................................................44
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................64
Appendix B
Strong CYP3A Inducers and Inhibitors ..............................................................68
Appendix C
Study Management During COVID-19 Pandemic ..............................................69
Appendix D
Responsibilities of the Investigator.....................................................................71
Appendix E
Protocol History................................................................................................73
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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
Compound:
Soticlestat (TAK-935)
Title of Protocol: A Phase 2, Prospective, Interventional, 
Open-Label, Multi-Site, Extension Study to Assess the 
Long-Term Safety and Tolerability of Soticlestat (TAK-
935) as Adjunctive Therapy in Patients with 
Developmental Epileptic Encephalopathies Including 
Dravet Syndrome, Lennox Gastaut Syndrome, CDKL5 
Deficiency Disorder, and Chromosome 15 Duplication 
Syndrome (ENDYMION 1)
IND No.: 133627
EudraCT No.: 2018-
002485-39
Study Number: TAK-935-18-001
Phase: 2
Study Design:
This is a multisite, open-label extension (OLE) study designed to obtain additional safety and tolerability data 
related to soticlestat (also known as TAK-935) administered long-term in subjects with developmental and epileptic 
encephalopathies who participated in a previous soticlestat clinical study. Additional aims are to explore the long-
term effects of soticlestat on seizure frequency and to assess the effects of soticlestat on quality-of-life measures.
All subjects will receive soticlestat twice a day (BID), with or without food, orally or via gastrostomy tube (G-tube) 
or percutaneous endoscopic gastrostomy (PEG) tube. A jejunostomy tube (J-tube) may be considered following 
approval by the medical monitor and sponsor. Subjects enrolled in clinical sites in China are not to receive study 
drug via G-tube, PEG tube, or J-tube. No subject will receive placebo treatment in this OLE study. The planned 
doses of soticlestat represent the intended therapeutic doses of soticlestat and include the full range of doses 
available for soticlestat. The maximum dose available for this study will be 600 mg/day (300 mg BID).
Subjects from 3 antecedent studies (TAK-935-2001, TAK-935-2002, and TAK-935-18-002) will be rolled over into 
this study. Subjects will be eligible for screening within 15 days of completing the last visit of the antecedent 
soticlestat study (except for adult subjects enrolled in the TAK-935-2001 study, who will be eligible for screening in 
this OLE study up to 15 months after completion of the antecedent study). A subject who completes the antecedent 
study between approximately 15 and 30 days before the Screening Visit of this OLE study can be entered in this 
study with the approval of the sponsor after considering the subject’s overall compliance in the antecedent study and 
after the subject meets all inclusion and no exclusion criteria for this study.
Study design, including timing of enrollment and dosing and titration schedule, is based upon the age of the subject 
(pediatric or adult), the type of antecedent study completed (blinded or unblinded), and how many days elapsed 
between completing the antecedent study and the Screening Visit in this study (≤15 days or >15 days). The last visit 
in the antecedent study can be combined with the first visit in this OLE.
Study procedures for subjects who complete antecedent studies >15 days before screening are as follows:

4-week Screening/Baseline Period.

2-week Dose Optimization Period (see Dosing and Titration Schedule, below).

Maintenance Period that continues until development is stopped by the sponsor, or the product is approved for 
marketing, or at any time at the discretion of the sponsor.

4-week Safety Follow-up Period of soticlestat dose tapering (up to 2 weeks) and safety follow up.
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At the Screening Visit (Visit 1), informed consent and/or assent (if applicable) is obtained from the subjects and/or 
subjects’ legally acceptable representative. Subjects will then undergo screening procedures to assess study 
eligibility in accordance with the study entry criteria. Identical assessments for subjects who complete the last visit 
of their antecedent protocol ≤30 days before the Screening Visit in this study do not need to be repeated. At this 
Screening Visit and at subsequent visits, subjects and/or subjects’ caregivers will be provided with a seizure diary 
and will be instructed to record seizure data on a daily basis. The 4-week Baseline Period seizure diary recording 
can begin the day after informed consent has been signed. At the end of the 4 week Baseline Period, subjects will 
return to the clinic on Visit 2 (Day 1).
Dosing and Titration Schedule
Subjects will initiate soticlestat at Dose 1, and the dose will be titrated up every 7 days (Day 8 and Day 15) as shown 
in the table below. Two days after each change in dose, subjects will be contacted by phone to monitor study drug 
compliance, concomitant medication use, and AEs. Subjects who cannot tolerate Dose 1 will be withdrawn from the 
study. After up-titration, subjects who cannot tolerate the new dose may have their dose reduced, based on the 
investigator’s judgment and in consultation with the subject’s caregiver, when applicable. Subjects will be contacted 
by phone 2 days following escalation to the maximum dose to assess safety and tolerability of the study drug. 
Dosing may be adjusted at the investigator’s discretion throughout the study; however, frequent adjustments are 
discouraged.
Adult subjects who cannot tolerate at least 100 mg BID dosing will be withdrawn from the study. Pediatric subjects 
who cannot tolerate Dose 1 will be withdrawn from the study.
The following is the dosing schedule by weight for subjects who complete the antecedent study >15 days before the 
Screening Visit of this study:
Weight 
(kg)
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
≥60 and 
Adults
Dose 1 
(mg/day)a,b
80
120
120
120
160
160
160
200
200
200
200
Dose 2 
(mg/day)a,b
160
200
240
240
280
280
320
360
360
360
400
Dose 3 
(mg/day)a,b
220
260
320
360
400
440
480
480
520
560
600
a Soticlestat dosing will be calculated based on body weight in pediatric subjects only. Dose will be recalibrated 
approximately every 6 months at clinic visits during the Maintenance Period, to ensure that the dose is current weight–
appropriate.
b Daily doses are divided equally and administered twice daily.
Subjects who complete double-blind antecedent studies ≤15 days before screening in this study will be managed as 
follows:

1-week Dose Optimization Period (see Dosing and Titration Schedule, below).

Maintenance Period until development is stopped by the sponsor, or the product is approved for marketing, or at 
any time at the discretion of the sponsor.

4-week Safety Follow-up Period of soticlestat dose tapering (up to 2 weeks) and safety follow-up.
Subjects who complete the antecedent study ≤15 days before the Screening Visit of this study will not undergo the 
4-week Baseline Period. These subjects may complete Visit 1 (Screening) and Visit 2 on the same day. At Visit 1, 
informed consent and/or assent (if applicable) is obtained from the subjects and/or subjects’ legally acceptable 
representative. Subjects will then undergo screening procedures to assess study eligibility in accordance with the 
study entry criteria. Identical assessments for subjects who complete the last visit of their antecedent protocol ≤30 
days before the Screening Visit in this study do not need to be repeated. Subjects and/or subjects’ caregivers will be 
provided with a seizure diary and will be instructed to record seizure data on a daily basis. For subjects in this group, 
the seizure diary data collected during the 4-week prospective Baseline Period of the antecedent study will be used 
as the baseline seizure data for endpoint analysis in this study. The seizure diary recording can begin as soon as the 
informed consent has been signed.
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Dosing and Titration Schedule
Subjects will initiate the soticlestat at Dose 1 and the dose will be titrated up at Day 8 as shown in the table below. 
After up-titration, subjects who cannot tolerate the new dose may have their dose reduced, based on the 
investigator’s judgment and in consultation with the subject’s caregiver, when applicable. Subjects will be contacted 
by phone 2 days following escalation to the maximum dose to assess safety and tolerability of the study drug. 
Dosing may be adjusted at the investigator’s discretion throughout the study; however, frequent adjustments are 
discouraged.
Adult subjects who cannot tolerate at least 100 mg BID dosing will be withdrawn from the study. Pediatric subjects
who cannot tolerate Dose 1 will be withdrawn from the study.
The following is the dosing schedule by weight for subjects who complete double-blind antecedent studies ≤15 days 
before the Screening Visit of this study:
Weight 
(kg)
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
≥60 and 
Adults
Dose 1 
(mg/day)a,b
160
200
240
240
280
280
320
360
360
360
400
Dose 2 
(mg/day)a,b
220
260
320
360
400
440
480
480
520
560
600
a Soticlestat dosing will be calculated based on body weight in pediatric subjects only. Dose will be recalibrated 
approximately every 6 months at clinic visits during the Maintenance Period, to ensure that the dose is current weight-
appropriate.
b Daily doses are divided equally and administered twice daily.
Subjects who complete the open-label antecedent study ≤15 days before screening in this study (only) will be 
managed as follows:

Maintenance Period until development is stopped by the sponsor, or the product is approved for marketing, or at 
any time at the discretion of the sponsor.

4-week Safety Follow-up Period of soticlestat dose tapering (up to 2 weeks) and safety follow-up.
Subjects who complete the open-label antecedent study ≤15 days before the Screening Visit of this study will not 
undergo the 4-week Baseline Period or the 2-week Dose Optimization Period. These subjects may complete Visit 1 
(Screening) and Visit 2 (Day 1) on the same day. At Visit 1, informed consent and/or assent (if applicable) is 
obtained from the subjects and/or subjects’ legally acceptable representative. Subjects will then undergo screening 
procedures to assess study eligibility in accordance with the study entry criteria. Identical assessments for subjects 
who complete the last visit of their antecedent protocol ≤30 days before the Screening Visit in this study do not need 
to be repeated. Subjects and/or subjects’ caregivers will be provided with a seizure diary and will be instructed to 
record seizure data on a daily basis. For subjects in this group, the seizure diary data collected during the 4-week 
prospective Baseline Period of the antecedent study will be used as the baseline seizure data for endpoint analysis in 
this study. The seizure diary recording can begin as soon as the informed consent has been signed.
Dose Tapering 
During the tapering period of not more than 14 days, the soticlestat dose will be decreased to the next lower level no 
more frequently than every 3 days based on the investigator’s discretion until soticlestat is discontinued. After 
tapering, subjects will complete a Safety Follow-up visit (Visit 11) approximately 15 days after the last dose of 
study drug and exit the study.
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
Received at least 10 weeks of treatment (combined Dose Optimization and Maintenance Period) with the study 
drug in a soticlestat clinical study and the subject did not have a serious or severe adverse event (AE) that, in the 
investigator’s or sponsor’s opinion, was related to the study drug and would make it unsafe for the subject to 
continue receiving the study drug.
Number of Subjects:
Approximately 160.
Number of Sites: 
Estimated total: Approximately 70.
Dose Levels:
Adult subjects: 100, 200, 300 mg BID
Pediatric subjects: Weight-based equivalent dosing in 
subjects with body weight of <60 kg.
Route of Administration:
Oral or via G-tube or PEG tube, or J-tube. 
Duration of Treatment:
Dose optimization period: 1 or 2 weeks 
Maintenance Period: until development is stopped by the 
sponsor, or the product is approved for marketing, or at 
any time at the discretion of the sponsor
Tapering period: 2 weeks
Period of Evaluation:
Screening/baseline period: Maximum of 4 weeks
Dose optimization period: 1 or 2 weeks
Maintenance Period: until development is stopped by 
the sponsor, or the product is approved for marketing, 
or at any time at the discretion of the sponsor.
Tapering period: 2 weeks 
Safety follow-up period: 2 weeks
Main Criteria for Inclusion:
Subjects must have participated in a previous soticlestat study and meet one of the following conditions: 

Successfully completed a soticlestat clinical study.

