Clinical trial NCT04938427
Conditions: Lennox Gastaut Syndrome (LGS)
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2021-11-08; Completion date: 2024-01-25
Enrollment: 270 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aims of the study are:

* to learn if soticlestat, when given as add-on therapy, reduces the number of major motor drop seizures in children, teenagers, and adults with Lennox-Gastaut Syndrome.
* to assess the safety profile of soticlestat when given in combination with other therapies.

Participants will receive their standard antiseizure therapy, plus either tablets of soticlestat or placebo. A placebo looks just like soticlestat but will not have any medicine in it. Participants will take soticlestat or placebo for 16 weeks, followed by a gradual dose reduction for 1 week. Then, participants will be followed up for 2 weeks.

Detailed description:
The drug being tested in this study is called soticlestat (TAK-935). Soticlestat will be assessed for efficacy, safety, and tolerability in pediatric and adult participants with LGS.

The study will enroll approximately 234 patients. Participants will be randomly assigned (by chance, like flipping a coin) in a 1:1 ratio to receive standard of care (SOC) plus one of the following adjunctive therapies which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

1. Soticlestat
2. Placebo (dummy inactive pill - this is a tablet/mini-tablet that looks like the study drug but has no active ingredient)

Participants will receive soticlestat or matching placebo based on their weight in the 4-week Titration Period. Following the Titration Period, participants will continue to receive the same dose in the 12-week Maintenance Period. The dose will then be down-tapered if participants decide to discontinue the treatment and/or are not deemed eligible to continue in Open-label extension (OLE).

This multi-center trial will be conducted worldwide. The overall time to participate in the study will be from 22-25 weeks. At the end of the treatment period, participants have the option to either complete the study and taper off the investigational product or to enter the OLE if they meet eligibility requirements. If participants discontinue, they will be followed-up on phone call approximately 14 days after the last dose of study drug for safety.

Arms: arm 1: Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment. arm 2: Participants weighing \<45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with the dose tapered down if participants decided to discontinue the treatment.

Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with the dose tapered down if participants decided to discontinue the treatment.
Interventions: intervention 1: Placebo intervention 2: Soticlestat
Intervention descriptions: intervention 1: Soticlestat placebo-matching mini-tablets or tablets. intervention 2: Soticlestat mini-tablets or tablets.