Received at least 10 weeks of treatment (combined Dose Optimization and Maintenance Period) with the study 
drug in a soticlestat clinical study and the subject did not have a serious or severe AE that, in the investigator’s 
or sponsor’s opinion, was related to the study drug and would make it unsafe for the subject to continue 
receiving the study drug.

In the opinion of the investigator, the subject has the potential to benefit from the administration of soticlestat 
(not applicable for Spain).
Main Criteria for Exclusion:

Clinically significant disease, that, in the investigator’s opinion, precludes study participation.

Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the investigator or 
defined as ‘yes’ to suicidal ideation question 4 or 5 on the Columbia-Suicide Severity Rating Scale [C-SSRS] at 
Screening) or appearing suicidal per investigator judgment.
Main Criteria for Evaluation and Analyses:
Primary Endpoints—Safety

Incidence of AEs.

Change from Baseline in behavioral and adaptive functional measures using the Vineland Adaptive Behavior 
Scale. 

Change from Baseline in behavior measures using total scores and subscale scores of the Aberrant Behavior 
Checklist-Community Edition for subjects ≥6 years of age. 

Change from Baseline in the Columbia-Suicide Severity Rating Scale categorization based on Columbia 
Classification Algorithm of Suicide Assessment categories 1, 2, 3, 4, and 5 for subjects ≥6 years of age.

Absolute values and change from Baseline in clinical laboratory assessments, vital sign measurements, body 
weight, and ECG parameters.

Incidence of potentially clinically significant clinical safety laboratory test values, vital signs, weight, height, 
and ECG evaluations.
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Secondary Endpoints 

Percent change from Baseline in all seizure 28-day frequency. 

Percent change from Baseline in drop seizure 28-day frequency. 

Percent change from Baseline in convulsive seizure 28-day frequency. 

Percent change from Baseline in motor seizure 28-day frequency. 

Change from Baseline in CGI-S.
Statistical Considerations:
All statistical analyses will be performed using SAS® software (SAS Institute Inc, Cary, NC) Version 9.4 or higher. 
All clinical study data will be presented in subject data listings. Data summaries will be presented for all endpoints 
and will include descriptive statistics (number of subjects [n], mean, standard deviation [SD], first quartile [Q1], 
median, third quartile [Q3], minimum, and maximum) for continuous variables and frequency and percentage for 
categorical and ordinal variables. If there are missing values, the number of missing will be presented, but without a 
percentage.
Baseline for efficacy analyses is the baseline of the antecedent study, except for subjects who rolled over more than 
15 days after completion of the antecedent study.
All enrolled subjects will be included in the intent-to-treat analysis set. 
All enrolled subjects who have received at least 1 dose of study drug and have been assessed for at least 1 day in the 
treatment period will be included in the modified intent-to-treat analysis set. 
Safety Analysis Set
All enrolled subjects who take at least 1 dose of study medication in this study will be included in the safety analysis 
set. All analyses will be conducted using the safety analysis set. based on the treatment that was actually 
administered to each subject in the antecedent study. In addition, subject disposition, demographics, and baseline 
characteristics will be summarized using the safety analysis set.
Safety Analyses
Descriptive statistics will be used to summarize all safety endpoints. Two-sided 95% confidence intervals (CIs) will 
be presented where meaningful. Data summaries will be displayed for incidence of AEs, clinical laboratory 
variables, vital sign measurements, body weight, body weight by age group, ECG parameters, as well as changes in 
behavioral and adaptive functioning measures using Vineland Adaptive Behavior Scale and subscales of Aberrant 
Behavior Checklist-Community Edition, as appropriate. Changes from Baseline to study timepoints in clinical 
chemistry and hematology results will be summarized descriptively. Each laboratory parameter will be classified as 
low, normal, or high relative to the parameter’s reference range. The number and percentage of subjects with shifts 
in clinical laboratory parameters will be summarized. Laboratory abnormalities for each treatment will also be 
summarized with shift tables. Listings of subjects with abnormal results will be provided. 
The number and percentage of subjects with Columbia-Suicide Severity Rating Scale assessments of suicidal 
ideation and behavior will also be summarized. 
Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized by preferred term and system organ class categories. Serious AEs (SAEs) and AEs leading to study 
discontinuation will also be summarized. 
The following definitions will be used for AEs:

Treatment-emergent AE (TEAE): Any AE that starts or increases in severity during or after the first dose of 
study drug.

Treatment-emergent SAE: A TEAE that is serious.
The incidence of TEAEs, discontinuations due to TEAEs, and drug-related, serious, and severe TEAEs will be 
summarized. Detailed listings of AEs, SAEs, related AEs, and discontinuations due to AEs will be provided.
Prior and concomitant medication use will be summarized by World Health Organization Anatomical Therapeutic 
Chemical (WHO ATC) classification system. Listings will be provided for all concomitant medications.
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Efficacy Analyses
Descriptive statistics will be used to summarize all efficacy endpoints (seizure frequencies over a 28-day period and 
CGI-S). Two-sided 95% CIs will be presented where meaningful. Changes in drop, convulsive, and motor seizure 
frequency will be calculated and summarized.
Sample Size Justification: No formal sample size calculation has been performed for this extension study. Subjects 
from the phase 2 studies TAK-935-2001, TAK-935-2002 (ELEKTRA) and TAK-935-18-002 (ARCADE) have the 
opportunity to roll over to this OLE study; therefore, there is the potential to enroll approximately 160 subjects.
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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 
clinical supplier list in the study manual. The identified vendors will perform these activities 
either in full or in partnership with the sponsor.
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and subinvestigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that 
must be signed by each investigator and subinvestigator before the study starts at their study site; 
in addition, any potential conflicts of interests that are not covered by this financial disclosure 
form should be disclosed separately to the sponsor before the start of the study at their site.
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to sponsor before the start of the study.
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
Term
Definition
24HC
24S-hydroxycholesterol
ABC-C
Aberrant Behavior Checklist-Community Edition
AE
adverse event
AED
antiepileptic drugs
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BID
twice a day
CDKL5
cyclin-dependent kinase-like 5
CH24H
cholesterol 24S-hydroxylase
CGI-S
Clinician’s Clinical Global Impression of Severity
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DEE
developmental and epileptic encephalopathy
Dup15q
chromosome 15q duplication
DS
Dravet syndrome
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EE
epileptic encephalopathy
EO
enzyme occupancy
G-tube
gastrostomy tube
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
iDMC
independent Data Monitoring Committee
IEC
independent ethics committee
IRB
institutional review board
IWRS
interactive web response system
J-tube
jejunostomy tube
LGS
Lennox-Gastaut syndrome
OLE
open-label extension
PEG tube
percutaneous endoscopic gastrostomy tube
PET
positron emission tomography
PD
pharmacodynamic(s)
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Term
Definition
PK
pharmacokinetic(s)
QTcF
corrected QT interval by Fridericia’s formula
SAE
serious adverse event
SoA
schedule of assessments
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VABS
Vineland Adaptive Behavior Scale
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4.0
INTRODUCTION
4.1
Background
Soticlestat (TAK-935) is a potent and selective cholesterol 24S-hydroxylase (CH24H) inhibitor 
currently in development for adjunct treatment of developmental and epileptic encephalopathies 
(DEEs). 
In the brain, cholesterol is metabolized by CH24H, which is specifically and constitutively 
expressed in neurons, to 24S-hydroxycholesterol (24HC). This cholesterol metabolite, 24HC, 
leaves the brain via lipoproteins and is excreted in bile. Aberrant cholesterol metabolism is 
implicated in epilepsy disorders and syndromes.
Under normal conditions, extracellular glutamate is sequestered by glutamate transporters on 
neighboring astrocytes that require adequate cholesterol levels to efficiently maintain lipid raft 
structures in the astrocyte plasma membrane. Upon central nervous system injury, CH24H is 
induced in reactive astrocytes and microglia. This leads to disruption in astrocytic glutamate 
homeostasis and a large increase in extracellular glutamate levels. As CH24H converts 
cholesterol essential for the integrity of plasma membrane lipid rafts to 24HC, the circulating 
levels of 24HC increase and may further contribute to underlying pathophysiological processes. 
Excessive extracellular glutamate and 24HC levels are thought to play major roles in 
excitotoxicity either through a sustained activation of the N-methyl-D-aspartate receptor channel 
or as a positive allosteric modulator of the receptor [1]. The processes may be equally important
in contributing to the enhanced glutamatergic activity observed in epilepsy disorders.
At the time of the initial protocol, soticlestat had been studied in 4 completed phase 1 clinical 
studies: a single-rising dose first-in-human study, a single-dose positron emission tomography 
(PET) target occupancy study (PET study), a multiple-rising dose study, and a single-dose 
relative bioavailability and food-effect study. The pharmacokinetics (PK) and 
pharmacodynamics (PD) of soticlestat in healthy subjects were characterized in these studies. In 
addition, the PET study provided clinical evidence of dose-dependent decreases in plasma 24HC 
concentrations and PET occupancy measurements that were dose- and time-dependent and 
correlated with circulating levels of 24HC. A phase 1b/2a study (TAK-935-2001) in 18 adults 
with DEE had recently completed (Section 4.2). In addition, to date, the following additional 
clinical studies have been completed: a phase 1, single- and multiple- rising dose study in 
Japanese subjects (TAK-935-1004); a phase 2 study in pediatric subjects with Dravet syndrome 
(DS) and Lennox-Gastaut syndrome (LGS) (TAK-935-2002); and a phase 2 study in pediatric 
subjects with chromosome 15q duplication (Dup 15q) and cyclin-dependent kinase-like 
5 (CDKL5) deficiency syndromes (TAK-935-18-002) (Section 4.2).
More information about these studies and 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). 
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4.2
Study Rationale
Epileptic encephalopathies (EEs) are a group of rare disorders in which unremitting epileptic 
activity contributes to severe cognitive and behavioral impairment that can worsen over time and 
lead to progressive cerebral dysfunction [2]. Epileptic encephalopathies typically start at an early 
age and manifest with seizures that are usually intractable, with electroencephalogram 
paroxysmal abnormalities. Severe neurocognitive deficits are commonly found in EEs, which 
may be susceptible to a common treatment. In a group of severe genetic disorders causing EE, 
the underlying genetic mutation also contributes to developmental delay. Hence, the 
International League Against Epilepsy expanded the concept of EE from the severe epilepsies 
with onset in infancy and childhood to epilepsy syndromes associated with encephalopathy that 
have a genetic etiology [3]. The revised classification now refers to DEEs. 
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 current IB), soticlestat is being evaluated as adjunctive therapy in 
pediatric and adult subjects with DS or LGS, highly impacted populations with great unmet need.
This OLE study is designed to obtain additional safety, tolerability, efficacy, 
 data 
related to soticlestat administered long-term in subjects who participated in either of the phase 
1b/2a or phase 2 clinical studies noted above.
5.0
STUDY OBJECTIVES AND ENDPOINTS
Study objectives and associated endpoints are presented in Section 5.1 and Section 5.2, 
respectively; the frequency and timing of study measurements is provided in the Schedule of 
Assessments (Appendix A). 
5.1
Objectives
5.1.1
Primary Objective
The primary objective of this study is to assess the long-term safety and tolerability of soticlestat 
when administered as adjunctive therapy to at least one anti-seizure therapy (ie, antiepileptic 
drugs [AEDs], vagal nerve stimulator, ketogenic diet or modified Atkins diet) in subjects with 
rare epilepsies.
5.1.2
Secondary Objectives
The secondary objectives, in subjects receiving soticlestat as adjunctive therapy to at least one 
anti-seizure therapy, are the following: 

To assess the effect of soticlestat on seizure frequency.