Protocol documents:
Prot_000.pdf: 
For non-commercial use only


TAKEDA PHARMACEUTICALS
PROTOCOL
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in 
Pediatric and Adult Subjects With Lennox-Gastaut Syndrome (LGS)
Study of Soticlestat as Adjunctive Therapy in Pediatric and Adult Subjects With 
Lennox-Gastaut Syndrome
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
Study Number:
TAK-935-3002
IND Number:
133627
EudraCT Number:
2021-002481-40
Compound:
Soticlestat
Date:
22 April 2022
Version/Amendment 
Number:
Amendment 2
Amendment History:
Date
Amendment Number
Amendment Type
Region
22 April 2022
Amendment 2
Substantial
Global
27 October 2021
Amendment 1 FR-IT-RS v1
Substantial
France, Italy, Serbia
23 March 2021
Initial protocol
Not applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided in the study manual.
Takeda Development Center (TDC)-sponsored investigators per individual country requirements 
will be provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study contact list.
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CONFIDENTIAL
1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual subjects in accordance with 
the requirements of this study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic signatures are provided on the last page of this document.
 MD, MPH
 Clinical Science
Neuroscience
Takeda
Date
 PhD
 Statistical and Quantitative Sciences
Takeda
Date
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CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix D). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix F of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 2 Summary of Changes
Protocol Amendment 2 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 2,
including those previously submitted in France, Italy, and Serbia. The primary reasons for 
Amendment 2 are to make slight changes to entry criteria to avoid unnecessary screen failures. The 
following table summarizes these changes.
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. 
Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
Changes originally provided in Amendment 1 FR-IT-RS v1 for France, Italy, Serbia now apply to all countries unless 
affected by “Additional changes” below.
1
Section 1.2 Approval
Changed personnel for signatures.
New assignments.
2
Section 2.0, STUDY 
SUMMARY Study Design, 
Exploratory Objectives
Section 5.1.3 Exploratory 
Objectives
Section 6.2.2 Endpoints
Section 9.1.15.6 EQ-5D-5L 
Quality of Life Scale
Added language to note that the 
EQ-5D 5-Level version quality of 
life scale measures the 
parent’s/caregiver’s quality of 
life.
Clarification.
3
Section 6.1.5 End of Study
Added definition of end of study.
Health authority request.
4
Section 9.1.11.3 Procedures 
for Clinical Laboratory 
Samples
Indicated the maximum volume of 
blood collected at any single visit 
and the total volume of blood 
collected in the study.
Health authority request.
5
Section 9.3.5.1 Collection of 
Plasma Samples for Soticlestat 
and ASM PK Evaluation
Section 9.3.5.2 Bioanalytical 
Methods for Soticlestat
Section 9.3.5.3 PK Parameters
Clarified that pharmacokinetic 
(PK) measurements include 
metabolite(s) of soticlestat.
Clarification.
6
Appendix B Strong CYP3A
Inducers
Updated table with additional 
examples of CYP3A 
inducers/CYP3A4 inhibitors.
Correction to maintain 
consistency with protocols 
TAK-935-TAK-935-3001 and 
TAK-935-3003.
7
Appendix C Virtual Visits and 
Trial Management During 
COVID-19 Pandemic and 
Other Extenuating 
Revised language regarding 
conditions under which virtual 
visits are allowed.
Clarification.
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
Circumstances
Additional changes in global Amendment 2.
8
Section 2.0, STUDY 
SUMMARY
Changed “TAK-935/OV935” to 
“TAK-935”
Added that plasma concentrations 
will be displayed graphically.
Corrections.
9
Section 2.0, STUDY 
SUMMARY
Changed number of estimated 
sites from 65 to 100.
Increases patient recruitment 
rate.
10
Section 2.0, STUDY 
SUMMARY
Increase maximum age to 55 
years.
More representative of LGS 
population.
11
Section 2.0, STUDY 
SUMMARY
Section 5.1.1 Primary 
Objectives
Primary objective removes safety: 
“To assess the efficacy of 
soticlestat…”
Safety objectives are described 
separately.
12
Section 2.0, STUDY 
SUMMARY
Section 5.1.3 Exploratory 
Objectives
Section 5.2.3 Exploratory 
Endpoints
Section 9.1.15.6 EQ-5D-5L 
Quality of Life Scale
Clarified the EQ-5D terminology.
Clarifies that EQ-5D comes in 
different versions and that the 
EQ-5D-5L version includes 2 
scales: one where each domain 
has 5 levels of possible response 
and one visual analogue scale.
13
Section 2.0, STUDY 
SUMMARY
Section 5.1.4 Safety 
Objectives
Section 5.2.4 Safety Endpoints
Separate incidence and change 
from baseline into separate safety 
objectives for laboratory values 
and electrocardiograms (ECGs).
Clarification.
14
Section 2.0, STUDY 
SUMMARY
Section 5.2.2 Secondary 
Endpoints
Reordered secondary endpoints to 
follow the order of secondary 
objectives.
Consistency.
15
Section 2.0, STUDY 
SUMMARY
Section 5.2.4 Safety Endpoints
Remove ophthalmological 
evaluations from safety endpoints.
Cataract as an adverse event of 
special interest is covered in the 
treatment-emergent adverse 
event (TEAE) endpoint, so no 
need to include this as a separate 
endpoint; ophthalmological 
evaluations will occur as 
scheduled; results will still be 
available and will be presented in 
safety analysis tables.
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
16
Section 2.0, STUDY 
SUMMARY
Section 6.1 Study Design
Appendix A Schedule of Study 
Procedures
Clarified minimum time between 
screening and randomization 
visits.
Minimum window of 28 days of 
screening data to establish 
baseline seizure frequency.
17
Section 6.1 Study Design
Appendix A Schedule of Study 
Procedures
Made study day and dose day 
numbers the same and added a
Day 0: randomization = Visit 2 = 
Day 0; first dose is taken the next 
day on Day 1 (or first day after 
study medication is received).
Clarifies the numbering.
18
Section 2.0, STUDY 
SUMMARY
Section 6.1 Study Design
Section 8.1.3 Dose and 
Regimen
Low-profile gastric tube 
(MIC-KEY button) used instead 
of percutaneous endoscopic 
gastrostomy.
Percutaneous endoscopic 
gastrostomy is a surgical 
procedure; MIC-KEY button is a 
device.
19
Section 2.0, STUDY 
SUMMARY
Section 6.1 Study Design
Appendix A Schedule of Study 
Procedures
Appendix C Virtual Visits and 
Trial Management During 
COVID-19 Pandemic and 
Other Extenuating 
Circumstances
Broadened option to have virtual 
visits to allow more flexibility for 
subjects/parents or caregivers who 
may have difficulties with travel 
for clinic visits, such as 
COVID-19 restrictions or other 
extenuating circumstances. Also 
allowed virtual visits to be done as 
clinic visits.
Allows more flexibility for 
subjects/parents or caregivers.
20
Section 2.0, STUDY 
SUMMARY
Section 6.1.1 Dose Titration 
Period (4 Weeks)
Appendix A Schedule of Study 
Procedures
Clarified timing and procedures of 
dose titration period.
Clarification.
21
Section 2.0, STUDY 
SUMMARY
Section 6.1.3 Study 
Discontinuation/Completion
Appendix A Schedule of Study 
Procedures
Clarified procedures and timing of 
dose taper period and final dose.
Clarification.
22
Section 6.1.5 End of Study
Section 6.1.5 End of Study 
Overall
Clarified overall end of study 
versus end of study for an 
individual subject.
Corrected inadvertent omission 
of the definition for individuals; 
definition for study overall was 
simplified based on the 
individuals’ definitions.
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
23
Section 6.2.2 Endpoints
Clarified that QI-disability 
measurement is for subjects and 
EQ-5D is for the parents or 
caregivers.
Clarifies the purpose of scales.
24
Section 7.1 Inclusion Criteria
No. 1
Allowed inclusion of subjects 
living in a residential facility.
Allows subject population that 
might otherwise be excluded.
25
Section 7.1 Inclusion Criteria
No. 2
Section 9.1.1 Informed 
Consent Procedure
Section 12.1 eCRFs
Section 12.2 Record Retention
Section 14.1 Study-Site 
Monitoring Visits
Section 15.1 IRB and/or IEC 
Approval
Section 15.2 Subject 
Information, Informed 
Consent, and Subject
Authorization
Section 15.3 Subject 
Confidentiality
Appendix D Responsibilities 
of the Investigator
Appendix E Elements of the 
Subject Informed Consent
All electronic (e)consent changed 
to consent.
Subjects/parents or caregivers 
prefer written consent and 
signatures.
26
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria, 
No. 4
Clarified that clinical diagnosis 
should be supported by variable 
combinations of typical clinical 
features (listed) and these are 
guidance only; final eligibility is 
confirmed by TESC.
Clarifies that the bullets are not a 
mandatory checklist of 
diagnostic criteria.
Chinese health authority request.
27
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria
No. 5
Clarified primary outcome seizure 
types used in calculating the 
number of seizures.
Clarifies that not all seizures will 
be used for calculations for 
eligibility.
28
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria
No. 7
Required prior treatment failure of 
1 ASM rather than 2.
Allows enrollment of subjects 
who were being unnecessarily 
excluded.
29
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria, 
Added new criterion: Artisanal 
cannabidiols are allowed (at 
consistent dose and from the same 
More representative of the 
patient population.
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
No. 8
Section 9.1.12 Documentation 
of Concomitant (Including 
ASM and Rescue) Medications
manufacturer) and do not count as 
an ASM.
(Subsequent numbering of 
inclusion criteria shift by +1 
relative to Amendment 1 
FR-IT-RS v1.)
30
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria
No. 9
Allowed fenfluramine and 
cannabidiol (Epidiolex) as ASMs 
where available and counted as an 
ASM. (Formerly No. 8.)
Some countries have these 
medications available as ASMs.
31
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria, 
No. 13
Section 9.1.3 Seizure 
Identification and Diagnostic 
Review Forms (TESC)
Added that TESC review may 
include review of 
electroencephalogram and 
magnetic resonance imaging 
results (if available and permitted 
by local regulations), and that 
sponsor may be consulted if 
needed. (Formerly No. 12).
Makes additional information 
available to TESC.
32
Section 2.0, STUDY 
SUMMARY
Section 7.1 Inclusion Criteria
No. 14
Clarified allowed contraceptive 
methods. (Formerly No. 13.)
Clarifies that highly effective 
contraception is acceptable, in 
addition to effective 
contraception.
33
Section 2.0, STUDY 
SUMMARY
Section 7.2 Exclusion Criteria, 
No. 3
Clarified the exclusion around 
participation in other clinical 
studies.
Clarifies that only trials related 
to treatment devices are 
excluded.
34
Section 7.2 Exclusion Criteria, 
No. 11
Section 9.1.11.3 Procedures 
for Clinical Laboratory 
Samples, Table 9.a
Clarified exclusion based on 
hepatitis history.
Added hepatitis screening to 
clinical laboratory tests.
Clarification.
Correction of omission.
35
Section 7.2 Exclusion Criteria, 
No. 14
Section 7.2 Exclusion Criteria, 
originally No. 15
Section 7.3 Excluded 
Medications
Section 7.4 Diet, Fluid, 
Activity Control
Appendix B Strong CYP3A
Inducers 
Removed inhibitors of CYP3A 
from the exclusion criteria, 
prohibited medications, and from 
the appendix. Allowed topical 
CYP3A inducers.
Deleted original criterion No. 15, 
“Unwilling to withhold the fruit 
and juice of grapefruit, Seville 
oranges, and starfruit from their 
diet during the entire clinical 
trial.”
(Subsequent numbering of 
exclusion criteria shift by -1 
Per recent interim PK results 
from a phase 1 study, 
TAK-935-1007, the effect of a 
strong CYP3A4 inhibitor, 
itraconazole, on the PK exposure 
measures of soticlestat is small 
(<25% on maximum 
concentration and area under the 
plasma concentration-time 
curves). Therefore, strong 
CYP3A4 inhibitors will be 
allowed in the study.
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
relative to Amendment 1 
FR-IT-RS v1.)
Deleted same prohibition from 
Section 7.4.
36
Section 8.4 Accountability and 
Destruction of Study Drugs
Allowed drug supplies to be 
destroyed at the site rather than 
being returned to the sponsor or 
designee.
Allows flexibility in destruction 
of study drug.
37
Section 9.1.6 Height and 
Weight
If unable to obtain height or 
weight, other sources (specified) 
may be used for these data, which 
may be used to determine the 
weight-based starting dose.
Allows flexibility (eg, for subject 
in a wheelchair).
38
Section 9.1.11.1
Ophthalmological Evaluation 
Procedure
Added preference to obtain a 
picture of the fundus from 
ophthalmoscopy.
Clarified that discontinued 
subjects should have 
ophthalmological evaluation at 
the ET visit.
Provides visual record of results.
Corrects omission of these 
subjects.
39
Section 9.1.11.3 Procedures 
for Clinical Laboratory 
Samples
Appendix A Schedule of Study 
Procedures
Appendix G Blood Volumes
Details on blood volumes added in 
prior local amendment corrected 
and moved to a new appendix.
Plasma sample for soticlestat and 
metabolite(s) PK moved from 
randomization visit (Visit 2) to 
screening (Visit 1); plasma 
sample for ASM analysis now 
required and moved from 
randomization visit (Visit 2) to 
screening (Visit 1); plasma 
sample for 24HC removed from 
randomization visit (Visit 2). 
(Keep the sample for 24HC at 
screening/Visit 1). This changes 
the blood volumes for these 2 
visits.
Main text focuses on blood 
volume maximums; details 
available in appendix.
Sampling changes allow more 
flexibility (allows Visit 2 to be a 
virtual visit).
40
Section 9.1.11.3 Procedures 
for Clinical Laboratory 
Samples, Table 9.a.
Added nitrite, urobilinogen, and 
microscopy to urinalysis.
Added footnote that urinalysis is 
the primary method. Urine 
dipstick may be used as a backup 
only.
In text, clarified that local 
laboratories are allowed before 
Corrects omission of tests.
Clarification.
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
randomization only if a screening 
laboratory value is missing, and 
after randomization only for 
emergent reasons, including 
pregnancy tests.
41
Section 9.1.14 Clinical 
Assessment of Suicidal 
Ideation and Behavior
Clarified that children under age 6 
at the start of the study will be 
evaluated with C-SSRS if and 
when they turn 6 during the study.
Allows C-SSRS assessment of 
this additional group of children.
42
Section 9.1.15.3 CGI-I Seizure 
Intensity and Duration
Changed “MMD seizures” to “the 
most impactful seizures.”
Correction.
43
Section 9.1.15.5 QI-Disability 
(Parent/Caregiver Version)
Removed reference to translation 
and validation.
Translation and validation are 
completed for all countries.
44
Section 9.1.16.1 Male Subjects 
and Their Female Partners
Clarified that sperm donation by 
subjects is not allowed.
It is difficult to track and report 
pregnancy resulting from
donated sperm. Sponsor does 
request that pregnancy of the 
subject’s partner be reported.
45
Section 9.1.16.2 Female 
Subjects and Their Male 
Partners
Appendix A Schedule of Study 
Procedures
Clarified definitions of nonfertile 
subjects.
Clarified timing of pregnancy 
tests.
Adds definition of nonfertile 
subjects per Takeda template. 
Clarifies timing of pregnancy 
test to allow virtual visit 
flexibility at Visit 2.
46
Section 9.1.17 Pregnancy
Added requirement to report 
pregnancy of female partners of 
male subjects.
There is no evidence suggesting 
any risk in pregnancy of female 
partners of male subjects. To be 
conservative, the sponsor will 
follow up on such pregnancy and 
newborn information. 
47
Section 9.2 Monitoring 
Subject Treatment Compliance
Additional instructions regarding 
the electronic daily seizure and 
medication diary.
Provides more clarification in 
regards the use of the electronic 
diary.
48
Section 9.3.5.1 Collection of 
Plasma Samples for Soticlestat 
and ASM PK Evaluation
Appendix A Schedule of Study 
Procedures
ASM levels are required and will 
be collected during Visits 1, 9, and 
11. 
ASM samples are necessary to 
measure ASM exposures to
evaluate the effect of soticlestat 
on concomitant ASM exposures.
49
Section 9.4 Biological Sample 
Retention and Destruction
Added provision for storage of 
leftover blood samples for further 
research.
Potential future research related 
to soticlestat and/or seizure 
disorders. 
50
Section 9.5.1 Unscheduled 
Visits
Clarified types of and reasons for 
unscheduled visits.
Clarification.
51
Section 10.1 Definitions
Clarified definitions to distinguish 
AEs and TEAEs.
Makes terminology consistent. 
Applies change throughout 
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Protocol Amendment 2 
Summary of Changes Since the Original Approved Protocol
No.
Sections Affected by Change
Description
Rationale
protocol.
52
Section 10.1.4 AEs of Special 
Interest
Removed instruction that an AE 
of special interest and clinical 
significance be recorded as a 
serious adverse event (SAE).
Correction.
53
Section 10.2.1.1 AE Collection 
Period
TEAE collection period was 
clarified.
Clarification.
54
Section 10.2.2 Collection and 
Reporting of SAEs
Indicated that contacts for SAE 
reporting are provided in the study 
manual.
Correction.
55
Section 13.2.1.2 mITT 
Analysis Set
Clarified that the mITT analysis 
set only includes subjects who 
have been assessed for seizures 
during the treatment period.
Clarification.
56 
Section 2.0, STUDY 
SUMMARY
Section 13.2.4 Efficacy 
Analysis
Section 13.2.6
Exploratory/Additional 
Analyses
Corrected analysis description, 
including planned statistical tests.
Correction.
57
Section 14.1, Study-Site 
Monitoring Visits
With the exception of visits in 
China, monitoring visits can be 
virtual or on site, as indicated in 
the clinical monitoring plan.
Clarification.
58
Appendix H Protocol History
Added history of Amendment 1 
FR-IT-RS v1 to this new 
appendix.
Template requirement.
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CONFIDENTIAL
TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................19
3.0
STUDY REFERENCE INFORMATION ......................................................................27
3.1
Study-Related Responsibilities.................................................................................27
3.2
Coordinating Investigator.........................................................................................27
3.3
List of Abbreviations ...............................................................................................28
3.4
Corporate Identification...........................................................................................29
4.0
INTRODUCTION.........................................................................................................30
4.1
Background .............................................................................................................30
4.2
Rationale for the Proposed Study.............................................................................31
4.3
Benefit/Risk Profile .................................................................................................31
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................32
5.1
Objectives................................................................................................................32
5.1.1
Primary Objectives ..........................................................................................32
5.1.2
Secondary Objectives ......................................................................................32
5.1.3
Exploratory Objectives ....................................................................................33
5.1.4
Safety Objectives.............................................................................................33
5.2
Endpoints.................................................................................................................34
5.2.1
Primary Endpoints ...........................................................................................34
5.2.2
Secondary Endpoints .......................................................................................34
5.2.3
Exploratory Endpoints .....................................................................................34
5.2.4
Safety Endpoints..............................................................................................35
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................35
6.1
Study Design ...........................................................................................................35
6.1.1
Dose Titration Period (4 Weeks)......................................................................39
6.1.2
Maintenance Period (12 Weeks) ......................................................................39
6.1.3
Study Discontinuation/Completion ..................................................................39
6.1.4
End of Study for Individual Subject .................................................................40
6.1.5
End of Study Overall .......................................................................................40
6.2
Justification for Study Design, Dose, and Endpoints ................................................40
6.2.1
Study Design ...................................................................................................40
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6.2.2
Endpoints ........................................................................................................41
6.2.3
Dose ................................................................................................................41
6.3
Premature Termination or Suspension of Study or Study Site...................................43
6.3.1
Criteria for Premature Termination or Suspension of the Study........................43
6.3.2
Criteria for Premature Termination or Suspension of Study Sites.....................43
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...........................................................................43
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............43
7.1
Inclusion Criteria .....................................................................................................44
7.2
Exclusion Criteria ....................................................................................................46
7.3
Excluded Medications..............................................................................................48
7.4
Diet, Fluid, Activity Control ....................................................................................48
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................49
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................51
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................51
8.1
Study Drug and Materials ........................................................................................51
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................51
8.1.1.1
Study Drug ..............................................................................................51
8.1.1.2
Rescue Medication ..................................................................................51
8.1.2
Storage ............................................................................................................51
8.1.3
Dose and Regimen...........................................................................................52
8.1.4
Overdose .........................................................................................................53
8.2
Study Drug Assignment and Dispensing Procedures ................................................53
8.3
Unblinding Procedures.............................................................................................54
8.4
Accountability and Destruction of Study Drugs .......................................................54
9.0
STUDY PLAN ..............................................................................................................55
9.1
Study Procedures.....................................................................................................55
9.1.1
Informed Consent Procedure............................................................................55
9.1.2
Historical Seizure Diary Review......................................................................56
9.1.3
Seizure Identification and Diagnostic Review Forms (TESC) ..........................56
9.1.4
Seizure Frequency ...........................................................................................56
9.1.5
Demographics, Medical History, and Medication History Procedure................57
9.1.6
Height and Weight...........................................................................................58
9.1.7
Concomitant Medications and Nonpharmacologic Therapies and Procedures...58
9.1.8
Vital Sign Procedure........................................................................................58
9.1.9
Physical Examination Procedure......................................................................59
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9.1.10
Neurological Examination Procedure...............................................................59
9.1.11
Safety Evaluations ...........................................................................................59
9.1.11.1
Ophthalmological Evaluation Procedure..................................................60
9.1.11.2
ECG Procedure........................................................................................60
9.1.11.3
Procedures for Clinical Laboratory Samples ............................................61
9.1.12
Documentation of Concomitant (Including ASM and Rescue) Medications .....63
9.1.13
Documentation of Concurrent Medical Conditions...........................................63
9.1.14
Clinical Assessment of Suicidal Ideation and Behavior....................................63
9.1.15
Health Outcome/Quality of Life Measures.......................................................64
9.1.15.1
CGI-I (Clinician) .....................................................................................64
9.1.15.2
Care GI-I (Caregiver) ..............................................................................64
9.1.15.3
CGI-I Seizure Intensity and Duration.......................................................64
9.1.15.4
CGI-I Nonseizure Symptoms...................................................................64
9.1.15.5
QI-Disability (Parent/Caregiver Version).................................................65
9.1.15.6
EQ-5D-5L Quality of Life Scale..............................................................65
9.1.16
Contraception and Pregnancy Avoidance Procedure ........................................65
9.1.16.1
Male Subjects and Their Female Partners ................................................65
9.1.16.2
Female Subjects and Their Male Partners ................................................65
9.1.16.3
General Guidance With Respect to the Avoidance of Pregnancy..............66
9.1.17
Pregnancy........................................................................................................67
9.1.18
Documentation of Screen Failure.....................................................................67
9.1.19
Documentation of Study Entrance....................................................................68
9.2
Monitoring Subject Treatment Compliance..............................................................68
9.3
Safety Monitoring....................................................................................................69
9.3.1
Reporting of Abnormal LFTs...........................................................................69
9.3.2
Reporting of QTcF Interval Increase................................................................69
9.3.3
Reporting of Perampanel Drug-Drug Interaction..............................................70
9.3.4
Reporting of Cataracts .....................................................................................70
9.3.5
PK and PD Measurements ...............................................................................70
9.3.5.1
Collection of Plasma Samples for Soticlestat and ASM PK Evaluation....70
9.3.5.2
Bioanalytical Methods for Soticlestat.......................................................71
9.3.5.3
PK Parameters.........................................................................................71
9.3.5.4
PD Measurements....................................................................................71
9.4
Biological Sample Retention and Destruction ..........................................................72
9.5
Schedule of Study Procedures..................................................................................72
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9.5.1
Unscheduled Visits..........................................................................................72
9.5.2
Poststudy Care.................................................................................................72
10.0
COLLECTION AND REPORTING OF ADVERSE EVENTS......................................73
10.1
Definitions...............................................................................................................73
10.1.1
AEs .................................................................................................................73
10.1.2
Additional Points to Consider for AEs .............................................................73
10.1.3
SAEs ...............................................................................................................75
10.1.4
AEs of Special Interest.....................................................................................75
10.1.5
Intensity of AEs...............................................................................................76
10.1.6
Causality of AEs..............................................................................................76
10.1.7
Relationship to Study Procedures.....................................................................76
10.1.8
Start Date.........................................................................................................77
10.1.9
Stop Date.........................................................................................................77
10.1.10 Frequency........................................................................................................77
10.1.11 Action Concerning Study Drug........................................................................77
10.1.12 Outcome..........................................................................................................77
10.2
Procedures...............................................................................................................78
10.2.1
Collection and Reporting of AEs .....................................................................78
10.2.1.1
AE Collection Period...............................................................................78
10.2.1.2
AE Reporting...........................................................................................78
10.2.2
Collection and Reporting of SAEs ...................................................................79
10.3
Follow-up of SAEs ..................................................................................................79
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...80
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................80
12.0
DATA HANDLING AND RECORDKEEPING............................................................80
12.1
eCRFs......................................................................................................................80
12.2
Record Retention .....................................................................................................81
13.0
STATISTICAL METHODS..........................................................................................82
13.1
Statistical and Analytical Plans ................................................................................82
13.2
Determination of Sample Size..................................................................................82
13.2.1
Analysis Sets ...................................................................................................82
13.2.1.1
ITT Analysis Set......................................................................................82
13.2.1.2
mITT Analysis Set...................................................................................83
13.2.1.3
Safety Analysis Set..................................................................................83
13.2.2
Analysis of Demographics and Baseline Characteristics...................................83
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13.2.3
Subject Disposition..........................................................................................83
13.2.4
Efficacy Analysis.............................................................................................83
13.2.5
Safety Analysis................................................................................................84
13.2.6
Exploratory/Additional Analyses .....................................................................84
13.3
Other Statistical Issues.............................................................................................84
13.3.1
Significance Levels..........................................................................................84
13.3.2
Missing or Invalid Data ...................................................................................85
13.3.3
Interim Analyses..............................................................................................85
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................85
14.1
Study-Site Monitoring Visits ...................................................................................85
14.2
Protocol Deviations..................................................................................................85
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................86
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................86
15.1
IRB and/or IEC Approval ........................................................................................86
15.2
Subject Information, Informed Consent, and Subject Authorization .........................87
15.3
Subject Confidentiality ............................................................................................88
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................89
15.4.1
Publication and Disclosure...............................................................................89
15.4.2
Clinical Trial Registration................................................................................89
15.4.3
Clinical Trial Results Disclosure......................................................................89
15.5
Insurance and Compensation for Injury....................................................................89
16.0
REFERENCES..............................................................................................................90
LIST OF IN-TEXT TABLES
Table 6.a
Dosing Schedules by Weight, 10 to <15 kg........................................................37
Table 6.b
Dosing Schedules by Weight, 15 to <30 kg........................................................37
Table 6.c
Dosing Schedules by Weight, 30 to <45 kg........................................................38
Table 6.d
Dosing Schedules by Weight, ≥45 kg.................................................................38
Table 9.a
Clinical Laboratory Tests...................................................................................62
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................36
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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................91
Appendix B
Strong CYP3A Inducers.....................................................................................97
Appendix C
Virtual Visits and Trial Management During COVID-19 Pandemic and Other 
Extenuating Circumstances ................................................................................98
Appendix D
Responsibilities of the Investigator...................................................................100
Appendix E
Elements of the Subject Informed Consent.......................................................102
Appendix F
Investigator Consent to Use of Personal Information........................................105
Appendix G 
Blood Volumes ................................................................................................106
Appendix H 
Protocol History...............................................................................................107
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
Soticlestat (also known as TAK-935)
Title of Protocol: A Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Efficacy, Safety, and Tolerability of Soticlestat 
as Adjunctive Therapy in Pediatric and Adult Subjects With 
Lennox-Gastaut Syndrome (LGS)
IND No.: 133627
EudraCT No.:
2021-002481-40
Study Number: TAK-935-3002 Amendment 2
Phase: 3
Study Design:
This is a phase 3, global, multicenter, 1:1 randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy, safety, and tolerability of soticlestat as an adjunctive therapy in pediatric and adult subjects with 
LGS. The treatment period is 16 weeks. The total duration of the study is approximately 25 weeks for subjects who 
complete the study and choose not to roll over to the open-label extension (OLE) study. For those who roll over to the 
OLE study, the study duration is 3 weeks shorter.
Approximately 234 male and female pediatric and adult subjects will be randomized.
The study will consist of the following periods:

4- to 6-week screening/baseline period. The minimum visit window for screening is 28 days (ie, Visit 2/Day 0
cannot occur earlier than 29 days after screening).

16-week full treatment period:
–
4-week titration period.
–
12-week maintenance period.

1-week taper period for those discontinuing study drug, followed by a 2-week safety follow-up visit or a phone 
call.
This is a 2-arm study. All subjects will be randomized at a 1:1 ratio to receive standard of care (SOC) plus one of the 
following adjunctive therapies: soticlestat or placebo.
Soticlestat or matching placebo added to current antiseizure therapy will be administered orally twice daily (BID) with 
or without food or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY button). A jejunostomy tube 
(J-tube) may be considered following written approval by the medical monitor or sponsor. Note: Study drug will be 
administered only orally for subjects enrolled in sites in jurisdictions where alternative means are not permitted.
All doses will be blinded and will undergo the same titration scheme, with the same number and type of 
tablets/mini-tabs. Subjects randomized to placebo will undergo a mock titration to ensure the blind is maintained (see 
tables below).
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The total daily dose of study drug (either placebo or soticlestat) will be calculated based on body weight at Visit 1 
(screening visit) and given BID starting on the morning after Visit 2/Day 0 (ie, on study Day 1) (see tables below). The 
100 mg BID dose (or 100 mg BID equivalent weight-based dosing for weight <45 kg) is the minimum dose allowed 
during the study. Subjects who cannot tolerate the minimal dose will be discontinued from the study. Subjects 
weighing <45 kg will be dispensed 20 mg mini-tablets or matching placebo. Subjects weighing ≥45 kg may be 
dispensed 20 mg mini-tablets or 100 mg tablets or matching placebo.
Dosing Schedules by Weight, 10 to <15 kg
Treatment 
Arm
10 to <15 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
40 mg BID
2 mini tabs 
soticlestat BID
60 mg BID
3 mini tabs 
soticlestat BID
100 mg BID
5 mini tabs 
soticlestat BID
PBO
---
2 mini tabs 
PBO BID
---
3 mini tabs 
PBO BID
---
5 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Dosing Schedules by Weight, 15 to <30 kg
Treatment Arm
15 to <30 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
60 mg BID
3 mini tabs 
soticlestat BID
120 mg BID
6 mini tabs 
soticlestat BID
200 mg BID
10 mini tabs 
soticlestat BID
PBO
---
3 mini tabs 
PBO BID
---
6 mini tabs 
PBO BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Dosing Schedules by Weight, 30 to <45 kg
Treatment Arm
30 to <45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
80 mg BID
4 mini tabs 
soticlestat BID
140 mg BID
7 mini tabs 
soticlestat BID
200 mg BID
10 mini tabs 
soticlestat BID
PBO
---
4 mini tabs 
PBO BID
---
7 mini tabs 
PBO BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
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Dosing Schedules by Weight, ≥45 kg
Treatment Arm
≥45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
100 mg BID
1 tab soticlestat 
BID 
OR
5 mini tabs 
soticlestat BID
200 mg BID
2 tabs 
soticlestat BID
OR
10 mini tabs 
soticlestat BID
300 mg BID
3 tabs 
soticlestat BID
OR
15 mini tabs 
soticlestat BID
PBO
---
1 tab PBO BID 
OR
5 mini tabs 
PBO BID
---
2 tabs PBO 
BID
OR
10 mini tabs 
PBO BID
---
3 tabs PBO 
BID
OR
15 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
The study design allows virtual visits if aligned with institutional or local guidelines, via phone or via any platforms 
approved by local regulations, in addition to the communication platform offered through the study. Screening (Visit 
1) and Visit 11 (Day 113)/early termination must be conducted in person; Visit 9 is to be conducted in person if 
possible but may be conducted virtually (via video or phone) in response to the coronavirus disease 2019 (COVID-19) 
pandemic and/or based on sponsor approval and if permitted by local regulations. In extenuating circumstances, the 
randomization visit (Visit 2) and Visit 11 (Day 113)/early termination can be virtual visits (only via video, not phone), 
with sponsor approval and if permitted by local regulations. In addition, any visit identified as a virtual visit in this 
protocol may be conducted in clinic and in person if requested by the subject/parent or guardian and/or at the 
investigator’s discretion.
Dose Titration Period (4 Weeks):
Subjects will take the first dose of study drug (Dose 1) the day after the study medication is received. Approximately 7 
days after initiating study medication, if there are no tolerability issues, study drug dose will be increased to Dose 2. 
After approximately 7 days on Dose 2, if there are no tolerability issues, study drug dose will be increased to Dose 3. 
If the subjects do not experience any tolerability issues, they will continue on Dose 3 for the remainder of the titration 
period. Subjects will only be allowed to increase their dose within the 4-week titration period before entering the 
12-week maintenance period. Decrease in dose level is allowed during the titration period if required for safety and 
tolerability. Subjects who cannot tolerate the minimum dose of 100 mg BID (or weight-based equivalent dosing <45 
kg) will be discontinued from treatment. The maximum allowed dose is 300 mg BID. The subjects/parents or 
caregivers will be contacted by phone within approximately 2 days following each dose escalation to assess safety and 
tolerability of the study drug. The final dose tolerated by the end of the 4-week titration period should be maintained 
until the end of the maintenance period, unless tolerability issues arise.
Maintenance Period (12 Weeks):
The dose level at the end of the titration period will be maintained until the end of the maintenance; period (dose 
increases are not permitted); however, during the maintenance period, the dose may be decreased by 1 dose level to the 
previous lower dose, for safety and tolerability issues. For example, Dose 3 may be reduced to Dose 2, and Dose 2 may 
be reduced to Dose 1. The minimum dose is Dose 1 (100 mg BID adult reference dose; or weight-based equivalent 
dosing for <45 kg); subjects who cannot tolerate the minimum dose of 100 mg BID will be discontinued from 
treatment. Dose changes during the maintenance period are allowed for safety or tolerability reasons as assessed by the 
investigator; however, if possible, dose changes will need to be discussed with the medical monitor and/or the sponsor.
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Study Discontinuation/Completion:
At Visit 11/early termination, subjects will have the option to enroll in the OLE study as per that study’s 
inclusion/exclusion criteria.
Subjects who enroll in the OLE study on the same day as Visit 11/early termination will take their final dose of 
double-blind study drug in the evening of the day of Visit 11/early termination and should continue to record seizures 
in the seizure diary until midnight of the day of Visit 11/early termination, at which time they will exit the study.
Subjects who do not roll over to the OLE study on the same day as Visit 11/early termination will take their final dose 
of double-blind study drug in the morning of Visit 11/early termination, followed by a taper period. The study drug 
dose will be tapered down to a lower dose (taper Dose 3 to Dose 2, taper Dose 2 to Dose 1) approximately every 3 days 
until the study drug dose is discontinued. The subject/parent or caregiver should continue to record seizures in the 
seizure diary until the safety follow-up phone call, which will occur approximately 14 days after the last dose of study 
drug. After completion of the safety follow-up phone call, the subject will exit the study.
Subjects/parents or caregivers who choose to enroll in the OLE study after Visit 11/early termination will continue the 
taper procedure until the investigator confirms eligibility for the OLE study; the subject will then exit the study and 
roll over to the OLE study.
Primary Objectives:

To assess the efficacy of soticlestat in reducing MMD seizure frequency as add-on therapy to SOC as compared 
with placebo during the full treatment period (titration + maintenance).
For European Medicines Agency (EMA) registration:

To assess the efficacy of soticlestat in reducing MMD seizure frequency as add-on therapy to SOC compared with 
placebo during the maintenance period only.
Secondary Objectives:
To assess the following in subjects taking soticlestat as compared with placebo during the full treatment period, unless 
otherwise noted:

Proportion of treatment responders defined as those with ≥50% reduction in MMD seizures from baseline during 
the maintenance period and the full treatment period. 

Effect on total seizure frequency of all seizure types during the maintenance period and the full treatment period.

Change from baseline in proportion of MMD seizure–free days.

Longest MMD seizure–free interval.

Number of days when rescue antiseizure medications (ASMs) are used.

Effect on the Clinical Global Impression of Improvement (CGI-I) (clinician) and Caregiver Global Impression of 
Improvement (Care GI-I).

Effect on CGI-I Seizure Intensity and Duration.

Effect on the CGI-I Nonseizure Symptoms completed by clinician with input from the caregivers.

Effect on Quality of Life Inventory-Disability (QI-Disability).
Exploratory Objectives:
To assess the following in subjects receiving soticlestat as compared with placebo during the full treatment period:

Seizure frequency of each seizure type per 28 days.

Health care resource utilization including but not limited to emergency room visits and hospitalizations.

Population pharmacokinetic (PK) and correlation of the population PK exposure parameters with 
pharmacodynamic (PD) (plasma 24S-hydroxycholesterol [24HC] levels) in subjects receiving soticlestat.

Correlation of change in PD (24HC) exposure and efficacy (change in MMD seizure over the full treatment 
period).

Effect on EQ-5D 5 Level version (EQ-5D-5L) quality of life scale for parents’/caregivers’ quality of life.
Safety Objectives:

To assess the incidence of treatment-emergent adverse events (TEAEs).
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
To assess the incidence of abnormal values and change for clinical laboratory evaluations, vital signs, 
electrocardiogram (ECG) parameters, and Columbia-Suicide Severity Rating Scale (C-SSRS) parameters.

To assess the incidence of new seizure types arising during soticlestat treatment that are not identified at the time 
of screening (by history) or during prospective baseline.
Subject Population: Pediatric and adult LGS subjects aged ≥2 and ≤55 years, inclusive, with treatment-resistant 
seizures (defined as having seizures despite appropriate trials of 1 or more ASMs), and are currently on stable 
antiseizure therapy, including 0 to 3 concomitant ASMs.
Number of Subjects:
Approximately 234 male and female pediatric and adult 
subjects will be randomized in a 1:1 ratio to receive 
soticlestat or placebo, resulting in approximately 117
subjects per arm. A minimum of 20 pediatric subjects aged 2 
through 6 years will be enrolled.
Number of Sites:
Global, multicenter study to be conducted at 
approximately 100 sites.
Dose Level(s):
300 mg BID (300 mg BID equivalent dose; weight-based 
dosing for <45 kg) soticlestat or matching placebo
Route of Administration:
Oral or via G-tube or MIC-KEY button.
Duration of Treatment:
16 weeks (titration and maintenance)
Period of Evaluation:
~25 weeks (including up to 6-week screening/baseline 
period, 16-week double-blind treatment period 
[4-week titration and 12-week maintenance periods], 
1-week taper period for those discontinuing study 
drug, followed by a 2-week safety follow-up visit)
Main Criteria for Inclusion:
Male or female and aged 2 to 55 years, inclusive, at the time of informed consent.
Documented clinical diagnosis of LGS supported by variable combinations of typical clinical features such as those 
noted below. (Note: These criteria are for guidance only as the final diagnostic eligibility decision is made by TESC.)

Onset of seizures usually between the ages of 1 and 8 years.

Presence of multiple seizure types: including drop seizures (eg, tonic-atonic seizures) and other seizure types 
including atypical absence seizures, tonic-clonic, myoclonic, and partial seizures.

History of abnormal electroencephalogram (EEG; eg, slow spike and wave [<2.5 Hz], slow or disorganized EEG 
background, generalized paroxysmal fast activity).