To assess the effect of soticlestat on the Clinical Global Impression of Severity (CGI-S) 
provided by the investigator.
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5.2.3
Exploratory Endpoints

Change from Baseline in overall Quality of Life Childhood Epilepsy score (pediatric 
subjects).

Change from Baseline in the Sleep Disruption Numerical Rating Scale.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Summary of Study Design
This is a multisite, OLE study designed to obtain additional safety and tolerability data related to 
soticlestat administered long-term in subjects with DEEs who participated in a previous 
soticlestat clinical study. Additional aims are to explore the long-term effects of soticlestat on 
seizure frequency and to assess the effects of soticlestat on quality-of-life measures.
Subjects will be eligible to enroll in this study within 15 days of completing the antecedent 
soticlestat study, except for adult subjects enrolled in the TAK-935-2001 study who will be 
eligible to enroll in this study up to 15 months after completion of the TAK-935-2001 study. In 
this OLE study, adults are defined as subjects who are 18 years or older.
A subject who completes the antecedent study between approximately 15 and 30 days before the 
Screening Visit can be enrolled in this study with the approval of the sponsor after considering 
the subject’s overall compliance and after the subject meets all inclusion and no exclusion 
criteria for this study.
Approximately 160 subjects from several antecedent studies will be rolled over into this study. 
Study design, including timing of enrollment and dosing and titration schedule, is presented in 
Section 8.2.
Subjects will receive soticlestat twice a day (BID) orally with or without food or via gastrostomy 
tube (G-tube) or percutaneous endoscopic gastrostomy (PEG) tube. A jejunostomy tube (J-tube) 
may be considered following approval by the sponsor and medical monitor. Subjects enrolled in 
clinical sites in China are not to receive study drug via G-tube, PEG tube, or J-tube. The planned 
doses of soticlestat represent the intended therapeutic doses of soticlestat and include the full 
range of doses available for soticlestat. Details of the dosing and titration schedules, including 
instructions for tapering doses of soticlestat after completion of treatment, are presented in 
Section 8.2. 
The Schedule of Study Procedures is presented by visit in Appendix A and study procedures are 
presented in detail in Section 9.0. The Screening/Baseline visit may occur on the same day as the 
end of treatment visit of the antecedent study or within 30 days after the end of treatment visit of 
the antecedent study. Identical assessments taken at the subject’s last visit of the antecedent 
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will be titrated as described in Section 8.2. This study will investigate long-term safety, 
tolerability, and effects on seizure frequency and quality of life of soticlestat in subjects who are 
also being treated with AEDs. 
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened up to 2 times, after approval by the medical monitor. Refer to Section 9.2 for 
additional information on recording screen failures.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
7.1
Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all the following criteria and 
none of the exclusion criteria (Section 7.2):
1. Subjects must have participated in a previous soticlestat study and meet one of the following 
conditions: 

Successfully completed a soticlestat clinical study.

Received at least 10 weeks of treatment (combined Dose Optimization and Maintenance 
Period) with the study drug in an antecedent placebo-controlled blinded soticlestat 
clinical study and the subject did not have a serious or severe AE that, in the 
investigator’s or sponsor’s opinion, was related to the study drug and would make it 
unsafe for the subject to continue receiving the study drug.
2. In the opinion of the investigator, the subject has the potential to benefit from the 
administration of soticlestat (not applicable for Spain).
3. The subject provides written informed consent, or the subject’s legal representative (ie, 
parent or legal guardian) provides written informed consent and the subject provides assent, 
before any study procedures are performed.
4. The subject and subject’s legal representative (ie, parent or legal guardian) (as applicable) are 
willing to comply with all study requirements.
5. From signing of informed consent, throughout the duration of the study, and for 30 days after 
last dose of study drug, female patients of childbearing potential* who are sexually active 
with a non-sterilized male partner** must agree to use a highly effective method of 
contraception (from the list below). In addition, they must not donate ova during this period.
*Females NOT of childbearing potential are defined as those who are prior to first menarche 
or who have been surgically sterilized (hysterectomy, bilateral oophorectomy, or tubal 
ligation) or who are postmenopausal (eg, defined as ≥1 year since last regular menses with a 
follicle-stimulating hormone level >40 IU/L or ≥5 years since last regular menses, confirmed 
before any study drug is administered).
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**Sterilized males should be ≥1 year post-vasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
A highly effective method of contraception is defined as one that has no higher than a 1% 
failure rate per year when used consistently and correctly. In this study, the only acceptable 
methods of contraception are as follows:
a) Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:

Oral.

Intravaginal.

Transdermal.
b) Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral.

Injectable.

Implantable.
c) Double-barrier methods (each time the patient has intercourse):

Sponge (plus spermicidal cream or jelly) PLUS male condom with or without 
spermicidal cream or jelly.

Cap (plus spermicidal cream or jelly) PLUS male condom with or without 
spermicidal cream or jelly.

Diaphragm (plus spermicidal cream or jelly) PLUS male condom with or without 
spermicidal cream or jelly.
d) Intrauterine device (Copper T PLUS condom).
e) Intrauterine hormone-releasing system.
f)
Sterilization:

Bilateral tubal occlusion.

Vasectomized partner (provided that the partner is the sole sexual partner of the 
patient and the absence of sperm in the ejaculate has been confirmed).
g) Sexual abstinence, if it is the preferred and usual lifestyle of the patient, will be 
considered an acceptable method of contraception on a case-by-case basis upon prior 
approval by the medical monitor. Patients practicing abstinence as a method of 
contraception must refrain from heterosexual intercourse throughout the duration of the 
study and for 30 days after last dose of study drug.
From signing of informed consent, throughout the duration of the study, and for 30 days 
after last dose of study drug, male patients (post-pubertal unless permanently 
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sterilized**) who are sexually active with a female partner of childbearing potential* 
must agree to use barrier contraception (eg, condom with or without spermicidal cream or 
jelly). In addition, they must not donate sperm during this period. 
7.2
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria:
1. Clinically significant disease, that, in the investigator’s opinion, precludes study 
participation.
2. Enrollment in any other clinical trial involving an investigational drug, device, or treatment 
in the past 90 days (with the exception of an antecedent study involving soticlestat).
3. Subject is currently pregnant or breastfeeding or is planning to become pregnant during the 
study or within 30 days of the last study drug administration.
4. Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the 
investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the C-SSRS at 
Screening) or appearing suicidal per investigator judgment.
7.3
Concomitant Medications
Use of strong inducers and inhibitors of cytochrome P450 (CYP)3A4 are prohibited, except for 
AEDs (eg, carbamazepine, phenobarbital, phenytoin). Refer to Appendix B for examples of 
prohibited CYP3A4 inducers and inhibitors. 
Vaccinations are allowed; however, the medical monitor should be informed about changes in 
the subject’s vaccination status.
Use of traditional Chinese medicines should be approved by the medical monitor at screening.
All medication including vitamin supplements, over-the-counter medications, and herbal 
preparations including (medical) marijuana and cannabidiol products will be collected 
throughout the study.
7.4
Discontinuations
7.4.1
Criteria for Discontinuation or Withdrawal of a Subject
The criteria for enrollment must be followed explicitly. If the investigative site identifies a 
subject who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor 
must be notified immediately. If the sponsor identifies a subject who did not meet enrollment 
criteria and who was inadvertently enrolled, the investigator site will be notified immediately. A 
discussion must occur between the sponsor and the investigator to determine whether the subject 
may continue in the study, with or without study drug. Inadvertently enrolled subjects may be 
maintained in the study and on study drug when the sponsor agrees with the investigator that it is 
medically appropriate for that subject. The subject may not continue in the study with or without 
study drug if the sponsor does not agree with the investigator’s determination that it is medically 
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appropriate for the subject to continue. The investigator must obtain documented approval from 
the sponsor to allow the inadvertently enrolled subject to continue in the study with or without 
study drug.
In addition, patients will be discontinued from the study drug (and/or from the study) in the 
following circumstances:

Liver function test abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a patient’s laboratory profile has returned to 
normal/baseline status, see Section 10.4.1), if the following circumstances occur at any time 
during study drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or
–
ALT or AST >5 × ULN and persists for >2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

A corrected QT interval by Fridericia’s formula (QTcF) >500 ms or an increase of QTcF 
>60 msec above baseline confirmed (persistent for at least 5 minutes) and determined 
postdose either during continuous 12-lead ECG monitoring or on a repeat 12-lead ECG. 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat ECG).

Greater than a 100% increase in 28-day seizure frequency from the 4-week prospective 
Baseline Period (see formula in Section 9.1.8) and considered by the investigator to be 
clinically significant worsening of the seizure frequency. For subjects who do not undergo 
the Baseline Period in this study, the seizure frequency from the Baseline Period of the 
antecedent study will be used.

Not tolerating the lowest dose of the titration schedule.

Enrollment in any other clinical study involving a study drug or enrollment in any other type 
of medical research judged not to be scientifically or medically compatible with this study.

Suicidal ideation:
–
Study staff trained in the administration of the C-SSRS will assess subject suicidality 
using the C-SSRS (see Section 9.1.14), eliciting answers from the subject or the subject’s 
caregiver. Subjects who experience suicidal ideation or attempt suicide will be 
immediately withdrawn from the study.
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
Investigator decision (physician decision):
–
The investigator decides that the subject should be discontinued from the study; for 
example, if the subject is not responding to the treatment.

Subject decision (withdrawal by subject or withdrawal by subject’s legal representative 
[parent or legal guardian]):
–
The subject or the subject’s legal representative (ie, parent or legal guardian) requests to 
be withdrawn from the study. The specific reason for discontinuation should be recorded 
in the electronic case report forms (eCRFs) 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 an AE should not be recorded in this category. 
Similarly, lack of efficacy should not be recorded in this category.

Sponsor decision:
–
The sponsor or its designee discontinues the study or discontinues the subject’s 
participation in the study for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and Good Clinical Practice (GCP).
–
The sponsor or its designee stops the clinical study at a particular site.

Adverse event:
–
If the investigator decides that the patient should be withdrawn because of a serious 
adverse event (SAE) 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 (refer to Section 10.2).

Lost to follow-up: The subject did not attend visits (clinical or virtual), and multiple attempts 
to contact the subjects were unsuccessful. Attempts to contact the subject must be 
documented in the subject’s source documents.

Other: The specific reason should be recorded in the eCRF.

Coronavirus disease 2019 (COVID-19)/pandemic: If, in the opinion of the investigator, the 
safety of a study 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.

Significant noncompliance with study drug (as described in Section 8.4).