Developmental delay or intellectual disability consistent with LGS.
The participant has had ≥8 MMD seizures each month in the 3 months before screening based on the historical 
information and has had ≥8 MMD seizures per 28 days during the 4- to 6-week prospective baseline period.
Weighs ≥10 kg at the screening visit (Visit 1).
Failure to control seizures despite appropriate trials of at least 1 ASM based on historical information and is currently 
on an antiseizure therapy (eg, ASMs, vagus nerve stimulation, ketogenic/modified Atkins diet) or other treatment 
options considered as SOC. 
Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing 
regimen and manufacturer should remain constant throughout the study. (Artisanal cannabidiols will not be counted as 
ASMs).
Currently taking 0 to 3 ASMs at stable doses for at least 4 weeks before the screening visit (Visit 1); benzodiazepines 
used chronically (daily) to treat seizures are considered ASMs. Fenfluramine and cannabidiol (Epidiolex) are allowed 
where available and should be counted as an ASM. ASM dosing regimen must remain constant throughout the study.
Female subjects of childbearing potential (defined as first menarche) must have a negative pregnancy test and agree to 
use an effective or highly effective method of birth control during the study and for 30 days following the last dose of 
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study drug.
Main Criteria for Exclusion:
Currently enrolled in a clinical study involving an investigational product (ie, not approved in that country, other than 
soticlestat) or concurrently enrolled in any other type of medical research judged not to be scientifically or medically 
compatible with this study. Note: Compatibility will be determined based on consultation with the medical monitor or 
the sponsor.
Participated in a clinical study involving another study drug in the last 30 days (or 5 half-lives of the study drug, 
whichever is longer) before screening (Visit 1).
Received soticlestat in a previous clinical study.
Known hypersensitivity to any component of the soticlestat formulation.
Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months 
immediately before screening (Visit 1). For the purpose of this exclusion criterion, status epilepticus is defined as 
continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to baseline in between 
seizures.
Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, 
ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, 
endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to 
participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to 
assess the clinical significance; however, consultation with the medical monitor may be warranted.
Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition, within the 2 years immediately before screening (Visit 1).
Abnormal and clinically significant ECG abnormality at screening (Visit 1) or before randomization (Visit 2), 
including QT interval with Fridericia correction method (QTcF) >450 ms, confirmed with a repeat ECG using manual 
measurement of QTcF. Clinically significant ECG abnormalities should be discussed with the medical monitor.
Abnormal clinical laboratory test results at screening (Visit 1) that suggest a clinically significant underlying disease 
that would compromise the well-being of the subject. If the subject has a serum alanine aminotransferase and/or 
aspartate aminotransferase level >2.5 times the upper limit of normal (ULN), the medical monitor should be consulted.
Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the last dose of study drug.
Criteria for Evaluation and Analyses:
Primary Endpoint:

Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving soticlestat as compared 
with placebo during the full treatment period.
For EMA registration:

Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving soticlestat as compared 
with placebo during the maintenance period.
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Secondary Endpoints:
To assess the following in subjects receiving soticlestat as compared with placebo during the full treatment period, 
unless otherwise noted:

Proportion of responders, defined as those with ≥50% reduction from baseline in MMD seizures during the 
maintenance period and the full treatment period.

Responder analysis of the proportion of subjects with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and 
>75% to ≤100% reduction in MMD seizures in a cumulative response curve.

Care GI-I (caregiver).

CGI-I (clinician).

CGI-I Nonseizure Symptoms.

Change in QI-Disability score.

CGI-I Seizure Intensity and Duration.

Percent change from baseline in frequency of all seizures per 28 days during the maintenance period and the full 
treatment period.

Percent change from baseline in MMD seizure frequency per 28 days during the maintenance period.

Change from baseline in proportion of MMD seizure-free days.

Longest MMD seizure–free interval.

Number of days when rescue ASM is used.
Exploratory Endpoints:
To assess the following in subjects receiving soticlestat as compared with placebo during the full treatment period:

Percent change from baseline in frequency per 28 days of each seizure type identified at the time of screening or 
baseline.

Health care resource utilization including but not limited to emergency room visits and hospitalizations.

Soticlestat exposure-PD (plasma 24HC level) and efficacy response analysis.

Percent change from baseline in plasma 24HC.

Plasma concentrations of soticlestat and the soticlestat metabolite(s) at multiple time points.

Population soticlestat PK modeling based on sparse PK.

Change in EQ-5D-5L and EQ visual analogue scale (EQ VAS) scores.
Safety Endpoints:

Incidence of TEAEs.

Incidence of abnormal values for clinical laboratory values and ECG evaluations.

Change from baseline in clinical laboratory evaluations, vital signs, C-SSRS, and ECG parameters.

Incidence of new seizure types arising post–study treatment initiation.
Statistical Considerations:
Efficacy Analyses
The seizure frequency will be calculated based on all data collected during the baseline and treatment periods. For all 
efficacy analyses on seizure frequency, baseline refers to the prospective 4- to 6-week baseline period. The efficacy 
endpoints will be summarized for each treatment group, and comparisons will be made between soticlestat and 
placebo groups. Percent change from baseline in MMD seizure frequency per 28 days will be analyzed using rank 
analysis of covariance (ANCOVA) with treatment group as the main effect; age group (≤6 years, >6 years) and 
baseline seizure frequency will be covariates. Sensitivity analyses will be performed using the van Elteren test and the 
Wilcoxon rank sum test. Gender will also be added to the rank ANCOVA model as a sensitivity analysis.
Percent change from baseline in frequency of all seizures per 28 days will be compared between soticlestat and 
placebo using rank ANCOVA, adjusting for baseline seizure frequency and age stratum. The Hodges-Lehmann 
estimator and the corresponding 95% CI comparing soticlestat and placebo will also be displayed.
The proportion of responders will be analyzed using a Cochran-Mantel-Haenszel test stratified by age group (≤6 years, 
>6 years).
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The main analysis for CGI-I (clinician), Care GI-I, CGI-I Seizure Severity and Duration, CGI-I Nonseizure 
Symptoms, and QI-Disability scores will be based on the responses at each subject’s last visit during which these 
instruments were utilized. The QI-Disability scores will be analyzed with a mixed model for repeated measures and 
the other scores will be analyzed using ordinal logistic regression. A sensitivity analysis will be performed using the 
van Elteren test stratified by the 2 age groups. A supportive analysis based on responses for completers at the end of 16 
weeks of treatment will also be performed using ordinal logistic regression.
The global type I error will be controlled using a hierarchical gatekeeping procedure on the primary and secondary 
endpoints. The order of testing will be soticlestat versus placebo for the primary endpoint, responder rate, Care GI-I, 
CGI-I (clinician), CGI-I Nonseizure Symptoms, QI-Disability, and CGI-I Seizure Intensity and Duration. All 
statistical tests will be 2-sided at the 5% significance level. Techniques for handling missing information with respect 
to reporting of seizures in the treatment period and with respect to subjects who discontinue early will be specified in 
detail in the statistical analysis plan (SAP).
Safety Analyses
Descriptive statistics will be used to summarize all safety endpoints for each of the 2 treatment groups. Two-sided 
95% CIs will be presented where meaningful. Data summaries will be displayed for incidence of AEs, clinical 
laboratory variables, vital signs, body weight, and ECG parameters, as appropriate.
Exploratory/Additional Analyses
Percent change from baseline in each seizure type frequency per 28 days during the full treatment period will be 
compared between soticlestat and placebo using rank ANCOVA, adjusting for baseline seizure frequency and age 
stratum. The Hodges-Lehmann estimator and the corresponding 95% CI comparing soticlestat and placebo will also 
be displayed.
Health care resource utilization, including but not limited to emergency room visits and hospitalizations, and the effect 
on the EQ-5D-5L quality of life scale will be analyzed for soticlestat and placebo. Descriptive and graphical analyses 
will be used to summarize results from the exploratory endpoints.
Alpha-1 acidic glycoprotein will be analyzed as part of the laboratory serum chemistry panel at each visit where PK 
samples are obtained.
Plasma concentrations of soticlestat and metabolite(s) will be summarized and displayed graphically per nominal time 
points. Mean plasma concentrations over time will be presented graphically.
Correlation of change in PD (24HC) exposure and efficacy (change in MMD seizure over the full treatment period) 
will be investigated.
Sample Size Justification: The study will randomize a total of approximately 234 subjects at a 1:1 ratio to receive 1 
dose level of soticlestat or placebo, resulting in approximately 117 subjects per arm.
The primary endpoint for this study is the percent change from baseline in MMD seizure frequency per 28 days. The 
definition for MMD is different for this study than for ELEKTRA, however, the variability of this endpoint is assumed 
to be the same. This leads to an assumption that the pooled SD of the percent change from baseline in MMD seizure 
frequency is 65%.
A difference of 26.5% in mean percent reduction in MMD seizure frequency between treatments is an appropriate 
target. A sample size of 117 subjects per treatment arm will provide at least 85% power at a two-tailed 5% significance 
level to detect a difference of 26.5% in mean percent reduction in seizure frequency between treatments using the 
Wilcoxon rank-sum test, assuming the pooled SD above of 65%.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research 
as well as study participation. The Signatory Coordinating Investigator will be required to review 
and sign the clinical study report and by doing so agrees that it accurately describes the results of 
the study.
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3.3
List of Abbreviations
24HC
24S-hydroxycholesterol
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASM
antiseizure medication
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
area under the plasma concentration-time curve
BID
twice daily 
Care GI-C
Caregiver Global Impression of Change
Care GI-I
Caregiver Global Impression of Improvement
CGI-C
Clinical Global Impression of Change
CGI-I
Clinical Global Impression of Improvement
CH24H
cholesterol-24-hydroxylase
COVID-19
coronavirus disease 2019
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DEE
developmental epileptic encephalopathy
DMC
Data Monitoring Committee
DRF
diagnostic review form
DS
Dravet syndrome
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture 
EEG
electroencephalogram
EO
enzyme occupancy
EQ-5D-5L
EQ-5D 5-level version
EQ VAS
EQ-5D visual analogue scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
G-tube
gastrostomy tube
hCG
human chorionic gonadotropin
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
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INR
international normalized ratio
IRB
institutional review board
ITT
intent-to-treat
IWRS
interactive web response system
J-tube
jejunostomy tube
LFT
liver function test
LGS
Lennox-Gastaut syndrome
MMD
major motor drop
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
OLE
open-label extension
PD
pharmacodynamic(s)
PK
pharmacokinetics
PTE
pretreatment event
QI-Disability
Quality of Life Inventory-Disability
QTc
corrected QT interval
QTcF
QT interval with Fridericia correction method
rSDV
remote Source Data Verification
SAE
serious adverse event
SAP
statistical analysis plan
SOC
standard of care
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TESC
The Epilepsy Study Consortium
ULN
upper limit of normal
US
United States
VNS
vagus nerve stimulation
WHO
World Health Organization
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
Lennox-Gastaut syndrome (LGS) is rare and is one of the most severe forms of childhood 
epilepsy. The syndrome usually has its onset between the ages of 1 and 8 years, but occasionally it 
occurs in children who are older than 8 years, or even into adulthood. LGS includes the presence of 
multiple seizure types: the hallmark tonic-atonic drop seizures. Other seizure types include 
atypical absence seizures, but tonic-clonic, myoclonic, and partial seizures are also frequently 
present. 
Soticlestat is a first-in-class small molecule inhibitor of cholesterol-24 hydroxylase (CH24H) in 
the brain. It is hypothesized that soticlestat treatment will decrease the levels of 
24S-hydroxycholesterol (24HC) and improve MMD seizure control in LGS subjects. Nonclinical 
studies have demonstrated that soticlestat modulates the glutamatergic signaling and significantly 
reduces spontaneous seizure in murine models of LGS. Clinical Study TAK-935-2002 
(ELEKTRA) showed efficacy of soticlestat in subjects with Dravet syndrome (DS) or LGS.
ELEKTRA was a phase 2, multicenter, randomized, double-blind, placebo-controlled study that 
evaluated the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) 
of soticlestat as adjunctive therapy in pediatric subjects aged ≥2 and ≤17 years with LGS or DS. A 
total of 141 subjects were enrolled (51 with DS and 90 with LGS), and 126 completed the study. 
Subjects were eligible for enrollment if they demonstrated ≥3 convulsive seizures (in the DS 
cohort) or ≥4 drop seizures (in the LGS cohort) during a minimum of 4 weeks during the 
prospective baseline period (based on the seizure diary records), and they were currently on a 
stable regimen of 1 to 4 concomitant antiseizure medications (ASMs). This study consisted of 
2 main periods, a 4- to 6-week screening/baseline period, followed by a 20-week treatment period 
(8-week titration and dose-optimization period and a 12-week maintenance period). Subjects who 
met the entry criteria were stratified by syndrome and randomized in a 1:1 ratio to soticlestat or 
matching placebo within each cohort. Subjects were dosed with oral 20 mg or 100 mg soticlestat 
tablets or matching placebo at 100 mg twice daily (BID) for 1 week, followed by 200 mg BID for 
another week, before titrating up to 300 mg BID, the maximum allowable dose. Subjects weighing 
<60 kg were dosed by weight.
In the DS cohort (n = 51), subjects treated with soticlestat demonstrated a 33.8% median reduction 
in convulsive seizure frequency compared with a 7.0% median increase seen in subjects taking 
placebo during the 20-week treatment period (median placebo-adjusted reduction in convulsive 
seizure frequency was 46.0%; p = 0.0007). The responder rate (≥50% reduction in convulsive 
seizure frequency compared with baseline) for subjects taking soticlestat in the DS cohort was 
30.8% while for placebo was 0%. In the LGS cohort (n=88), soticlestat decreased drop seizures by 
a median of 20.6% as compared with a median decrease of 6% in the placebo group (median 
placebo-adjusted reduction in seizure frequency was 14.8%, p=0.1279) during the 20-week 
treatment period. Other secondary endpoints included the Clinical Global Impression of Change 
(CGI-C) and the Caregiver Global Impression of Change (Care GI-C). For the CGI-C, more 
soticlestat-treated DS and LGS subjects showed improvement than those receiving placebo 
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(26.9% versus 8% and 27.9% versus 11.1%, respectively) as deemed by the investigator. 
Caregivers also rated greater improvement in 57.7% and 51.2% of soticlestat-treated DS and LGS 
subjects compared with 32% and 28.9% of those receiving placebo, respectively, as assessed by 
the Care GI-C.
In ELEKTRA, soticlestat was generally well tolerated and safety data were consistent with 
findings in previous studies. The incidence of treatment-emergent adverse events (TEAEs) was 
similar in the treatment and placebo groups with 57 (80.3%) (n=57) of soticlestat subjects 
experiencing at least 1 TEAE compared with 52 (74.3%) of placebo subjects. The most common 
TEAEs in the soticlestat group were upper respiratory tract infection, pyrexia, seizure, 
nasopharyngitis, decreased appetite, and vomiting. The most frequent TEAEs reported in 
soticlestat-treated subjects with ≥5% difference from placebo were lethargy and constipation. The 
incidence of serious TEAEs was similar in both soticlestat and placebo groups, with 11 (15.5%) in 
the soticlestat group experiencing at least 1 serious TEAE compared with 13 (18.6%) in the 
placebo group. Four soticlestat (5.6%) subjects discontinued the study compared with 3 in the 
placebo group (4.3%) due to TEAEs. 
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of soticlestat may be found in the current edition of the Investigator’s 
Brochure (IB).
4.2
Rationale for the Proposed Study
Soticlestat has shown antiseizure efficacy in nonclinical studies, including models relevant to the 
rare developmental epileptic encephalopathies (DEEs) that are inadequately treated by current 
adjunctive antiepileptic drugs. In phase 1 studies in healthy adult subjects and in phase 1b/2a 
(TAK-935-2001) and phase 2 (ELEKTRA) studies in adult and pediatric subjects with DEEs, 
acceptable PK and safety characteristics have been observed.
Based on the efficacy, safety, and tolerability data collected in the phase 2 ELEKTRA study, 
combined with the safety and tolerability data from phase 1 and other completed or ongoing 
studies (please see the IB), soticlestat is being proposed as adjunctive therapy in pediatric and adult 
subjects with LGS, a highly impacted population with great unmet need. This phase 3 study will 
evaluate the efficacy, safety, and tolerability of soticlestat in this population. The current study is 
designed to further characterize the effects of soticlestat on MMD seizure frequency by using a 
seizure diary in subjects with LGS. Additional aims are to assess efficacy by the investigator 
(characterized by Clinical Global Impression of Improvement [CGI-I]) as well as by the 
caregivers, CGI-I in nonseizure-related symptoms, impact on quality of life, and the safety, 
tolerability, PK, and PD (24HC) of soticlestat administration in pediatric and adult subjects with 
LGS.
4.3
Benefit/Risk Profile
In the phase 1b/2a TAK-935-2001, phase 2 TAK-935-2002 (ELEKTRA), and open-label pilot 
TAK-935-18-002 (ARCADE) studies, the safety and tolerability data indicate that soticlestat was 
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generally well tolerated in subjects with DEEs at doses up to 300 mg BID (weight-based dosing for 
<60 kg).
The following have been identified as important potential risks and are being closely monitored 
during the clinical development program:

Neurological and psychiatric effects (clinical safety data and risks associated with compounds 
affecting glutamate excitotoxicity).

Cognitive effects (soticlestat inhibition of neuronal CH24H and clinical safety data).

Suicidal ideation or behaviors (class effect of ASMs).

Cataracts (nonclinical data).

Corrected QT interval (QTc) prolongation (nonclinical data).
More information about the known and expected benefits and reasonably anticipated AEs of 
soticlestat may be found in the current edition of the IB. This study will further examine risk and 
establish benefit in LGS. This study will enroll subjects aged 2 to 55 years, inclusive. 
LGS is characterized by multiple treatment-resistant seizure types, abnormal 
electroencephalogram (EEG), and intellectual impairment. Given the severe, profound, and 
chronic nature of LGS, its impact on quality of life, and its associated signs and symptoms, and 
considering the potential benefits that can be conferred to patients affected by LGS, the 
benefit-risk profile is acceptable for this population.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives

To assess the efficacy of soticlestat in reducing MMD seizure frequency as add-on therapy to 
standard of care (SOC) as compared with placebo during the full treatment period (titration + 
maintenance).
For European Medicines Agency (EMA) registration:

To assess the efficacy of soticlestat in reducing MMD seizure frequency as add-on therapy to 
SOC compared with placebo during the maintenance period only.
5.1.2
Secondary Objectives
To assess the following in subjects taking soticlestat as compared with placebo during the full 
treatment period, unless otherwise noted:

Proportion of treatment responders defined as those with ≥50% reduction in MMD seizures 
from baseline during the maintenance period and the full treatment period. 
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
Effect on total seizure frequency of all seizure types during the maintenance period and the full 
treatment period.

Change from baseline in proportion of MMD seizure–free days.

Longest MMD seizure–free interval.

Number of days when rescue ASMs are used.

Effect on the Clinical Global Impression of Improvement (CGI-I) (clinician) and Caregiver 
Global Impression of Improvement (Care GI-I).

Effect on CGI-I Seizure Intensity and Duration.

Effect on the CGI-I Nonseizure Symptoms completed by clinician with input from the 
caregiver.

Effect on Quality of Life Inventory-Disability (QI-Disability).
5.1.3
Exploratory Objectives
To assess the following in subjects receiving soticlestat as compared with placebo during the full 
treatment period:

Seizure frequency of each seizure type per 28 days.

Health care resource utilization including but not limited to emergency room visits and 
hospitalizations.

Population PK and correlation of the population PK exposure parameters with PD (plasma 
24HC levels) in subjects receiving soticlestat.

Correlation of change in PD (24HC) exposure and efficacy (change in MMD seizure over the 
full treatment period).

Effect on EQ-5D 5-Level version (EQ-5D-5L) quality of life scale for parents’/caregivers’ 
quality of life.
5.1.4
Safety Objectives

To assess the incidence of TEAEs.

To assess the incidence of abnormal clinical laboratory values and electrocardiogram (ECG) 
evaluations.

To assess change from baseline in clinical laboratory values, vital signs, ECG parameters, and 
Columbia-Suicide Severity Rating Scale (C-SSRS) responses.

To assess the incidence of new seizure types arising during soticlestat treatment that are not 
identified at the time of screening (by history) or during prospective baseline.
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5.2
Endpoints
5.2.1
Primary Endpoints

Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving 
soticlestat as compared with placebo during the full treatment period.
For EMA registration:

Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving 
soticlestat as compared with placebo during the maintenance period.
5.2.2
Secondary Endpoints
To assess the following in subjects receiving soticlestat as compared with placebo during the full 
treatment period, unless otherwise noted:

Proportion of responders defined as those with ≥50% reduction from baseline in MMD 
seizures during the maintenance period and the full treatment period.

Responder analysis of the proportion of subjects with ≤0%, >0% to ≤25%, >25% to ≤50%, 
>50% to ≤75%, and >75% to ≤100% reduction from baseline in MMD seizures in a cumulative 
response curve.

Care GI-I (caregiver).

CGI-I (clinician).

CGI-I Nonseizure Symptoms.

Change in QI-Disability score.

CGI-I Seizure Intensity and Duration.

Percent change from baseline in frequency of all seizures per 28 days during the maintenance 
period and the full treatment period.

Percent change from baseline in MMD seizure frequency per 28 days during the maintenance 
period.

Change from baseline in proportion of MMD seizure–free days.

Longest MMD seizure–free interval.

Number of days when rescue ASM is used.
5.2.3
Exploratory Endpoints
To assess the following in subjects receiving soticlestat as compared with placebo during the full 
treatment period:

Percent change from baseline in frequency per 28 days of each seizure type identified at the 
time of screening or baseline.
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
Health care resource utilization including but not limited to emergency room visits and 
hospitalizations.

Soticlestat exposure-PD (plasma 24HC level) and efficacy response analysis.

Percent change from baseline in plasma 24HC.

Plasma concentrations of soticlestat and the soticlestat metabolite(s) at multiple time points.

Population soticlestat PK modeling based on sparse PK.

Change in EQ-5D-5L and EQ-5D Visual Analogue Scale (EQ VAS) scores.
5.2.4
Safety Endpoints

Incidence of TEAEs.

Incidence of abnormal clinical laboratory values and ECG evaluations.

Change from baseline in clinical laboratory values, vital signs, ECG parameters, and C-SSRS 
responses.

Incidence of new seizure types arising post–study treatment initiation.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3, global, multicenter, 1:1 randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and tolerability of soticlestat as an adjunctive 
therapy in pediatric and adult subjects with LGS. The treatment period is approximately 16 weeks. 
The total duration of the study is approximately 25 weeks for subjects who complete the study and 
choose not to roll over to the open-label extension (OLE) study. For those who roll over to the 
OLE study, the study duration is 3 weeks shorter.
Approximately 234 male and female pediatric and adult subjects will be randomized. 
This study consists of the following periods:

4- to 6-week screening/baseline period. The minimum duration for screening is 28 days 
(ie, Visit 2/Day 0 cannot occur earlier than 29 days after screening).

16-week treatment period.

4-week titration period.

12-week maintenance period.

1-week taper period for those discontinuing study drug, followed by a 2-week safety follow-up 
visit or phone call.
This is a 2-arm study. All subjects meeting entry criteria will be randomized at a 1:1 ratio to 
receive SOC plus 1 of the following adjunctive therapies: soticlestat or placebo.
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Soticlestat or matching placebo added to current antiseizure therapy will be administered orally 
BID with or without food or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY 
button). A jejunostomy tube (J-tube) may be considered following approval by the medical 
monitor or sponsor. Note: Study drug will be administered only orally for subjects enrolled in sites 
in jurisdictions where alternative means are not permitted.
A schematic of the study design is shown in Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
BID: twice daily; OLE: open-label extension. 
All doses will be blinded; subjects on soticlestat or placebo will undergo the same titration scheme, 
with the same number and type of tablets (mini-tablets or tablets). Subjects randomized to placebo 
will undergo a mock titration to ensure the blind is maintained (see Table 6.a through Table 6.d).
The total daily dose of study drug (either placebo or soticlestat) will be calculated based on body 
weight at screening (Visit 1) and given BID starting on the morning after Visit 2/Day 0 (ie, on 
study Day 1) or on the day after receiving study medication. The dosing schedules by weight are 
shown in Table 6.a through Table 6.d. The minimum dose allowed during the study is 100 mg BID 
(weight-based dosing <45 kg). Subjects who cannot tolerate the minimum dose will be 
discontinued from the study. Subjects weighing <45 kg will be dispensed 20 mg mini-tablets or 
matching placebo. Subjects weighing ≥45 kg may be dispensed 20 mg mini-tablets or 100 mg 
tablets, or matching placebo.
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Table 6.a
Dosing Schedules by Weight, 10 to <15 kg
Treatment 
Arm
10 to <15 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
40 mg 
BID
2 mini tabs soticlestat 
BID
60 mg 
BID
3 mini tabs 
soticlestat BID
100 mg 
BID
5 mini tabs 
soticlestat 
BID
PBO
---
2 mini tabs PBO BID
---
3 mini tabs PBO 
BID
---
5 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Table 6.b
Dosing Schedules by Weight, 15 to <30 kg
Treatment Arm
15 to <30 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
60 mg BID
3 mini tabs 
soticlestat 
BID
120 mg 
BID
6 mini tabs 
soticlestat BID
200 mg 
BID
10 mini tabs 
soticlestat BID
PBO
---
3 mini tabs 
PBO BID
---
6 mini tabs PBO 
BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
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Table 6.c
Dosing Schedules by Weight, 30 to <45 kg
Treatment 
Arm
30 to <45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
80 mg BID
4 mini tabs 
soticlestat 
BID
140 mg 
BID
7 mini tabs 
soticlestat BID
200 mg 
BID
10 mini tabs 
soticlestat BID
PBO
---
4 mini tabs 
PBO BID
---
7 mini tabs PBO 
BID
---
10 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
Table 6.d
Dosing Schedules by Weight, ≥45 kg
Treatment 
Arm
≥45 kg Weight Reference Dose
Dose 1 (Days 1-7):
Adult Reference 
100 mg BID
Dose 2 (Days 8-14):
Adult Reference 
200 mg BID
Dose 3 (Days 15-28):
Adult Reference 
300 mg BID
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini-tablets
(mg/dose)
No. Tablets/ 
Mini- tablets
Soticlestat
100 mg 
BID
1 tab soticlestat 
BID 
OR
5 mini tabs 
soticlestat BID
200 mg 
BID
2 tabs soticlestat 
BID
OR
10 mini tabs 
soticlestat BID
300 mg 
BID
3 tabs soticlestat 
BID
OR
15 mini tabs 
soticlestat BID
PBO
---
1 tab PBO BID 
OR
5 mini tabs 
PBO BID
---
2 tabs PBO BID 
OR
10 mini tabs 
PBO BID
---
3 tabs PBO BID
OR
15 mini tabs 
PBO BID
BID: twice daily; No.: number; PBO: placebo.
The study design allows virtual visits if aligned with institutional or local guidelines, via phone or 
via any platforms approved by local regulations, in addition to the communication platform 
offered through the study. Screening (Visit 1) and Visit 11/early termination must be conducted in 
person; Visit 9 is to be conducted in person if possible, but may be conducted virtually (via video 
or phone) in response to the coronavirus disease 2019 (COVID-19) pandemic and/or based on 
sponsor approval and if permitted by local regulations. In extenuating circumstances, the 
randomization visit (Visit 2), and Visit 11/early termination can be virtual visits (only via video, 
not phone), with sponsor approval and if permitted by local regulations. In addition, any visit 
identified as a virtual visit in this protocol may be conducted in clinic and in person if requested by 
the subject/parent or guardian and/or at the investigator’s discretion. Appendix C has additional 
information on virtual visits.
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In the event of rescreening, the subject may not need to repeat all assessments for the screening 
visit (Visit 1); this will need to be discussed with the medical monitor and/or sponsor.
6.1.1
Dose Titration Period (4 Weeks)
Subjects will take the first dose of study drug (Dose 1) the day after the study medication is 
received. Approximately 7 days after initiating study medication, if there are no tolerability issues, 
study drug dose will be increased to Dose 2. After approximately 7 days on Dose 2, if there are no 
tolerability issues, study drug dose will be increased to Dose 3. If the subjects do not experience 
any tolerability issues, they will continue on Dose 3 for the remainder of the titration period. 
Subjects will only be allowed to increase their dose within the 4-week titration period before 
entering the 12-week maintenance period. Decrease in dose level is allowed during the titration 
period if required for safety and tolerability. Subjects who cannot tolerate the minimum dose of 
100 mg BID (or weight-based equivalent dosing <45 kg) will be discontinued from treatment. The 
maximum allowed dose is 300 mg BID. The subjects/parents or caregivers will be contacted by 
phone within approximately 2 days following each dose escalation to assess safety and tolerability 
of the study drug. The final dose tolerated by the end of the 4-week titration period should be 
maintained until the end of the maintenance period, unless tolerability issues arise.
6.1.2
Maintenance Period (12 Weeks)
The dose level at the end of the titration period will be maintained until the end of the maintenance
period (dose increases are not permitted); however, during the maintenance period, the dose may 
be decreased by 1 dose level to the previous lower dose, for safety and tolerability issues. For 
example, Dose 3 may be reduced to Dose 2, and Dose 2 may be reduced to Dose 1. The minimum 
dose is Dose 1 (100 mg BID adult reference dose; or weight-based equivalent dosing for <45 kg); 
subjects who cannot tolerate the minimum dose of 100 mg BID will be discontinued from 
treatment. Dose changes during the maintenance period are allowed for safety or tolerability 
reasons as assessed by the investigator; however, if possible, dose changes will need to be 
discussed with the medical monitor and/or the sponsor.
6.1.3
Study Discontinuation/Completion
At Visit 11/early termination, subjects will have the option to enroll in the OLE study as per that 
study’s inclusion/exclusion criteria.
Subjects who enroll in the OLE study on the same day as Visit 11/early termination will take their 
final dose of double-blind study drug in the evening of the day of Visit 11/early termination and 
should continue to record seizures in the seizure diary until midnight of the day of Visit 11/early 
termination, at which time they will exit the study.
Subjects who do not roll over to the OLE study on the same day as Visit 11/early termination will 
take their final dose of double-blind study drug in the morning of Visit 11/early termination, 
followed by a taper period. The study drug dose will be tapered down to a lower dose (taper Dose 
3 to Dose 2, taper Dose 2 to Dose 1) approximately every 3 days until the study drug dose is 
discontinued. The subject/parent or caregiver should continue to record seizures in the seizure 
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diary until the safety follow-up phone call, which will occur approximately 14 days after the last 
dose of study drug. After completion of the safety follow-up phone call, the subject will exit the 
study.
Subjects/parents or caregivers who choose to enroll in the OLE study after Visit 11/early 
termination will continue the taper procedure until the investigator confirms eligibility for the OLE 
study; the subject will then exit the study and roll over to the OLE study.
6.1.4
End of Study for Individual Subject
The end of study for an individual subject who does not enroll in the OLE study on the same day as 
Visit 11/early termination is either:

The day of the scheduled safety follow-up phone call or visit.
OR
Midnight of the day after Visit 11/early termination but before the scheduled safety follow-up 
phone call, if, in agreement with the investigator, the subject/parent or caregiver decides on that 
day to enroll in the OLE study.
The end of study for an individual subject who enrolls in the OLE study on the same day as 
Visit 11/early termination is midnight of that same day.
6.1.5
End of Study Overall
The overall end of the study is defined as the date of last individual subject’s end of study (as 
defined in Section 6.1.4. 
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group study to further evaluate 
the safety, tolerability, and efficacy of soticlestat as adjunctive therapy in pediatric and adult 
subjects with LGS.
Randomization of subjects in the study will be stratified by age group and country. The strata for 
stratification by age group will be: ≤6 years and >6 years; these age-group randomization strata 
will be included as a fixed effect factor in the statistical model for the analysis of the primary 
endpoint.
The strata for stratification by country will be: China, Japan, and the rest of the world. This country 
stratification is planned to be implemented for an administrative reason and therefore will not be 
included in the primary analysis model.
During this study, subjects will continue their current ASMs; therefore, placebo was chosen as the 
control group to provide maximum difference between the treatment and control arms.
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6.2.2
Endpoints
An ideal outcome measure for assessment of seizures should be clinically relevant, easily 
identifiable, and reliably counted by the parent or caregiver. The primary endpoint is percent 
change from baseline in MMD seizure frequency per 28 days for those subjects on soticlestat 
compared with placebo during the 16-week treatment period (for EMA regions, analysis will only 
include MMD seizure frequency during the 12-week maintenance period). In close cooperation 
with researchers in the epilepsy field and epileptologists, and in consent with The Epilepsy Study 
Consortium (TESC) and consistent with the International League Against Epilepsy seizure 
classification, the sponsor will evaluate soticlestat’s effect in the percent change from baseline in 
MMD seizures compared with placebo during the full treatment period (or maintenance period for 
EMA registration regions) as the primary efficacy endpoint using the modified intent-to-treat 
(mITT) analysis set.
The secondary and exploratory endpoints defined are clinically meaningful and consistent with 
seizure studies in similar populations. The secondary efficacy endpoints and exploratory endpoints 
could elucidate benefits outside of seizure reduction to demonstrate soticlestat’s potential impact 
on overall quality of life for the subjects (QI-Disability) and for the parents/caregivers 
(EQ-5D-5L) and explore the potential for 24HC to be a biomarker for optimal demonstration of 
efficacy.
Measurement of plasma 24HC levels is included in this study as a PD biomarker related to the 
mechanism of action of soticlestat.
The safety-related endpoints of TEAEs, clinical laboratory test results, vital sign measurements, 
C-SSRS measurements, and ECG parameters selected for this study are standard methods for 
assessing safety and tolerability in clinical studies as well as the potential risks for soticlestat.
6.2.3
Dose
Dose selection is based on a comprehensive analysis of the safety, tolerability, PK, and PD data 
from 4 completed single- and multiple-dose phase 1 studies in healthy subjects; the safety, 
tolerability, and PK data from the phase 1b/2a study of soticlestat as adjunctive therapy in adult 
subjects with DEEs; and the efficacy, safety, PK, and PD data in the ELEKTRA study in pediatric 
subjects with DS or LGS, where the same target dose of 300 mg BID (weight-based equivalent in 
pediatrics) demonstrated statistically significant and clinically meaningful seizure reduction in DS 
subjects while maintaining a favorable safety and tolerability profile. Numerical reduction in 
seizure frequency was also noted in subjects with LGS.
The efficacy of soticlestat is related to CH24H inhibition and a decrease in 24HC levels in humans. 
The extent of CH24H inhibition required for efficacy was estimated in an animal model of 
epilepsy. In a mouse pentylenetetrazol-induced kindling development model, effects of soticlestat 
on seizure severity were associated with the degree of CH24H inhibition (Nishi et al. 2020). A 
75% reduction in the severity score was associated with 90% reduction in brain 24HC levels. The 
minimum required 24HC lowering for efficacy was approximately 60%, yielding 40% decrease in 
the severity score. The 24HC lowering effect was then converted into 65% of the CH24H enzyme 
occupancy (EO) rate, using a model established in mice (Target occupancy evaluation for 
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cholesterol 24-hydroxylase (CH24H) inhibitor, soticlestat, with liquid chromatography/tandem 
mass spectrometry. Report number:16354). In summary, these preclinical pharmacology studies 
suggest that high degree of target occupancy (≥65%) and 24HC reduction (≥60%) are considered 
to be related to the efficacy in the nonclinical animal model. 
The target dose of 300 mg BID (weight-based equivalent in pediatrics) will achieve the degree 
target occupancy and 24HC reduction required for efficacy. Based on a population PK/PD/EO 
model using data from 4 phase 1 studies in healthy subjects, the phase 1b/2a study in adult subjects 
with DEEs, and the TAK-935-2002 (ELEKTRA) study in pediatric subjects with DS or LGS, the 
300 mg BID dose (weight-based equivalent in pediatrics) is estimated to achieve approximately 
90% EO with approximately 82% decrease in 24HC level and potentially resulting in efficacy.
In addition, the same soticlestat target dose of 300 mg BID (adult reference dose; weight-based 
equivalent dosing <60 kg) was administered in ELEKTRA, and demonstrated seizure reduction in 
LGS subjects while maintaining a favorable safety and tolerability profile. Approximately 79% of 
subjects in the double-blind, randomized, placebo-controlled ELEKTRA study were able to be 
titrated up to and maintained on 300 mg BID (or adult weight-based equivalent) until the end of the 
maintenance period. Soticlestat-treated subjects with LGS reported a 20.6% median reduction in 
drop seizures while those subjects receiving placebo experienced a median decrease of 6% in drop 
seizures (median placebo-adjusted reduction in seizure frequency was 14.8%) over the 20-week 
treatment period. Responder rates (≥50% reduction in drop seizure frequency compared with 
baseline) for soticlestat-treated subjects with LGS were 16.3% versus 13.3% in placebo, 
respectively. Soticlestat was generally safe and well tolerated at this dose in this study, and safety 
was consistent with previous studies with no new signals identified. The incidence of TEAEs was 
similar between the DS and LGS strata compared with placebo with 57 soticlestat subjects (80.3%) 
experiencing at least 1 TEAE compared with 52 placebo subjects (74.3%). The most frequent 
TEAEs reported in soticlestat-treated subjects with ≥5% difference from placebo were lethargy 
and constipation. The incidence of serious adverse events (SAEs) was similar in both soticlestat 
and placebo groups, with 11 (15.5%) in the soticlestat group experiencing at least 1
treatment-emergent SAE compared with 13 (18.6%) in the placebo group. There were no deaths 
reported. The combination of drop seizure reduction and favorable tolerability and safety profile in 
ELEKTRA support the selection of 300 mg BID as the soticlestat target dose (adult reference dose; 
weight-based equivalent dosing <45 kg BID).
Before reaching the target dose in the current study, subjects will receive the minimum soticlestat 
dose (ie, 100 mg BID adult equivalent dose for 1 week, followed by 200 mg BID adult equivalent 
dose for 1 week) in the titration phase. The goal of titration is to reach the target final dose of 300 
mg BID adult equivalent dose after a 14-day titration period; the same titration regimen was 
evaluated in study ELEKTRA and demonstrated a favorable safety and tolerability profile in 
addition to drop seizure reduction as above. 
The weight-based equivalent dosing in pediatrics was determined using the population PK model. 
Simulations were conducted using body weight intervals of 1 kg, dose strengths from 40 to 300 mg 
using 20 mg mini-tablets and 100 mg tablets, and a BID dosing regimen. A total of 10,000 
simulations of steady-state exposure (median area under the plasma concentration-time curve 
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[AUC]) were performed. A threshold for the fraction of subjects at or above the reference value 
was set to 35%. Setting the percentage threshold at “35%” ensures the safety of pediatric subjects 
as the reference AUC values are median steady-state AUC values in adults, ie, 50% of the adult 
population has AUCs above the reference AUC values while no more than 35% of pediatric 
population will have AUCs above the reference AUC values). Furthermore, an effort has been 
made to keep pediatric exposure from exceeding the 90th percentile of the adult exposure. The 
resulting weight-based equivalent dosing in pediatrics is provided in Table 6.a through Table 6.d.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known benefit-risk profile for soticlestat, such that the benefit-risk is 
no longer acceptable for subjects participating in the study.

The Data Monitoring Committee (DMC) recommends that the study should be suspended or 
terminated.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or is otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of termination 
or study suspension.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization or first dose. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, based on discussions and approval by the medical monitor and sponsor.
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7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
1. In the opinion of the investigator, the subject or the subject’s parent or legal guardian or 
caregiver is capable of understanding and complying with protocol requirements including the 
use of digital tools, complete appropriate assessments, maintain an accurate and complete 
daily seizure diary and take study drug for the duration of the study. 
If the subject is living in a residential facility, a minimally possible number of staff member(s) 
at the facility who are the subject’s primary caretaker(s) may be identified as caregivers who 
(per investigator’s judgement) are capable of complying with protocol requirements as 
indicated above. 
2. The subject or the subject’s parent or legal guardian is willing and able to read, understand, and 
sign and date an informed consent form (ICF), assent form (if applicable), and any required 
privacy authorization before the initiation of any study procedures. 
3. The subject is male or female and aged 2 to 55 years, inclusive, at the time of informed 
consent.
4. Documented clinical diagnosis of LGS supported by variable combinations of typical clinical 
features such as those noted below. (Note: These criteria are for guidance only because the 
final diagnostic eligibility is adjudicated by TESC.)
Onset of seizures usually between the ages of 1 and 8 years.
Presence of multiple seizure types: including drop seizures (eg, tonic-atonic seizures) and 
other seizure types including atypical absence seizures, tonic-clonic, myoclonic, and 
partial seizures.
History of abnormal EEG (eg, slow spike and wave [<2.5 Hz], slow or disorganized EEG 
background, generalized paroxysmal fast activity).
Developmental delay or intellectual disability consistent with LGS.
5. Has had ≥8 MMD seizures each month in the 3 months prior to screening based on the 
historical information and has had ≥8 MMD seizures per 28 days during the 4- to 6-week 
prospective baseline period. The seizure frequency will be calculated as: 
(total number of seizures) / (total number of days seizures were assessed) × 28.
The total number of seizures includes only primary outcome seizure types with documentation 
TESC approval:
–
Hemi-clonic or focal clonic.
–
Focal to bilateral tonic-clonic.
–
Generalized tonic-clonic.
–
Bilateral clonic.
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–
Focal seizures with major motor signs (eg, hypermotor seizures or involving major body 
areas such as lower extremities or trunk) leading to fall or likely fall.
–
Tonic seizures involving major body areas such as lower extremities or trunk leading to fall 
or likely fall.
–
Atonic seizures involving major body areas such as lower extremities or trunk leading to 
fall or likely fall.
–
Convulsive status.
6. Weighs ≥10 kg at the screening visit (Visit 1).
7. Failure to control seizures despite appropriate trials of at least 1 ASM based on historical 
information and is currently on an antiseizure therapy (eg, ASMs, vagus nerve stimulation 
[VNS], ketogenic/modified Atkins diet) or other treatment options considered as SOC.
8. Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before the screening 
visit (Visit 1); the dosing regimen and manufacturer should remain constant throughout the 
study. (Artisanal cannabidiols will not be counted as ASMs.)
9. Currently taking 0 to 3 ASMs at stable doses for at least 4 weeks before the screening visit 
(Visit 1); benzodiazepines used chronically (daily) to treat seizures are considered ASMs. 
Fenfluramine and cannabidiol (Epidiolex) are allowed where available and counted as an 
ASM. ASM dosing regimen must remain constant throughout the study.
10. If using a VNS, the subject must have had VNS placed at least 3 months before the screening 
visit (Visit 1) with stable settings for 4 weeks; VNS parameters must remain constant 
throughout the study (VNS will not be counted as an ASM).
11. If on ketogenic diet (or any other diet used for treatment of epilepsy, such as modified Atkins 
diet), the subject must have started the diet at least 3 months before the screening visit 
(Visit 1), and the subject’s diet should be stable for 4 weeks before the screening visit (Visit 1); 
the subject should continue this diet throughout the duration of the study (ketogenic diet, or 
any other diet for the treatment of epilepsy will not be counted as an ASM).
12. The use of felbamate is allowed provided that the subject does not meet the liver function test 
(LFT) exclusion criteria, the dose has been stable for at least 6 months before screening 
(Visit 1), and the subject has had stable liver function (as determined by serum aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT] levels) and hematology 
laboratory tests during the course of treatment.
13. Approved to participate by the sponsor’s designee (ie, TESC) based on the review of medical 
history and seizure classification, as well as review of EEG and imaging results (if available 
and permitted by local regulations). The sponsor may be consulted if needed.
14. Female subjects of childbearing potential (defined as first menarche) must have a negative 
pregnancy test and agree to use an effective or highly effective method of birth control during 
the study and for 30 days following the last dose of study drug.
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Effective contraceptive methods include the following:

Double-barrier method (contraceptive sponge, diaphragm, or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, PLUS condom with or without spermicide.
Highly effective contraceptive methods include the following:

Nonhormonal methods: 
–
Intrauterine device (IUD). 
–
Bilateral tubal occlusion. 
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success). 
–
Sexual abstinence:
Sexual abstinence may be considered as a method only if defined as refraining from 
heterosexual intercourse and determined to be the usual lifestyle before entering the 
study with reliability of abstinence for the duration of the study participation and for 30 
days after last dose of study drug.