Lack of efficacy.
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).
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7.4.2
Discontinuation of Study Sites/Site Terminated by Sponsor
Study site participation may be discontinued if the sponsor or its designee, the investigator, or 
the institutional review board/independent ethics committee (IRB/IEC) of the study site judges it 
necessary for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP.
7.4.3
Discontinuation of the Study/Study Terminated by Sponsor
The study will be discontinued if the sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Materials and Supplies
The sponsor will supply the study sites with 100 mg soticlestat tablets and 20 mg soticlestat 
mini-tablets. Each bottle will contain a label that includes pertinent study information and 
caution statements.
Clinical study materials will be labeled according to each country’s regulatory requirements. 
If a subject is unable to come for a clinic visit to obtain study drug, the study drug may be 
shipped via a courier service.
8.1.1
Storage
Soticlestat tablets/mini-tablets are packaged in high-density polyethylene bottles with induction 
seals and child-resistant caps. 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.
8.2
Treatments Administered and Assignment to Treatment
All subjects will receive soticlestat BID, with or without food, orally or via G-tube or PEG tube. 
A J-tube may be considered following approval by the sponsor and medical monitor. Subjects 
enrolled in clinical sites in China are not to receive study drug via G-tube, PEG tube, or J-tube. 
No subject will receive placebo treatment in this OLE study. The planned doses of soticlestat 
represent the intended therapeutic doses of soticlestat and include the full range of doses 
available for soticlestat. Subjects will be titrated up to the maximum dose based on weight (see 
Sections 8.2.1 and 8.2.2). The maximum dose available for this study will be 600 mg/day 
(300 mg BID).
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Tablets/mini-tablets may be crushed and mixed well in applesauce or thick liquid, for taste 
masking, prior to dosing. The amount of applesauce or liquid needed is dependent upon the 
number of tablets/mini-tablets the subject is taking. One-half teaspoon or 2.5 mL of applesauce 
or thick liquid is needed for each mini-tablet taken and 2 teaspoons or 10 mL, respectively, is 
needed for each tablet taken.
For subjects receiving study drug via G-tube or PEG tube (or J-tube if approved by the sponsor 
and medical monitor), tablets/mini-tablets will be crushed, suspended in water, and the 
suspension will be administered via the G-tube, PEG tube, or J-tube. Complete instructions will 
be provided to subjects/caregivers in a document provided outside of the protocol. Other 
medications or enteral feeds should not be given concurrently with soticlestat. Subjects enrolled 
in clinical sites in China are not to receive study drug via G-tube, PEG tube, or J-tube.
If a subject misses a dose, the missed dose should be skipped, and the subject should continue 
with his/her normal dosing schedule. The scheduled dose can be administered or taken up to 
4 hours after the scheduled time of dosing. If the subject/caregiver remembers after 4 hours of 
the scheduled time of dosing, the dosing should be skipped and reported as a missed dose in their 
seizure diary and on the next clinic visit. 
Subjects from 3 phase 1b/2a and phase 2 antecedent studies may be rolled over into this study. 
Subjects will be eligible for screening within 15 days of completing the last visit of the 
antecedent soticlestat study (except for adult subjects enrolled in the TAK-935-2001 study, who 
will be eligible for screening in this OLE study up to 15 months after completion of the 
antecedent study). A subject who completes the antecedent study between approximately 15 and 
30 days before the Screening Visit of this OLE study may be entered in this study with the 
approval of the sponsor after considering the subject’s overall compliance in the antecedent 
study and after the subject meets all inclusion and no exclusion criteria for this study. 
Study design, including timing of enrollment and dosing and titration schedule, is based upon the 
age of the subject (pediatric or adult), the type of antecedent study completed (blinded or 
unblinded), and how many days elapsed between completing the antecedent study and the 
Screening Visit in this study (≤15 days or >15 days). In this OLE study, adults are defined as 
subjects who are 18 years or older.
8.2.1
Subjects Who Complete Antecedent Studies >15 Days Before Screening in This 
Study
Subjects who complete an antecedent study >15 days before screening in this study will be 
managed as follows:

4-week Screening/Baseline Period.

2-week Dose Optimization Period (Table 8.a).

Maintenance Period until development is stopped by the sponsor, or the product is approved 
for marketing, or at any time at the discretion of the sponsor.
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
4-week Safety Follow-up Period of soticlestat dose tapering (up to 2 weeks) and safety 
follow-up.
At the Screening Visit (Visit 1), informed consent and/or assent (if applicable) is obtained from 
the subjects and/or subjects’ legally acceptable representative. Subjects will then undergo 
screening procedures to assess study eligibility in accordance with the study entry criteria. 
Identical assessments for subjects who complete the last visit of their antecedent protocol 
≤30 days before the Screening Visit in this study do not need to be repeated. At this Screening 
Visit and at subsequent visits, subjects and/or subjects’ caregivers will be provided with a seizure 
diary and will be instructed to record seizure data on a daily basis. The seizure diary data 
collected during the 4-week Baseline Period will be used as the baseline for endpoint analysis in 
this study. The 4-week Baseline Period seizure diary recording can begin the day after informed 
consent has been signed. At the end of the 4-week Baseline Period, subjects will return to the 
clinic on Visit 2 (Day 1).
Dosing and Titration Schedule
Subjects will initiate the soticlestat at Dose 1, and the dose will be titrated up every 7 days 
(Day 8 and Day 15) as shown in Table 8.a. Two days after each change in dose, subjects will be 
contacted by phone to monitor study drug compliance, concomitant medication use, and AEs. 
Subjects who cannot tolerate Dose 1 will be withdrawn from the study. After up-titration, 
subjects who cannot tolerate the new dose may have their dose reduced, based on the 
investigator’s judgment and in consultation with the subject’s caregiver, when applicable. 
Subjects will be contacted by phone 2 days following escalation to the maximum dose to assess 
safety and tolerability of the study drug. Dosing may be adjusted at the investigator’s discretion 
throughout the study; however, frequent adjustments are discouraged.
Adult subjects who cannot tolerate at least 100 mg BID dosing will be withdrawn from the study. 
Pediatric subjects who cannot tolerate Dose 1 will be withdrawn from the study.
Table 8.a
Dosing Schedule by Weight for Subjects Who Complete the Antecedent 
Study >15 Days Before the Screening Visit of This Study
Weight (kg)
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
≥60 and 
Adults
Dose 1 
(mg/day)a,b
80
120
120
120
160
160
160
200
200
200
200
Dose 2 
(mg/day)a,b
160
200
240
240
280
280
320
360
360
360
400
Dose 3 
(mg/day)a,b
220
260
320
360
400
440
480
480
520
560
600
a Soticlestat dosing will be calculated based on body weight in pediatric subjects only. Dose will be recalibrated 
approximately every 6 months at clinic visits during the Maintenance Period, to ensure that the dose is current 
weight-appropriate.
b Daily doses are divided equally and administered twice daily.
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8.2.2
Subjects Who Complete Double-blind Antecedent Studies ≤15 Days Before 
Screening in This Study
Subjects who complete a double-blind antecedent study ≤15 days before screening in this study 
will be managed as follows:

1-week Dose Optimization Period (Table 8.b).

Maintenance Period until development is stopped by the sponsor, or the product is approved 
for marketing, or at any time at the discretion of the sponsor.

4-week Safety Follow-up Period of soticlestat dose tapering (up to 2 weeks) and safety 
follow-up. 
Subjects who complete the antecedent study ≤15 days before the Screening Visit of this study 
will not undergo the 4-week Baseline Period. These subjects may complete Visit 1 (Screening) 
and Visit 2 on the same day. At Visit 1, informed consent and/or assent (if applicable) is 
obtained from the subjects and/or subjects’ legally acceptable representative. Subjects will then 
undergo screening procedures to assess study eligibility in accordance with the study entry 
criteria. Identical assessments for subjects who complete the last visit of their antecedent 
protocol ≤30 days before the Screening Visit in this study do not need to be repeated. Subjects 
and/or subjects’ caregivers will be provided with a seizure diary and will be instructed to record 
seizure data on a daily basis. For subjects in this group, the seizure diary data collected during 
the 4-week prospective Baseline Period of the antecedent study will be used as the baseline 
seizure data for endpoint analysis in this study. The seizure diary recording can begin as soon as 
the informed consent has been signed. 
Dosing and Titration Schedule
Subjects will initiate the soticlestat at Dose 1 and the dose will be titrated up at Day 8 as shown 
in Table 8.b. After up-titration, subjects who cannot tolerate the new dose may have their dose 
reduced, based on the investigator’s judgment and in consultation with the subject’s caregiver, 
when applicable. Subjects will be contacted by phone 2 days following escalation to the 
maximum dose to assess safety and tolerability of the study drug. Dosing may be adjusted at the 
investigator’s discretion throughout the study; however, frequent adjustments are discouraged.
Adult subjects who cannot tolerate at least 100 mg BID dosing will be withdrawn from the study. 
Pediatric subjects who cannot tolerate Dose 1 will be withdrawn from the study.
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Table 8.b
Dosing Schedule by Weight for Subjects Who Complete the Double-blind 
Antecedent Study ≤15 Days Before the Screening Visit of This Study
Weight (kg)
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
≥60 and 
Adults
Dose 1 
(mg/day)a,b
160
200
240
240
280
280
320
360
360
360
400
Dose 2 
(mg/day)a,b
220
260
320
360
400
440
480
480
520
560
600
a Soticlestat dosing will be calculated based on body weight in pediatric subjects only. Dose will be recalibrated 
approximately every 6 months at clinic visits during the Maintenance Period, to ensure that the dose is current 
weight-appropriate.
b Daily doses are divided equally and administered twice daily.
8.2.3
Subjects Who Complete the Open-Label Antecedent Study ≤15 Days Before 
Screening in This Study (Only)
Subjects who complete the open-label antecedent study ≤15 days before screening in this study 
(only) will be managed as follows: 

Maintenance Period until development is stopped by the sponsor, or the product is approved 
for marketing, or at any time at the discretion of the sponsor.

4-week Safety Follow-up Period of soticlestat dose tapering (up to 2 weeks) and safety 
follow-up. 
Subjects who complete the open-label antecedent study ≤15 days before the Screening Visit of 
this study will not undergo the 4-week Baseline Period or the 2-week Dose Optimization Period. 
These subjects may complete Visit 1 (Screening) and Visit 2 (Day 1) on the same day. At Visit 1, 
informed consent and/or assent (if applicable) is obtained from the subjects and/or subjects’ 
legally acceptable representative. Subjects will then undergo screening procedures to assess 
study eligibility in accordance with the study entry criteria. Identical assessments for subjects 
who complete the last visit of their antecedent protocol ≤30 days before the Screening Visit in 
this study do not need to be repeated. Subjects and/or subjects’ caregivers will be provided with 
a seizure diary and will be instructed to record seizure data on a daily basis. For subjects in this 
group, the seizure diary data collected during the 4-week prospective Baseline Period of the 
antecedent study will be used as the baseline seizure data for endpoint analysis in this study. The 
seizure diary recording can begin as soon as the informed consent has been signed. 
Dosing and Titration Schedule
Pediatric and adult subjects whose antecedent study was an open-label study will be started on 
the same soticlestat dose that they had maintained at the end of the antecedent study. Dosing may 
be adjusted at the investigator’s discretion throughout the study; however, frequent adjustments 
are discouraged. Dosing will be calculated based on body weight in pediatric subjects only. Dose 
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will be recalibrated approximately every 6 months at clinic visits during the Maintenance Period, 
to ensure that the dose used is weight-appropriate. 
8.2.4
Dose Tapering 
During the tapering period of not more than 14 days following the final maintenance visit, the 
soticlestat dose will be decreased to the next lower level no more frequently than every 3 days 
based on the investigator’s discretion until soticlestat is discontinued. After tapering, subjects 
will complete a Safety Follow-up visit approximately 15 days after the last dose of study drug 
and exit the study.
8.2.5
Investigator Responsibilities for Drug Administration
The investigator or his/her designee is responsible for the following:

Explaining the correct use of the investigational agent(s) to the subject/site personnel/legal 
representative.

Verifying that instructions are followed properly.

Maintaining accurate records of study drug dispensing and collection.

Returning or destroying all unused medication to the sponsor or its designee at the end of the 
study.
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 of clinical study materials. 
Subjects or the subject’s legal representative (ie, parent or legal guardian) 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 clinical trial material provided to the investigator will be stored in a secure and locked place 
and allocated and dispensed by qualified personnel and through interactive web response system 
(IWRS). Detailed records of the amounts of the study drug received, dispensed, and remaining at 
the end of the study will be maintained.
Soticlestat tablets/mini-tablets will be administered orally or via G-tube, PEG tube, or J-tube at 
approximately the same times on each day. The actual times of all dose administrations 
 
 will be recorded in each subject’s source documents and transcribed into 
eCRFs.
8.3
Blinding
This is an open-label study. There will be no blinding. 
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8.4
Treatment Compliance
Subject compliance with study medication will be assessed at each visit. Subjects and/or 
subjects’ caregivers will be required to bring study drug bottles/unused study drug to each 
dispensing site visit. The date and time of each dose will be recorded in the source documents 
and in the eCRFs. All subjects and/or subjects’ caregivers should be re-instructed about the 
dosing requirements during study visits. The authorized study personnel conducting the re-
education must document the process in the subject source records.
Subjects who are significantly noncompliant will be discontinued from the study. A subject will 
be considered significantly noncompliant if he or she intentionally misses more than 20% of 
study medication between any 2 visits during the study. 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.
9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures to be performed and data to be collected. 
For each procedure, subjects are to be assessed by the same investigator or site personnel 
whenever possible. Study procedures and their timing are summarized in the Schedule of Study 
Procedures (Appendix A).
9.1.1
COVID-19 Pandemic Study Procedures
Please see Appendix C.
9.1.2
Informed Consent Procedures
Remote consenting is allowed for subjects rolling over to ENDYMION 1 from an antecedent 
soticlestat trial. Consent can be performed in the manner approved by the Institutional Review 
Board or Ethics Committee (eg, video, phone, telehealth/telemedicine, email, and/or mail). A 
signed document is required (either wet or electronic signature) before study drug can be 
dispensed. 
Two copies of the Informed Consent Form (ICF) will be sent to the subject’s home via courier 
and/or emailed to the subject/subject’s caregiver in advance of the planned screening visit date. 
Mailing/courier materials needed for returning 1 original copy of the signed consent form will be 
provided to the subject/caregiver if a wet signature is used.
On the agreed upon consent date, the investigator or a delegated member of the site staff will 
contact the subject/subject’s caregiver via video, phone, or telehealth/telemedicine utilized by the 
institution, outline the study procedures within the consent form, discuss any questions from 
subject/subject’s caregiver, and obtain verbal consent and ultimately, written and signed. 
Conduct of this process will be documented in the source documents by the site staff. 
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Please ensure the following is documented in the source document but not limited to the 
following:

The date and time of the consent discussion.

Method of conducting consent discussion (video, phone, or telehealth/telemedicine).

Name and relationship of individuals who were present during the consent discussion.

Name and relationship of individuals who signed the consent.

Responses to any questions asked by the subject and/or caregiver.

Confirmation that the subject/caregiver questions were adequately answered.

Confirmation by the Investigator or delegated staff member that the subject/caregiver is 
willing to participate in the study and signed the consent during the discussion.

Verbal confirmation from the subject/caregiver that they wish to participate in the trial and 
have signed and dated the consent form in their possession.