Hormonal methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug OR 
combined with a barrier method (male condom, female condom or diaphragm) if for 
shorter duration until she has been on contraceptive for 3 months.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter until she has 
been on the contraceptive for 3 months.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. Investigator site personnel directly affiliated with this study and/or their immediate family.
Note: Immediate family is defined as a spouse, parent, child, or sibling, whether biological or 
legally adopted.
2. Takeda employees or immediate family members.
3. Currently enrolled in a clinical study involving an investigational product or treatment device 
(ie, not approved in that country, other than soticlestat), or concurrently enrolled in any other 
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type of medical research judged not to be scientifically or medically compatible with this 
study. 
Note: Compatibility will be determined based on consultation with the medical monitor or the 
sponsor.
4. Participated in a clinical study involving another study drug in the last 30 days (or 5 half-lives 
of the study drug, whichever is longer) before screening (Visit 1).
5. Received soticlestat in a previous clinical study.
6. Known hypersensitivity to any component of the soticlestat formulation.
7. Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times 
in the 3 months immediately before screening (Visit 1). For the purpose of this exclusion 
criterion, status epilepticus is defined as continuous seizure activity lasting longer than 5 
minutes or repeated seizures without return to baseline in between seizures.
8. Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, 
cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, 
urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive 
tumors, or other abnormality that may impact the ability to participate in the study or that may 
potentially confound the study results. It is the responsibility of the investigator to assess the 
clinical significance; however, consultation with the medical monitor may be warranted.
9. Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-V), within the 2 years immediately before the 
screening visit (Visit 1).
10. Considered by the investigator to be at imminent risk of suicide or injury to self, others, or 
property, or the subject has attempted suicide within 12 months before the screening visit 
(Visit 1). Subjects who have positive answers on item numbers 4 or 5 on the C-SSRS before 
dosing (Visit 2) are excluded. This scale will only be administered to subjects aged ≥6 years.
11. The following medical histories:
a) History of HIV infection (subject who has tested positive for HIV-1/2 antibodies.
b) History of hepatitis B infection or current active infection.
Note: Subjects who have been vaccinated against hepatitis B (hepatitis B surface 
antibody-positive) and who test negative for other markers of prior hepatitis B infection 
(eg, negative for hepatitis B core antibody) are eligible.
c) History of hepatitis C infection or current active infection.
Note: Subjects who test positive for hepatitis C antibody are eligible if they have a negative 
hepatitis C viral load by quantitative polymerase chain reaction.
12. Abnormal and clinically significant ECG abnormality at screening (Visit 1) or before dosing 
(Visit 2), including QT interval with Fridericia correction method (QTcF) >450 ms confirmed 
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with a repeat ECG using manual measurement of QTcF. Clinically significant ECG 
abnormalities should be discussed with the medical monitor. 
13. Abnormal clinical laboratory test results at screening (Visit 1) that suggest a clinically 
significant underlying disease that would compromise the well-being of the subject. If the 
subject has serum ALT and/or AST level >2.5 times the upper limit of normal (ULN), the 
medical monitor should be consulted.
14. Unable to withhold the use of strong inducers of cytochrome P450 (CYP) 3A during the entire 
clinical trial, except for ASMs (eg, carbamazepine, phenobarbital, phenytoin) and topical 
preparations.
15. Use of herbal preparations (when used as an ASM) during the entire clinical trial.
16. Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the 
last dose of study drug.
7.3
Excluded Medications
Strong CYP3A inducers are excluded from screening (Visit 1) until the end of the follow-up visit, 
except for ASMs (eg, carbamazepine, phenobarbital, phenytoin) and topical preparations; refer to 
Appendix B for examples.
The use of herbal preparations (when used as an ASM) are not permitted.
Vaccinations are allowed; however, the medical monitor and sponsor should be informed about 
changes in the subject’s vaccination status and document it under the concomitant medication 
section of the electronic case report form (eCRF).
The use of felbamate is allowed provided that the subject meets the relevant inclusion and 
exclusion criteria.
If the subject is using VNS, the device must have been placed at least 3 months before the 
screening visit with stable settings for >1 month; VNS parameters must remain constant 
throughout the study (VNS will not be counted as an ASM).
All medications, including vitamin supplements and over-the-counter medications, will be 
documented throughout the study. 
Subjects are instructed not to take any medications, including over-the-counter products, without 
first consulting with the investigator.
7.4
Diet, Fluid, Activity Control
If the subject is on a ketogenic diet (or other diet used as antiseizure therapy, such as modified 
Atkins diet), they must have started the ketogenic diet at least 3 months before the screening visit 
(Visit 1), and their diet should be stable for 1 month before the screening visit (Visit 1); the diet 
should be continued throughout the duration of the study.
As the effect of a strong CYP3A4 inhibitor on the PK of soticlestat is small (<25%), consumption 
of the fruit and juice of grapefruit, Seville oranges, and starfruit is permitted.
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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the eCRF using the categories detailed in this section. For screen failure subjects, refer 
to Section 9.1.18.
Study subjects will be withdrawn from the study/study drug for the following reasons:
1. Failure to meet continuation criteria: Enrollment in any other clinical study involving an 
investigational product or enrollment in any other type of clinical trial judged not to be 
scientifically or medically compatible with this study.
2. Withdrawal by investigator (Note: The specific reason for discontinuation must be recorded in 
the eCRF, and is only to be used if no other pertinent reason for discontinuation is applicable):
a) The investigator decides that the subject should be discontinued from the study.
b) If the subject, for any reason, requires treatment with another therapeutic agent, 
discontinuation from the study occurs before introduction of the new agent.
3. Withdrawal by subject/parent or legal guardian (Note: The specific reason for discontinuation 
should be recorded in the eCRF and is only to be used if no other pertinent reason for 
discontinuation is applicable). All attempts should be made to determine the underlying reason 
for the withdrawal and, where possible, the primary underlying reason should be recorded (ie, 
withdrawal due to a TEAE should not be recorded in this category. Similarly, lack of efficacy 
should not be recorded in this category).
4. Sponsor decision:
a) The sponsor or its designee discontinues the study.
b) The sponsor or its designee discontinues the subject’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP.
c) The sponsor or its designee stops the clinical study at a particular site.
5. Discontinuation due to AE: The subject has experienced an AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health, or the 
subject is unwilling to continue because of the AE.
If the investigator decides that the subject should be withdrawn because of an AE or a 
clinically significant laboratory value, the study drug is to be discontinued and appropriate 
measures are to be taken. The sponsor or its designee is to be alerted immediately.
a) LFT abnormalities: Study drug should be discontinued immediately (withdrawal of the 
subject from the study should be discussed with the sponsor/medical monitor) with 
appropriate clinical follow-up, including repeat laboratory tests, until a subject’s laboratory 
profile has returned to normal/baseline status (see Section 9.3.1) if the following 
circumstances occur at any time during study drug treatment:
i. Serum ALT or AST >8 times the ULN, or
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ii. Serum ALT or AST persistently >5 times the ULN that persists for more than 
2 weeks, or
iii. Serum ALT or AST >3 times the ULN in conjunction with elevated total bilirubin >2 
times the ULN or international normalized ratio (INR) >1.5, or
iv. Serum ALT or AST >3 times the ULN with appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
b) QTcF >500 ms or an increase of QTcF >60 msec above baseline.
Note: Study drug should be discontinued immediately (withdrawal of the subject from the 
study should be discussed with the sponsor/medical monitor) with appropriate clinical 
follow-up and confirmation by repeat ECG with manual measurement of the QTcF interval 
if the QTcF is >500 ms or if there is an increase of QTcF >60 msec above baseline.
c) Greater than a 100% increase in 28-day seizure frequency from the 4- to 6-week 
prospective baseline period and considered by the investigator to be clinically significant 
worsening of the seizure frequency that is related to the study drug.
d) Not tolerating the lowest dose of the study drug.
e) Suicidal ideation: Subjects who experience suicidal ideation or who attempt suicide will be 
immediately withdrawn from the study.
6. Lost to follow-up: The subject did not attend visits, and multiple attempts to contact the 
subjects were unsuccessful. Attempts to contact the subject must be documented in the 
subject’s source documents.
7. Pregnancy: Female subject of childbearing potential is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.17.
8. Other: The specific reason should be recorded in the eCRF.
9. COVID-19/pandemic: If, in the opinion of the investigator, the safety of a trial subject is at risk 
because the subject cannot complete key evaluations or adhere to critical mitigation steps, then 
the investigator should consider discontinuing that subject. In addition, for any such subject 
with COVID-19 diagnosis or in a pandemic circumstance, GCP for AE reporting processes 
will apply.
10. Noncompliance with study drug.
11. Significant protocol deviation: The discovery following randomization that the subject failed 
to meet protocol entry criteria or did not adhere to protocol requirements, and/or continued 
participation poses an unacceptable risk to the subject’s health.
Subjects who discontinue the study drug and/or study early will have end-of-study 
procedures/early termination visit performed as shown in the schedule of assessments 
(Appendix A). Precise reason for discontinuation will be recorded in the eCRF; for example, 
instead of “withdrawal by the subject/parent or legal guardian” or “withdrawal by the 
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investigator,” a more accurate reason will need to be recorded in the eCRF if applicable 
(eg, discontinuation due to AEs, discontinuation due to lack of efficacy).
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to a TEAE 
should not be recorded in the “withdrawal by subject/parent or legal guardian” category).
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term “study drug” refers to all or any of the drugs defined below.
8.1.1.1
Study Drug
The sponsor will supply the study sites with soticlestat 20 mg mini-tablets, soticlestat 100 mg 
tablets, matching placebo mini-tablets, and matching placebo tablets. Study drug will be supplied 
in high-density polyethylene bottles with induction seal and child-resistant caps. Each bottle will 
contain a label that includes pertinent study information and caution statements.
Clinical study materials will be labeled according to the country’s regulatory requirements.
All subjects will continue on SOC antiseizure therapies throughout the study.
8.1.1.2
Rescue Medication
Rescue ASMs as per SOC will be allowed throughout the study and their use recorded in the daily 
electronic seizure and medication diary. Rescue medication will not be supplied by the sponsor.
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is dispensed or 
returned to the sponsor or designee for destruction. Study drug must be stored under the conditions 
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specified on the label and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every day.
Please refer to the pharmacy manual for additional information related to the study drug. In 
instances where the protocol and pharmacy manual text conflict, the pharmacy manual text shall 
supersede the text in the protocol.
8.1.3
Dose and Regimen
This study involves a comparison of soticlestat to matching placebo.
The investigator or his/her designee is responsible for the following:

Explaining the correct use of the study drug to the subject/parent or caregiver.

Verifying that instructions are followed properly.

Maintaining accurate records of study drug dispensing and collection.