Method by which the signed consent will be provided to the site (ie email, postal 
mail/courier, or in person at next on-site visit).
Once all questions regarding study participation are answered and verbal consent is obtained, the 
subject/caregiver will sign and date the consent form. If possible, a scanned copy of the signed 
consent form should be emailed to the site as evidence of the consent agreement prior to study 
drug dispensation. In addition, one of the original signed consent forms must be provided to the 
site using the provided shipping/courier supplies (if this is not possible, the original signed 
consent form should be brought to the site at the time of the next on-site visit).
The investigator or delegated staff will sign and date a copy of the consent form and mail or 
email a copy to the subject/caregiver.
Original copies of the signed consent forms will be maintained by the site.
9.1.2.1
Materials and Supplies
To ensure the safe and continued study participation, once verbal consent from the 
subject/caregiver is received, sites will arrange for delivery of intellectual property, paper copies 
of applicable scales, and the seizure and dosing diary to the subject’s home via courier. 
Administration of the ENDYMION 1 study drug should begin according to the Day 1 procedures 
indicated in Appendix A.
9.1.2.2
Screening/Baseline Visit
Ensure remote consent processes are in place to allow rollover from antecedent soticlestat study 
without an on-site subject visit. Consent can be done by video, phone, telehealth/telemedicine, 
and/or mail. A signed document is required (either wet or electronic signature) before study drug 
can be assigned or dispensed. Mailed/emailed study documents should be sent to the subject 
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prior to the phone visit. Investigational Product, applicable scales and seizure and dosing diaries 
will be delivered to the subject’s home via courier.
9.1.3
Demographics, Medical History, and Medication History Procedures
Demographic information may be collected via video, phone, or telehealth/telemedicine by site 
staff.
Demographic information to be obtained will include year of birth, gender, ethnicity, and race as 
described by the subject/caregiver. 
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. Medical 
and medication history data from antecedent studies may be carried over and recorded in the 
eCRFs in this study if these data are available; otherwise, new medical and medication history 
data should be collected at the screening of this study. For subjects with ongoing AEs in the 
antecedent study, their ongoing AEs should be recorded as medical history in this OLE study.
9.1.4
Physical Examination Procedure
Physical examinations may be conducted via video, phone, or telehealth/telemedicine by site 
staff or locally by Health Care Practitioners (HCP) or Primary Care Physicians (PCP).
The physical examination will consist of the following body systems: (1) head, eyes, ears, nose, 
and throat; (2) cardiovascular system; (3) respiratory system; (4) gastrointestinal system; 
(5) dermatologic system; (6) extremities; (7) musculoskeletal system; (8) lymph nodes; 
(9) psychiatric status; and (10) other. The physical examination must be captured in the source 
document and eCRF.
9.1.5
Neurological Examination Procedure
Neurological examinations may be conducted via video, phone, telehealth/telemedicine by site 
staff or locally by HCP or PCP.
A separate neurological examination will be performed and collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, motor function, and 
sensation.
As part of the neurological exam, vision testing should include fundoscopy (including 
examination of the optic disc), best corrected visual acuity using a pocket vision screening card 
or wall card, and visual field assessment. If this is not possible to perform, justification should be 
provided.
9.1.6
Height and Weight
Height and weight data may be obtained locally by HCP or PCP.
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Height and weight are to be measured while the subject is wearing indoor clothing and with 
shoes off. If unable to obtain height or weight, data may be collected from other sources 
(eg, medical records or the subject’s caretaker). The investigator must document in the source 
document the reason for not obtaining height or weight (eg, the subject is in a wheelchair).
9.1.7
Vital Signs Measurements
Vital signs data may be obtained locally by HCP or PCP.
Vital signs to be measured are temperature, blood pressure, heart rate (beats per minute), and 
respiratory rate. 
Vital signs should be measured at the same time of day across visits, if possible. When vital 
signs are scheduled at the same time as blood draws, the blood draw will take priority and vital 
signs will be obtained within 15 minutes before or after the scheduled blood draw, if possible.
All vital signs data collected at study visits will be recorded on the source documents and in the 
eCRF. 
9.1.8
Seizure and Dosing Diary Procedure
At Visit 1 and at every subsequent clinic visit, the subject and/or subject’s caregiver will be sent 
a seizure and dosing diary via courier and specific instructions to ensure compliance with the 
seizure and study drug recording. The seizure events will be recorded starting at the 
Screening/Baseline Period up until the Follow-up Visit. In preparation for each remote clinic 
visit, the seizure and dosing diary will be collected from the subject’s home either via courier or 
sent electronically to the site by the subject and/or subject’s caregiver for review. Seizure diaries 
may be returned via courier as frequently as every month for convenience of the subject and/or 
subject’s caregiver and the site. The PI will continue to review with the subject and/or subject’s 
caregiver for proper recording and accountability via video, phone, telehealth/telemedicine.
The 28-day seizure frequency will be calculated from the seizure diary using the following 
formula:
(# of seizures) / (# of days seizures were assessed) 28
9.1.9
Documentation of Concomitant Medications
Concomitant medications may be collected via telehealth/telemedicine video, phone, 
telehealth/telemedicine by site staff. Concomitant medication is any drug given in addition to the 
study drug. These may be prescribed by a physician or they may be over-the-counter 
medications. At the time of each study visit, subjects and/or caregivers will be asked whether 
subjects have taken any medication other than the study drug (used from signing of informed 
consent through the end of the study), and all medication including vitamin supplements, over-
the-counter medications, and herbal preparations including (medical) marijuana and cannabidiol 
products, must be recorded in the source document and eCRF. Documentation will include 
generic medication name, dose, unit, frequency, route of administration, start and end dates, and 
reason for use.
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9.1.10
Documentation of Concurrent Medical Conditions
Concurrent medical conditions may be collected via video, phone, telehealth/telemedicine by site 
staff.
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 on the Medical 
History form.
9.1.11
Procedures for Clinical Laboratory Samples
Clinical laboratory samples may be collected and analyzed by a local laboratory at the 
investigator’s discretion with results sent to the clinical site.
Blood samples are to be collected at the time points stipulated in the Schedule of Study 
Procedures (Appendix A). Samples will be collected in accordance with local laboratory 
procedures. 
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 approximate 
volume of blood collected at any single visit and the approximate total volume of blood collected 
in the study will be given in the laboratory and/or study manual.
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
Serum (Concomitant AEDs) a
RBC
WBC with differential (% and 
absolute)
Hemoglobin
Hematocrit
Platelets
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Carbamazepine
Clobazam
N-Desmethylclobazam
Valproic acid
Phenytoin
Topiramate
Lamotrigine
Rufinamide
Zonisamide
Phenobarbital
Levetiracetam
Lacosamide
10-hydroxycabazepine (metabolite of 
oxcarbazepine)
Oxcarbazepine
Cannabidiol (CBD)
Other:
Human chorionic gonadotropin (for pregnancy) b 
AED: antiepileptic drug; ALT: alanine aminotransferase AST: aspartate aminotransferase; GGT: gamma glutamyl 
transferase; hCG human chorionic gonadotropin: HDL: high-density lipoprotein; LDL: low-density lipoprotein 
RBC: red blood cell; WBC: white blood cell.
a As applicable, at investigator discretion.
b Only for sexually active female patients of childbearing potential. An additional serum hCG pregnancy test will be 
performed at the final maintenance visit. Additional pregnancy tests (urine only) may be performed throughout the 
study at the investigator’s discretion.
9.1.12
Contraception and Pregnancy Avoidance Procedure
Pregnancy testing may be completed by a local laboratory at the investigator’s discretion.
Please refer to Section 7.1 for detailed contraception requirements.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study and for 30 days after the last dose of study drug. This may be 
signed by the legally authorized representative of the subject. 
All sexually active female subjects of childbearing potential must have a negative urine or serum 
human chorionic gonadotropin (hCG) pregnancy test at Screening (Visit 1) before receiving any 
dose of study drug. Additional pregnancy tests (urine only) may be performed by local 
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laboratory throughout the study at the investigator’s discretion. During the study, subjects will 
receive continued guidance with respect to the avoidance of pregnancy and ova or sperm 
donation as part of the study procedures. An additional serum hCG pregnancy test will be 
performed at the subject’s last clinic visit. 
9.1.13
ECG Procedure
ECGs may be obtained locally by HCP or PCP.
A 12-lead ECG will be recorded as indicated in Appendix A. If subjects receive the soticlestat 
dose in the clinic, the ECG should be performed approximately 30 min (±10 min) after dosing. If 
the subject cannot tolerate being supine, a sitting ECG may be obtained. The investigator (or a 
qualified observer at the study site) will interpret the ECG using 1 of the following categories: 
within normal limits, abnormal but not clinically significant, or abnormal and clinically 
significant. The interpretation of the ECG will be recorded in the source documents and in the 
eCRF. The time that the ECG was performed will be recorded. The following parameters will be 
recorded on the eCRF from the subject’s ECG trace: heart rate, RR interval, PR interval, QT 
interval, QRS interval with QTcF (corrected QT interval). ECG traces recorded on thermal paper 
will be photocopied to avoid degradation of trace over time.
9.1.14
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior assessments may be conducted via video, phone, or 
telehealth/telemedicine by a qualified rater from the clinical site.
Suicidal ideation and behavior will be assessed in subjects at least 6 years of age using 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) [5]. 
Two versions of the C-SSRS will be used in this study, the Screening/Baseline C-SSRS Lifetime 
and the Since-Last-Visit C-SSRS. C-SSRS scale will be provided to clinical sites electronically 
or paper copy via courier. C-SSRS may not be provided to the subject and/or subject’s caregiver.
Study staff trained in the administration of the C-SSRS will assess subject suicidality using the 
C-SSRS, eliciting answers from the subject or the subject’s legal representative. 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, the subject may be discontinued as described in 
Section 7.4.1.
9.1.15
Aberrant Behavior Checklist
The Aberrant Behavior Checklist assessment may be conducted via video, phone, or 
telehealth/telemedicine by a qualified rater from the clinical site.
Behavior will be assessed with the ABC-C questionnaire, which is a rating scale that measures 
the severity of a range of problem behaviors commonly observed in individuals with intellectual 
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and developmental disabilities [6]. It is completed by the caregiver. It is an empirically 
developed scale designed to measure psychiatric symptoms and behavioral disturbance exhibited 
by individuals across 5 domains with 58 items: irritability, agitation, and crying (15 items); 
lethargy, social withdrawal (16 items); stereotypy (7 items); hyperactivity/noncompliance 
(16 items); and inappropriate speech (4 items).
ABC-C scale will be provided to clinical sites by site electronically or paper copy via courier and 
may also be provided electronically or via courier to the subject and/or subject’s caregiver for 
reference during remote conduct of the scale via video, phone, or telehealth/telemedicine.
If the subject is unable to comply with the ABC-C due to the language barrier (eg, unavailability 
of validated test in subject’s language) the investigator may also use clinical judgment to assess 
for behavior.
9.1.16
Vineland Adaptive Behavior Scale
The Vineland Adaptive Behavior Scale assessment may be conducted via video, phone, or 
telehealth/telemedicine by a qualified rater from the clinical site. 
The VABS, 3rd edition, Parent Caregiver Form (VABS-3 Parent Caregiver Form), is a 
parent-report questionnaire of adaptive functioning or how an individual behaves in their 
day-to-day life at home and in the community [7]. It assesses adaptive functioning across 
4 domains: motor, communication, daily living, and socialization. The interview takes about 
20 minutes to complete.
VABS assessment will be provided to clinical sites electronically or paper copy via courier and 
may also be provided electronically or via courier to the subject and/or subject’s caregiver for 
reference during remote conduct of the scale via video, phone, or telehealth/telemedicine.
If the subject is unable to comply with the VABS due to the language barrier (eg, unavailability 
of validated test in subject’s language), the investigator may also use clinical judgment to assess 
for adaptive function and behavior.
9.1.17
Quality of Life in Childhood Epilepsy
The Quality of Life in Childhood Epilepsy assessment may be conducted via 
telehealth/telemedicine by a qualified rater from the clinical site.
The Quality of Life in Childhood Epilepsy is a parent-reported questionnaire that evaluates 
health-related quality of life in children ages 4 to 18 years old [8]. It contains 76 items with 
16 subscales covering 7 domains of life function: physical activities, social activities, cognition, 
emotional wellbeing, behavior, general health, and general quality of life.
This scale will only be used for pediatric subjects.
Quality of Life in Childhood Epilepsy scale will be provided to clinical sites electronically or 
paper copy via courier and may be provided electronically or via courier to subject and/or 
subject’s caregiver for reference during remote conduct of the scale via video, phone, or 
telehealth/telemedicine.
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according to the procedure outlined in Section 10.2. In the event of drug overdose, the patient 
should be treated symptomatically.
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) and anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not worsen are not AEs.
Takeda has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to study drug are to be 
reported. Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug 
safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s pre-existing 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
Seizures in this subject population will be measured using the seizure diary and seizure 
frequency as a primary study endpoint. For the purpose of this study, reporting of seizures should 
meet the AE/SAE reporting requirements. As seizures are considered a baseline condition, 
seizures should be reported as an AE/SAE if: (1) there is a clear increase in the frequency of 
seizures compared to the subject’s baseline, (2) there is an emergence of a new seizure type, or 
3) the subject experiences status epilepticus, and any other time the investigator feels the seizure 
should be captured as an AE/SAE, in which case the investigator should document his/her 
reasoning. All seizures will be captured in the seizure diary collected at the site during the study 
and will be analyzed by the sponsor along with the reportable SAEs in evaluating risk:benefit. 
The sponsor will report the SAE events of seizure that meet these criteria in an aggregated 
unblinded report at the conclusion of the study. 
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs. If a subject experiences an AE after signing informed 
consent, but prior to receiving study drug, the event will be reported, but will be included in the 
subject’s medical history unless the event is serious, or the investigator feels the event may have 
been caused by a protocol procedure.
In addition, all AEs occurring after the subject receives the first dose of study drug must be 
reported to Takeda or its designee via the eCRF. 
For subjects with ongoing AEs in the antecedent study, their ongoing AE should be recorded as 
medical history in this OLE study.
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10.1.1
Severity Assessment
Investigators will be instructed to rate the severity of AEs using the following criteria:
Mild
Events require minimal or no treatment and do not interfere with the subject’s daily activities.
Moderate
Events result in a low level of inconvenience or concerns with the therapeutic measures. Moderate 
events may cause some interference with functioning.
Severe
Events interrupt a subject’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually incapacitating.
Change in severity of an AE should be documented based on specific guidelines in the eCRF 
Completion Guidelines.
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE.
10.1.2
Causality Assessment
Investigators will be instructed to report to the sponsor or its designee their assessment of the 
potential relatedness of each AE to protocol procedure and/or study drug via the eCRF.
An investigator causality assessment must be provided for all AEs (both serious and nonserious). 
This assessment must be recorded in the eCRF and any additional forms as appropriate.
Relationship of AEs to the defined study treatment (soticlestat [after the start of soticlestat on 
Day 1]), will be determined by the investigator according to the following criteria. Please note 
that not all criteria must be present to be indicative of a particular relationship.
Not Related
Exposure to the defined study treatment did not occur, or the occurrence of the 
AE is not reasonably related in time
Unlikely Related
The AE occurred in a reasonable time after the defined study treatment and is 
doubtfully related to the investigational agent/procedure
Possibly Related
The defined study treatment and the AE were reasonably related in time, and 
the AE could be explained equally well by causes other than exposure to the 
defined study treatment
Related
The defined study treatment and the AE were reasonably related in time, and 
the AE was more likely explained by exposure to the defined study treatment 
than by other causes, or the defined study treatment was the most likely cause 
of the AE
If a subject’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to the sponsor or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.1.3
SAEs
SAE collection begins after the subject has signed informed consent. If a subject experiences an 
SAE after signing informed consent, but prior to receiving study drug, the event will be reported, 
but will be classified as a pretreatment SAE unless the investigator feels the event may have been 
caused by a protocol procedure.
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Planned surgeries and/or hospitalizations should not be reported as SAEs unless the underlying 
medical condition has worsened during the course of the study.
Study site personnel must alert the sponsor or its designee of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method. If alerts are issued via 
telephone, they are to be immediately followed with official notification on study-specific SAE 
forms. This 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information.
An SAE is any AE from this study that results in 1 or more of the following outcomes:

Results in death.

Requires or prolongs hospitalization.

Is life-threatening (that is, immediate risk of dying).

Persistent or significant disability/incapacity.

Congenital anomaly or birth defect.

Other medically important serious event.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
SAEs occurring up to and including the subject’s last study visit will be collected, regardless of 
the investigator’s opinion of causation.
10.1.4
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study drug or procedure. United States 
21 Code of Federal Regulations 312.32 and European Union Clinical Trial Directive 2001/20/EC 
and the associated detailed guidance or national regulatory requirements in participating 
countries require the reporting of SUSARs. The sponsor has procedures that will be followed for 
the recording and expedited reporting of SUSARs that are consistent with global regulations and 
the associated detailed guidance.
10.2
Reporting AEs
All nonserious AEs must be recorded in the eCRF upon awareness. 
Any AE that meets SAE criteria (Section 10.1.3) must immediately (ie, within 1 business day) be 
sent to the sponsor upon learning of any SAE that occurs (whether or not attributable to the study 
drug). It is the investigator’s responsibility to ensure that SAE reporting procedures are followed 
appropriately. All SAE reports and any revisions to an SAE report must be sent by fax or email. 
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All supporting source information concerning the SAE (eg, hospital records) should also be 
provided by fax or email.
Country-specific fax numbers and email addresses will be provided in a separate document.
If there is a question concerning an SAE, the site needs guidance regarding the reporting of an 
SAE, the site is returning a call from a sponsor safety specialist, or the site urgently needs to 
report an SAE or make the sponsor aware of an SAE, the safety hotline should be used (country-
specific hotline numbers provided in a separate document).
If an SAE is reported via the hotline, the site should first submit the SAE paper form and then 
enter the SAE in the eCRF. Any AE that meets SAE criteria must be entered into the electronic 
data capture (EDC) system immediately (ie, within 1 business day) after site personnel first 
learns about the event in addition to faxing/emailing the SAE report form. Once the qualifying 
SAE data are entered into EDC, the sponsor will be notified by an email alert, which will contain 
high-level safety information. If a site makes an initial report of an SAE by the safety hotline, the 
site must subsequently enter all applicable information into the EDC system immediately 
thereafter.
All SAEs must be reported starting from the time that informed consent for study participation is 
provided. If the investigator becomes aware of an SAE within 30 days after the patient’s last 
dose of study drug or within 30 days after the last study visit, the SAE must be reported. SAEs 
must be followed until the event resolves, the event or sequelae stabilize, or it is unlikely that 
additional information can be obtained after demonstration of due diligence with follow-up 
efforts (ie, the patient or health care practitioner is unable to provide additional information, or 
the patient is lost to follow-up). SAEs that occur more than 30 days after the last dose of study 
drug or more than 30 days after the last study visit, do not need to be reported unless the 
investigator considers them related to study drug.
10.2.1
Sponsor Reporting Requirements
The sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use Section 6 of the current 
IB as the Reference Safety Information. The expectedness and reporting criteria of an SAE will 
be determined by the sponsor from the Reference Safety Information.
10.2.2
Investigator Reporting Requirements
The investigator must fulfill all local regulatory obligations required for the study investigators. 
It is the principal investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at 
his or her site. Investigators will also be notified of all SUSAR events that occur during the 
clinical study. Each site is responsible for notifying its IRB/IEC of these additional SAEs. 
For blinded studies, investigators will receive blinded information unless unblinded information 
is judged necessary for safety reasons.
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10.3
Exposure During Pregnancy and/or Lactation
Soticlestat should not be administered to pregnant or lactating females because the potential for 
adverse reactions to soticlestat in pregnant females, fetuses, and nursing infants is unknown.
If any subject is found to be pregnant during the study, she should be withdrawn and the study 
drug should be immediately discontinued.
Pregnancy data will be collected during this study for all subjects. Exposure during pregnancy 
(also referred to as exposure in-utero) can be the result of either maternal exposure or 
transmission of drug product via semen following paternal exposure.
Exposure during pregnancy must be recorded and the subject followed until the outcome of the 
pregnancy is known (spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality), even if the subject discontinues study drug or discontinues from the study.
If a subject within this study or a subject’s partner becomes pregnant while treated or exposed to 
study drug, the investigator must submit a pregnancy form to the sponsor via the same method as 
SAE reporting. Pharmacovigilance will supply the investigator with a copy of a “Pregnancy 
Reporting and Outcome/Breast Feeding” Form. When the outcome of the pregnancy becomes 
known, the form should be completed and returned via the same methods as for SAE reporting. 
If additional follow-up is required, the investigator will be requested to provide the information.
Exposure of an infant to a sponsor product during breastfeeding must also be reported and any 
AEs experienced by the infant must be reported to the sponsor Pharmacovigilance or designee 
via the same methods as for SAE reporting (Section 10.1.3).
Pregnancy is not regarded as an AE unless there is a suspicion that study drug may have 
interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet criteria for an SAE 
(such as ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs.
10.4
Safety Monitoring
The sponsor’s medical monitor and/or Pharmacovigilance physician will monitor safety data 
throughout the course of the study. 
An independent Data Monitoring Committee (iDMC) will monitor the subjects’ safety (see 
Section 11.0).
10.4.1
Reporting of Abnormal Liver Function Tests
If a subject is noted to have ALT or AST elevated >3 times the ULN on 2 consecutive occasions, 
the abnormality should be recorded as an AE. 
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, the event should be recorded as an SAE 
and reported as per Section 10.2. The investigator must contact the medical monitor for 
discussion of the relevant patient details and possible alternative etiologies, such as acute viral 
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hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions. 
Follow-up laboratory tests must also be performed. In addition, clinically significant liver 
function test increases are to be recorded in the AE page and if considered an SAE must follow 
the SAE process.
10.7
Appropriateness of Measurements
All efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
DEE. 
11.0
STUDY-SPECIFIC COMMITTEES
Details of the iDMC will be captured in the iDMC charter before the start of the study. An iDMC 
will monitor the subjects’ safety in accordance with the iDMC charter, details of which will be 
captured before the start of the study. The iDMC will consist of at least 3 external, independent, 
nonsponsor experts responsible for monitoring the safety data to ensure that the study does not 
pose unacceptable risks to the subjects.
12.0
DATA QUALITY ASSURANCE
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following:

Provide instructional material to the study sites, as appropriate.

Sponsor start-up training to instruct the investigators and study coordinators. This training 
will give instruction on the protocol, the completion of the eCRFs, and study procedures.

Make periodic visits to the study site.

Be available for consultation and stay in contact with the study site personnel by email, 
telephone, and/or fax.

Review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection.

Conduct a quality review of the database.
In addition, the sponsor or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site. The study may be audited by the sponsor or 
its representatives, and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRBs/IECs 
with direct access to original source documents.
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12.1
Data Collection and Storage
All clinical raw data will be recorded promptly, accurately, and legibly, either directly into the 
data capture system as e-source data, or indelibly on paper (eg, ECG readings). A detailed list of 
the type (electronic or paper) and location for all source data will be included in the Trial Master 
File. When recorded electronically, case report forms will be electronically generated. All raw 
data will be preserved to maintain data integrity. The investigator or designee will assume the 
responsibility of ensuring the completeness, accuracy, and timeliness of the clinical data.
The EDC system is fully validated and Code of Federal Regulations Title 21 Part 11 compliant. 
The EDC system will maintain a complete audit trail of all data changes. At each scheduled 
monitoring visit, the investigator or designee will cooperate with the sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system.
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries.
The investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms) 
designed to record all observations and other pertinent data for each subject receiving study drug 
or placebo.
The investigator will allow sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/IEC to have direct access to all documents pertaining to the 
study.
13.0
STATISTICAL METHODS AND PLANNED ANALYSES
13.1
General Considerations
All statistical analyses will be performed using SAS® software (SAS Institute Inc, Cary, NC) 
Version 9.4 or higher. All clinical study data will be presented in subject data listings. Data 
summaries will be presented for all endpoints and will include descriptive statistics (number of 
subjects [n], mean, SD, first quartile [Q1], median, third quartile [Q3], minimum, and maximum) 
for continuous variables, and frequency and percentage for categorical and ordinal variables. If 
there are missing values, the number of missing will be presented, but without a percentage.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan which will be finalized and approved prior to database lock. 
Additional exploratory analyses of the data may be conducted as deemed appropriate.
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13.2
Determination of Sample Size
No formal sample size calculation has been performed for this extension study. A study size of 
approximately 160 subjects is based on the estimated number of subjects who are expected to 
enroll from the antecedent soticlestat studies.
13.3
Definition of Baseline
Baseline for analyses is the baseline of the antecedent study, except for subjects who completed 
the antecedent study >15 days before the Screening Visit of this study, in which case the 4-week 
Baseline Period of this study will be used.
Unless otherwise specified in this section, all the summary tables by visit will use the values 
from the scheduled visit. The unscheduled visit may be used for the calculation of the overall 
change from baseline, for example, the worst change postdose. 
13.4
Analysis Sets
13.4.1
Safety Analysis Set
All enrolled subjects who take at least 1 dose of study medication in this study will be included 
in the safety analysis set. The safety set will be the primary population for all safety analyses.
In addition, subject disposition, demographics, and baseline characteristics will be summarized 
using the safety analysis set.
13.4.2
Intent-to-Treat Analysis Set
All enrolled subjects will be included in the intent-to-treat analysis set.
13.4.3
Modified Intent-to-Treat Analysis Set
All enrolled subjects who have received at least 1 dose of study drug and have been assessed for 
at least 1 day in the treatment period will be included in the modified intent-to-treat analysis set.
13.5
Demographics and Baseline Characteristics
Demographic characteristics include age, gender, race, ethnicity, and study center. Baseline 
characteristics include baseline body weight and height). Summary statistics by treatment group 
and overall will include counts and percentages for discrete variables, and means, SD, Q1, 
medians, Q3, minimum, and maximum for continuous variables.
13.6
Subject Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given.
Disposition data will be summarized and provided in subject listings.
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13.7
Concomitant Medications and Non-Pharmacologic Therapies and Procedures
Concomitant medications will be coded using the WHO Drug Dictionary. A by-subject listing of 
concomitant medications will include all medications taken during the study regardless of the 
timing for the start of the medication. All medications started prior to 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 treatment as well 
as the number and percentage of subjects who took each type of medication will be presented. 
Medications will be listed according to their WHO Drug Dictionary Anatomical 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.
13.8
Treatment Compliance 
Treatment compliance will be summarized by daily dose over the entire treatment period. 
Compliance rates during the treatment period will be derived using the following formula:
100*(Total number of tablets/mini-tablets dispensed – Total number of tablets/mini-tablets 
returned) / (Expected number of tablets/mini-tablets)
Compliance rates will be presented for the safety analysis set using summary statistics and 
percentage for the frequency distributions (0% to <20%, 20% to 40%, 40% to <60%, 60% to 
<80%, 80% to <100%, 100% to ≤120%) by daily dose and overall.
13.9
Safety Analyses
Descriptive statistics will be used to summarize all safety endpoints. Two-sided 95% CIs will be 
presented where meaningful. Data summaries will be displayed for incidence of AEs, clinical 
laboratory variables, vital sign measurements, body weight, ECG parameters, as well as changes 
in behavioral and adaptive functioning measures using VABS and subscales of ABC-C, as 
appropriate. Changes from Baseline to study timepoints in clinical chemistry and hematology 
results will be summarized descriptively. Each laboratory parameter will be classified as low, 
normal, or high relative to the parameter’s reference range. The number and percentage of 
subjects with shifts in clinical laboratory parameters will be summarized. Laboratory 
abnormalities for each treatment will also be summarized with shift tables. Listings of subjects 
with abnormal results will be provided. 
The number and percentage of subjects with C-SSRS assessments of suicidal ideation and 
behavior will also be summarized. 
Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by preferred term (PT) and system organ class (SOC) categories. 
Serious AEs and AEs leading to study discontinuation will also be summarized.
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13.12
Other Statistical Issues
13.12.1
Significance Levels
Not Applicable. There will be no formal hypothesis testing for this study.
13.12.2
Missing or Invalid Data
Techniques for handling missing information with respect to reporting of seizures in the 
treatment period (Dose Optimization and Maintenance) will be specified in detail in the 
statistical analysis plan.
13.13
Ad hoc/Interim Analyses 
Ad hoc and/or interim analyses may be performed at the discretion of the sponsor to facilitate 
planning of the soticlestat development program. Final analyses will be performed after the last 
subject completes the study and the database is locked.
14.0
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS
14.1
Informed Consent
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the subject’s willingness to continue his or her participation in the study.
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative. This includes obtaining the appropriate signatures and dates on the ICF prior 
to the performance of any protocol procedures and prior to the administration of study drug.
A legal representative must give informed consent for a child to participate in this study. In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
14.2
Ethical Review
The sponsor or its representatives must approve all ICFs before they are used at investigative 
sites(s). All ICFs must be compliant with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline on GCP. 
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Documentation of IRB/IEC approval of the protocol and the ICF must be provided to the sponsor 
before the study may begin at the investigative site(s). The IRB/IEC(s) will review the protocol 
as required.
The study site’s IRB/IEC(s) should also be provided with the following:

The current IB and updates during the study.

ICF.

Relevant curricula vitae.
14.3
Regulatory Considerations
This study will be conducted in accordance with:

Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines.

The ICH GCP Guideline (E6).

Applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable IRB/IEC(s).
Some of the obligations of the sponsor may be assigned to a third-party organization.
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data.
14.4
Confidentiality
The sponsor affirms that subject’s rights to protection against invasion of privacy are in 
compliance with ICH and other local regulations (whichever is most stringent). Information 
about subjects and their records will be kept confidential by the sponsor and its representatives. 
Study-related records identifying subjects will be kept confidential and, to the extent permitted 
by applicable laws and/or regulations will not be made publicly available. 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the subject and/or subject’s custodial parent or guardian, except as necessary for monitoring 
and auditing by the sponsor, its designee, Food and Drug Administration (FDA), Health 
Authorities, Ethics Committees, and/or IRBs.
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties.
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If any of the results of the study are published, subject’s identity will remain confidential.
The sponsor requires the investigator to permit sponsor representatives and, when necessary, 
representatives from FDA and other regulatory authorities, monitor, auditor, IRB to have access 
to study-related medical records in accordance with local privacy laws.
14.5
Investigator Information
Physicians with a specialty in neurology and/or epilepsy disorders will participate as 
investigators in this clinical study.
14.6
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a sponsor representative.
14.7
Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study. 
The sponsor’s responsible medical officer (or designee) and statistician will approve the final 
clinical study report for this study, confirming that, to the best of their knowledge, the report 
accurately describes the conduct and results of the study.
14.8
Publication Policy
The full terms regarding publication of the results of this study are outlined in the Clinical Study 
Agreement, Statement of Agreement, or the Master Clinical Study Agreement. Publication is 
permitted only after multi-center results are available and all disclosure requirements for clinical 
study registries have been met. Any data to be submitted for publication, including abstract 
submissions or presentations, are required to be submitted to Takeda for review at least 30 days
prior to submission.
15.0
LIST OF REFERENCES
1. Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, et al. The major 
brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-
methyl-D-aspartate receptors. J Neurosci 2013;33(44):17290-300.
2. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised 
terminology and concepts for organization of seizures and epilepsies: report of the ILAE 
Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51(4):676-85.
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Appendix A
Schedule of Study Procedures
Assessment
Screening/
Baselinea
Year 1
Year 2
Year 3
Year 4+
Follow-
up
Study Week(s)
-4 to -1
1
4
12
24
36
48
65
78
91
104
117
130
143
156
Every 
26 weeks
EOM+4
Study Day(s)
-28 to -1
1
29
85
169
253
337
456
547
638
729
820
911
1002
1093
--
EOM+28
Visit Windows 
(Days)
±3
±7
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±7
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--, EOM
--
Informed 
Consent/Assent
X
Inclusion/Exclusion
X
Medical historyb
X
Concomitant 
medicationsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological 
examinationd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum/urine 
pregnancy teste
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
hematology and 
serum chemistry
X
X
X
X
X
X
X
X
X
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Assessment
Screening/
Baselinea
Year 1
Year 2
Year 3
Year 4+
Follow-
up
Study Week(s)
-4 to -1
1
4
12
24
36
48
65
78
91
104
117
130
143
156
Every 
26 weeks
EOM+4
Study Day(s)
-28 to -1
1
29
85
169
253
337
456
547
638
729
820
911
1002
1093
--
EOM+28
Visit Windows 
(Days)
±3
±7
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±7
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--, EOM
--
Serum sample for 
AED analysis
X
X
X
X
X
X
X
X
12-lead ECGg
X
X
X
X
X
X
X
X
Dispense seizure 
diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Xh
Collect seizure diary 
data
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Xh
X
Contact IWRS for 
subject 
ID/medication 
ID/subject status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Xh
Study drug return for 
compliance/
accountability
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Xh
X
CGI-S
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
VABS
X
X
X
X
X
X
X
X
ABC-C
X
X
X
X
X
X
X
X
QoLCE
X
X
X
X
X
X
X
X
X
SDNRS
X
X
X
X
X
X
X
X
X
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Assessment
Screening/
Baselinea
Year 1
Year 2
Year 3
Year 4+
Follow-
up
Study Week(s)
-4 to -1
1
4
12
24
36
48
65
78
91
104
117
130
143
156
Every 
26 weeks
EOM+4
Study Day(s)
-28 to -1
1
29
85
169
253
337
456
547
638
729
820
911
1002
1093
--
EOM+28
Visit Windows 
(Days)
±3
±7
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±30
±7
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
--, EOM
--
; ABC-C, Aberrant Behavior Checklist-Community Edition; AED, antiepileptic drug; CGI-S, Clinician’s Clinical Global 
Impression of Severity; C-SSRS, Columbia-Suicide Severity Rating Scale; ECG, electrocardiogram; eCRF, electronic case report form; EOM, end of 
Maintenance Period; ID, identification number; IWRS, interactive web response system; 
; QoLCE, Quality of Life in Childhood 
Epilepsy; SDNRS, Sleep Disruption Numerical Rating Scale; VABS, Vineland Adaptive Behavior Scale. 
After 4 years of participation in the study (at the Week 208 visit), subjects will be re-evaluated: the first visit in Year 4 will be scheduled for Week 182. Subjects 
may continue the use of soticlestat as the discretion of the investigator, until development is stopped by the sponsor, or the product is approved for marketing, or 
at any time at the discretion of the sponsor. Starting with the subject’s last visit on the maintenance dose, the subject will begin an up to 2-week period of dose 
tapering that will be followed approximately 2 weeks later by the Follow-up Visit. A subject who decides to terminate treatment between scheduled visits should 
be scheduled for an EOM visit, have visit assessments performed, be started on dose tapering, and have a follow-up visit scheduled. 
a The Screening/Baseline visit may occur within 15 days of the end of treatment visit for the antecedent study and may occur on the same day. Identical 
assessments taken at the subject’s last visit of the antecedent study do not need to be repeated at Visit 1 of this study if these 2 visits are ≤30 days apart. Baseline 
evaluations are to be done for subjects who completed the antecedent study >30 days before Screening in this study. The last visit in the antecedent study can be 
combined with the screening/baseline visit and Visit 2 (Day 1) in this study.
b Medical history data from antecedent studies may be carried over and recorded in the eCRF in this study if these data are available; otherwise, new medical 
history data should be collected at the Screening Visit of this study. For subjects with ongoing adverse events in the antecedent study, their ongoing adverse 
events should be recorded as medical history in this open-label extension study.
c Concomitant medication data from antecedent studies may be carried over and recorded in the eCRF in this study if these data are available; otherwise, new 
concomitant medication data should be collected at the Screening Visit of this study. 
d Eye examination (including fundoscopy, best corrected visual acuity, and visual field assessments) as part of the neurological examination.
e Additional pregnancy tests (urine only) may be performed throughout the study at the investigator’s discretion. A serum (rather than urine) pregnancy test will 
be performed at the subject’s last clinic visit.
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g ECGs will be conducted and analyzed locally according to the site’s standard operating procedures. If subjects receive the soticlestat dose in the clinic, the ECG 
should be performed approximately 30 min (±10 min) after dosing. 
h After Visit 15 and after every visit thereafter within the Maintenance Period, 4-month supplies of study drug and seizure diaries may be delivered to participants 
3 months before the next scheduled visit. Promptly after receiving these supplies, participants will return unused study drug and completed seizure diaries to their 
study sites. 
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Appendix B
Strong CYP3A Inducers and Inhibitors
Strong inducers and inhibitors of CYP3A are prohibited, except antiseizure medications. 
Examples are listed below.
Strong Inducers of CYP3A
Strong Inhibitors of CYP3A
Apalutamide
Boceprevir
Enzalutamide
Cobicistat
Mitotane
Danoprevir and ritonavir
Rifampin
Elvitegravir and ritonavir
St. John’s wort
Grapefruit juice
Indinavir and ritonavir
Itraconazole
Ketoconazole
Lopinavir and ritonavir
Paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
Posaconazole
Ritonavir
Saquinavir and ritonavir
Telaprevir
Tipranavir and ritonavir
Telithromycin
Troleandomycin
Voriconazole
Clarithromycin
Idelalisib
Nefazodone
Nelfinavir
Source: fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers. Inhibitors, Table 3-3; inducers, Table 3-2. Accessed 06 June 2021.
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Appendix C
Study Management During COVID-19 Pandemic
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. This section 
addresses situations in which scheduled in-person clinic visits are not feasible due to local, 
regional or national restrictions.
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 study due to the ongoing COVID-19 pandemic. These modified study 
procedures are to be used only during the COVID-19 pandemic.
Due to the COVID-19 pandemic, 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 studies during 
the pandemic.
The study design includes virtual visits except for baseline, and randomization/dosing visits, 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 for these 2 visits to monitor subject safety. During the COVID-
19 pandemic, sites are encouraged to discuss subjects and their continued virtual participation 
with the medical monitor. COVID-19 vaccination of subjects is allowed during the study.
Video, phone, or telehealth/telemedicine options will be used to conduct the virtual visits. The 
site will ensure that any related subject data privacy aspects are appropriately managed and will 
obtain subjects’ consent for the use of virtual visits.
ECGs, clinical laboratory samples, and physical examinations may be performed/collected and 
analyzed by a local laboratory/facility at the investigator’s discretion with results sent to the 
clinical site.
In case subjects are not able to attend the planned clinic visits, Direct to Patient study drug 
shipment may be considered using a specialized courier vendor. A process has been put in place 
to ensure shipment traceability, proper temperature control conditions, intellectual property 
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 
Direct to Patient 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 
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verification may be considered for critical data related to subject’s safety and any key variables 
to ensure data accuracy/integrity.
If remote source data verification 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 (non routine/non standard 
panel) assessments are NOT performed on potential subjects, before 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 (e)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 an (e)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 
eCRFs, 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 destruction locally at site (if approved by sponsor or designee) or return of 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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Rationale for Amendment 2
This document describes the changes in reference to the protocol incorporating amendment 
No. 2. The primary reasons for this amendment are to extend the Maintenance Period (including 
additional scheduled clinic visits 26 weeks apart) and amend the visit schedule after Year 1, 
amend the visit schedule of assessments, incorporate changes initiated by administrative letters, 
and resolve inconsistencies with antecedent protocols.
Changes Implemented by Amendment 2
The following major changes were implemented for this amendment:

Amended the title of the protocol.

Changed the frequency and timing of visits in Year 2 and extended the Maintenance Period 
past Year 2.

Added new secondary objectives.

Added new secondary endpoints.

Clarified that inclusion criterion 2 is not applicable to Spain.

Added the option of administering TAK-935 by jejunostomy tube.

Amended contraception and pregnancy avoidance text.

Revised the pregnancy avoidance period and text.

Provided for recalibration of dose with current weight for pediatric patients.

Added a criterion for patient discontinuation related to prolongation of a corrected QT 
interval.

Added a criterion for patient discontinuation related to suicidal ideation.

Revised the text for investigator decision for patient discontinuation.

Defined a missed dose.

Clarified that all identical assessments at the last visit of an antecedent protocol ≤30 days 
before the Screening Visit in this study do not need to be repeated.

Deleted the dosing card from the protocol.

Clarified the eye examination and vision testing.

Added an as-needed urine pregnancy test.

Added the Clinician’s Clinical Global Impression of Severity (CGI-S) to the objectives, 
assessments, and endpoints. 
 

Amended the maximum blood volume collected per visit. 
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
Replaced the interim analysis section with ad hoc analysis section. 
 

Added an independent Data Monitoring Committee. 
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. The synopsis was edited to reflect the changes implemented in the 
protocol. A detailed description of and rationale for changes implemented by Amendment 2 are 
provided in Appendix A.
Protocol Amendment 1 ES v1 was a local amendment and is not applicable to the global 
protocol.
Rationale for Amendment 1
This document describes the changes in reference to the protocol incorporating amendment 
No. 1. The primary reasons for this amendment are to incorporate changes initiated by 
administrative letters and resolve inconsistencies with the antecedent protocols.
Changes Implemented by Amendment 1
The following major changes were implemented for this amendment:

Added 
 as a prohibited concomitant medication.

Removed urinalysis from safety assessments.

Added 2 new forms of approved contraceptive methods and clarified the duration of 
contraceptive use.

Added a 4-week Screening/Baseline Period for pediatric patients who complete the 
antecedent study >15 days before the Screening Visit.

Clarified the duration for avoidance of pregnancy and donation of sperm and ova for male 
and female patients, respectively.
Administrative and minor grammatical, editorial, and formatting changes were made for 
clarification purposes only. A detailed description of and rationale for changes implemented by 
Amendment 1 are provided in Appendix 5.
For non-commercial use only

For non-commercial use only