Returning or destroying all unused study drugs to the sponsor or its designee at the end of the 
study after the monitor completes final accountability and reconciliation.
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical study materials. Clinical supply manager review and approval are 
required before proceeding.
Subject/parent or caregiver will be instructed to contact the investigator as soon as possible if he or 
she has a complaint or problem with the study drug so that the situation can be assessed.
All study drug provided to the investigator will be stored in a secure place and allocated and 
dispensed by appropriately trained persons. The allocation and dispensing of the study drug will be 
fully documented and verified by a second person. Detailed records of the amounts of the study 
drug received, dispensed, and remaining at the end of the study will be maintained.
All subjects will receive study drug BID orally with or without food or via G-tube or MIC-KEY 
button. A J-tube may be considered following written approval by the sponsor and medical 
monitor.
Note: Study drug will be administered only orally for subjects enrolled in sites in jurisdictions 
where alternative means are not permitted.
The study site personnel will indicate how many tablets/mini-tablets should be taken per day in a 
separate dosing instruction. All doses will be blinded; placebo and soticlestat-treated subjects will 
undergo the same titration scheme with the same number/type of tablets. See Section 6.1.1 for a 
detailed description of the titration scheme.
Tablets/mini-tablets may be crushed and mixed well in applesauce, yogurt, or other liquid of 
similar consistency before dosing. The amount of applesauce, yogurt, or other liquid of similar 
consistency needed is dependent upon the number of tablets/mini-tablets the subject is taking. 
Approximately one-half teaspoon or 2.5 mL of applesauce or yogurt or other liquid of similar 
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consistency is needed for each mini-tablet taken, and 2 teaspoons or 10 mL is needed for each 
tablet taken.
For subjects receiving study drug via G-tube or MIC-KEY button, study drug will be crushed and 
suspended in water, and the suspension will be administered via the G-tube or MIC-KEY button
(or J-tube using a syringe if approved by the sponsor and medical monitor). Complete instructions 
for the G-tube, MIC-KEY button, or J-tube will be provided to the subject/parent or caregiver. 
Other medications or enteral feeds should not be given concurrently with the study drug.
Soticlestat or placebo tablets should be administered at approximately the same times each day. 
The actual date, time, and dose of study drug administrations before PK sample collection will be 
recorded. The actual date and time of all PK sample collections will also be recorded.
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/parent or caregiver remembers after 4 hours of the 
scheduled time of dosing, the dosing should be skipped and reported as a missed dose in their 
electronic daily seizure and medication diary and on the next clinic visit.
The planned daily dose and tablet count to be administered to subjects during the titration period is 
shown in Section 6.1. During the titration period, 2 days after each dose escalation or taper, the 
subject/parent or caregiver will be contacted by phone (safety check phone call) to monitor study 
drug compliance, to assess the tolerability and safety of the study drug, and to monitor concomitant 
medication use and TEAEs.
The subject or the subject’s parent or caregiver should return unused study drug at each study visit 
to allow the investigator or designee to evaluate subject’s compliance with the dosing instructions.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at doses above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated TEAEs) will be documented on an Overdose 
page of the eCRF to capture this important safety information consistently in the database. Cases 
of overdose without manifested signs or symptoms are not considered TEAEs. TEAEs associated 
with an overdose will be documented on TEAE eCRFs according to Section 10.2.1. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically, as determined by the 
investigator.
8.2
Study Drug Assignment and Dispensing Procedures
Sites should refer to the interactive web response system (IWRS) manual for specific instructions. 
The subjects will be assigned to receive their treatment according to the randomization schedule. 
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The investigator or investigator’s designee will access the IWRS at the Visit 1 (screening/baseline) 
to obtain the subject number. At Visit 2 (randomization), the investigator or the investigator’s 
designee will use the IWRS to randomize eligible subjects into the study. During this visit, the 
investigator or designee will provide the necessary subject identifying information, including the 
subject number assigned at screening. The medication identification number of the study drug to 
be dispensed will then be provided by the IWRS. If study drug supplied is lost or damaged, the site 
can request a replacement from IWRS (refer to the IWRS manual provided separately). At 
subsequent drug-dispensing visits, the investigator or designee will again access the IWRS to 
request additional study drug for a subject. The medication identification number of the study drug 
to be dispensed will be provided by the IWRS.
8.3
Unblinding Procedures
Unblinding should only be considered for the safety of the subject. The study drug blind shall not 
be broken by the investigator unless information concerning the study drug is necessary for the 
medical treatment of the subject. All study assessments and causality assessment should be 
performed, if possible, prior to unblinding. In the event of a medical emergency, if possible, the 
medical monitor or sponsor should be contacted before the study drug blind is broken to discuss 
the need for unblinding. If unblinding is deemed necessary by the investigator, the investigator can 
unblind the subject’s treatment allocation using IWRS. The investigator must note the date, time, 
and reason for unblinding in subject’s source documents.
If an investigator, site personnel performing assessments, or subject is unblinded, the subject must 
be discontinued from the study. The investigator should inform the sponsor that the subject was 
unblinded; however, they are not required to reveal to the sponsor the subject’s treatment 
allocation.
In cases where there are ethical reasons to have the subject remain in the study, the investigator 
must obtain specific approval from the sponsor’s medical monitor for the subject to continue in the 
study.
When a TEAE is an unexpected, related SAE, the blind will be broken by the sponsor only for that 
specific subject for reporting purposes and to adhere to regional regulatory requirements for 
unblinding investigators. The blind will be maintained for persons responsible for the ongoing 
conduct of the study (such as the monitors, investigators, etc.) and those responsible for data 
analysis and interpretation of results at the conclusion of the study, such as biometrics personnel. 
Unblinded information will only be accessible to those who need to be involved in the safety 
reporting to health authorities, ethics committees, and/or IRBs.
Investigators will receive only blinded information unless unblinded information is judged 
necessary for regulatory requirements or safety reasons.
8.4
Accountability and Destruction of Study Drugs
Drug supplies, including the number of returned tablets to sites, will be counted and reconciled at 
the site before being returned to the sponsor or designee or destroyed at the site.
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The investigator or designee must ensure that the study drug is used in accordance with the 
protocol and is dispensed only to subjects enrolled in the study. The investigator or designee is 
responsible for ensuring that the study drug provided to the subject and returned from the subject is 
accounted for and noted in source documents. To document appropriate use of study drug, the 
investigator or designee must maintain records of all study drug delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee. If any dispensing 
errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
Periodically, throughout and at the conclusion of the study, the monitor or a sponsor representative 
will conduct an inventory of unused study drug. At the completion of the study, a final study drug 
accountability review will be conducted before the unused study drugs are returned to the sponsor 
or its designee for destruction. All study drug not returned to the site by a subject must be 
investigated by the site and appropriately documented. 
Destruction at the site, where applicable, must be in accordance with local standard practice with 
prior approval from the sponsor/CRO. 
Please refer to the pharmacy manual for additional information related to the study drug. In 
instances where the protocol and pharmacy manual text conflict, the pharmacy manual text shall 
supersede the text in the protocol.
The site must have destruction procedures in place and be able to supply a Certificate of 
Destruction (COD) or similar document once destruction is completed. Sites shall also document 
the event in the IWRS.
9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
schedule of study procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
The investigational site is responsible for the consenting process. The requirements of informed 
consent are described in Section 15.2.
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9.1.2
Historical Seizure Diary Review
Per inclusion criteria, historical seizure information will be used to support study entry. It is very 
common for caregivers of subjects with LGS to maintain daily seizure diaries that capture both 
seizure type and frequency and days when no seizures occur as part of their SOC treatment 
regimen. A 3-month (12-week) daily historical seizure diary will be reviewed at screening 
(Visit 1) to determine eligibility. In the event that daily seizure diaries are not routinely maintained 
as part of the SOC, the investigator will be asked to review in detail with the subject/caregiver the 
number of seizures over the last 3 months for each seizure type and attest eligibility to the study at 
screening (Visit 1).
9.1.3
Seizure Identification and Diagnostic Review Forms (TESC)
Per inclusion criteria, enrollment into the study is based on subject having ≥8 MMD seizures each 
month in the 3 months prior to screening based on the historical information and having ≥8 MMD 
seizures per 28 days during the 4- to 6-week prospective baseline period (Days -42 to Day -1). To 
confirm diagnosis, standardize seizure identification and classification, and approve seizures that 
will be recorded by the parent/caregiver in the electronic daily seizure and medication diary, a 
Seizure Identification Form (SIF)/Diagnostic Review Form (DRF) will be submitted to, reviewed, 
and approved by TESC. In addition, previously prepared documents (including, but not limited to, 
EEG and imaging results and summary reports) may be sent to TESC as part of the SIF/DRF for 
diagnosis evaluation, if allowed by local regulations. Submission of these materials is expected 
shortly after the screening visit and needs to be approved before randomization.
All new reports of seizures (parent or caregiver descriptions) identified by the parent or caregiver 
after screening (Visit 1) must also be reviewed by the investigator and approved by TESC to 
confirm seizure classification. A new DRF must be submitted to TESC for review and approval for 
all new seizures and/or recurrence of past (>1 year) identified seizures throughout the course of the 
study. Only seizure classification/descriptions approved by TESC will be collected in the 
electronic seizure and medication diary for this study.
9.1.4
Seizure Frequency
The primary efficacy measure is the percent change from baseline in MMD seizure frequency per 
28 days in subjects on soticlestat as compared with placebo during the treatment period (or during 
the 12-week maintenance period only for EMA registration regions). Secondary efficacy measures 
include the proportion of responders defined as those with a ≥50% reduction in MMD seizures 
from baseline.
Seizure frequency will be collected via an electronic daily seizure and medication diary. The 
electronic diary will allow a 7-day window for data entry/correction by the subject/parent or 
caregiver. In the event of a device malfunction, the subject/parent or caregiver should contact the 
site as soon as possible for the back-up solution (access to web back-up) to record daily seizures 
and medications. The backup paper daily seizure and medication diary will be utilized to ensure 
compliance and reduce the incidence of missed entries only in cases when the web backup is not 
available. The electronic daily seizure and medication diary is an observer-reported clinical 
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outcome assessment measure that captures seizures noted as occurring as individual seizures and 
seizures occurring in a cluster. Countable and uncountable seizures occurring within a cluster will 
be captured. Subject/parent or caregiver will be the observers and reporters in the current study. 
Subject/parent or caregiver will be educated on the importance to record seizures throughout the 
day to ensure that the daily diary assessment is completed each evening, even if no seizures 
occurred.
MMD seizures include:

Hemi-clonic or focal clonic.

Focal to bilateral tonic-clonic.

Generalized tonic-clonic.

Bilateral clonic.

Focal seizures with major motor signs (eg hypermotor seizures or involving major body areas 
such as lower extremities or trunk) leading to fall or likely fall.

Atonic seizures involving major body areas such as lower extremities or trunk leading to fall or 
likely fall.

Tonic seizures involving major body areas such as lower extremities or trunk leading to fall or 
likely fall.

Convulsive status.
At the screening visit (Visit 1), the subject/parent or caregiver will be provided with the electronic 
daily seizure and medication diary and specific instructions to ensure compliance with the seizure 
recording. In addition, a corresponding web backup solution and paper daily seizure and 
medication diary will be provided in the case of an electronic diary device malfunction. All seizure 
events will be recorded starting at the screening/baseline period up until the follow-up visit. At 
each visit, the electronic diary will be reviewed, and paper diary collected, if applicable. All entries 
will be reviewed by the investigator with the subject/parent or caregiver at the time of each visit to 
ensure proper recording. Any new seizures that may have occurred since the last visit must be 
reviewed by the investigator and approved by TESC via submission of a DRF. Only seizure 
classification/descriptions approved by TESC will be collected in the electronic daily seizure and 
medication diary for this study.
For the prospective baseline period, the seizure frequency will be calculated as:
(total number of seizures) / (total number of days seizures were assessed) × 28.
Seizure frequency calculated through this method will be used to confirm the eligibility.
9.1.5
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic ethnicity, 
and race as described by the subject at screening.
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Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.13).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 6 months before signing of informed 
consent. 
All ASMs stopped prior to signing of informed consent should be recorded.
9.1.6
Height and Weight
Weight and height are to be measured while the subject is wearing indoor clothing and with shoes 
off. If unable to obtain height or weight, data that was obtained ≤30 days before the screening visit 
may be collected from other sources (eg, medical records or the subject’s caregiver). The 
investigator must record in the source document the reason for not obtaining height or weight (eg, 
the subject is in a wheelchair). These data may be used to determine the weight-based starting 
dose.
9.1.7
Concomitant Medications and Nonpharmacologic Therapies and Procedures
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. A by-subject listing of concomitant medications will include all medications 
(including vaccinations) taken during the study regardless of the timing for the start of the 
medication. All medications started before the administration of the study drug will be included in 
the data but will be identified as “prior” in the listing. Only the concomitant medication use will be 
summarized.
The number and percentage of subjects who took at least 1 medication during the double-blind 
period as well as the number and percentage of subjects who took each type of medication will be 
presented for each treatment group. Medications will be listed according to their WHO Drug 
Dictionary Anatomic Therapeutic Chemical (ATC) class level 4 and preferred drug name within 
ATC class level 4 by decreasing frequency of incidence for all active treatment groups combined. 
The list of excluded medications is provided in Appendix B.
9.1.8
Vital Sign Procedure
The following vital signs will be recorded at the times specified in Appendix A: height (cm), 
weight (kg), systolic and diastolic blood pressure (mm Hg), heart rate (beats/min), respiratory rate 
(breaths/min), and temperature (°C or °F). If clinically significant vital sign changes from 
screening/baseline are noted, the changes will be documented as TEAEs in the TEAE eCRF. 
Screening/baseline events will be documented in the Medical History eCRF. Clinical significance 
is defined as any variation in vital signs that has medical relevance and may result in an alteration 
in medical care. The investigator will continue to monitor the subject until the parameter returns to 
baseline or until the investigator determines that follow-up is no longer medically necessary.
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9.1.9
Physical Examination Procedure
A physical examination will be performed at the times specified in Appendix A. Each examination 
will include the following assessments: eyes; ears; nose; throat; cardiovascular system; respiratory 
system; gastrointestinal system; dermatologic system; musculoskeletal system; extremities; 
nervous system; lymph nodes; and other.
If clinically significant changes from screening/baseline are noted, the changes will be 
documented as TEAEs in the TEAE eCRF. Screening/baseline events will be documented in the 
medical history eCRF. Clinical significance is defined as any variation in physical findings that 
has medical relevance and may result in an alteration in medical care. The investigator will 
continue to monitor the subject until the parameter returns to baseline or until the investigator 
determines that follow-up is no longer medically necessary.
9.1.10
Neurological Examination Procedure
A separate neurological examination will be performed and results collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, motor function (including 
strength and reflexes), and sensation.
9.1.11
Safety Evaluations
Investigators are responsible for monitoring the safety of subjects who have entered this study and 
for alerting the sponsor or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
TEAEs that are serious, considered related to the study treatment or the study, or that caused the 
subject to discontinue before completing the study. The subject should be followed until the event 
is resolved or explained. Frequency of follow-up evaluation is left to the discretion of the 
investigator.
The following additional clinical safety monitoring and expanded evaluation by the previously 
established DMC for soticlestat phase 3 clinical studies to utilize the following:

Electronic data capture (EDC) will have a specific flag that will be checked at enrollment for 
subjects on concomitant perampanel.

Electronic daily seizure and medication diary will be used for the phase 3 studies. This will
enable review of blinded seizure count data for subjects on concomitant perampanel (and all 
subjects included in phase 3).

The contract research organization (CRO) and sponsor medical monitors will closely monitor 
the seizure frequency counts entered in the electronic daily seizure and medication diary for 
subjects on concomitant perampanel and will have a standing agenda item to review data for 
subjects on perampanel in the medical monitor review meetings.
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
If there is a significant increase in seizure frequency rate noted for the subjects on concomitant 
perampanel (blinded review), an ad hoc DMC meeting will be called for an unblinded review 
and recommendation by the independent DMC members.

There will be a standing agenda item for review of seizure frequency rate and safety data for all 
subjects on concomitant perampanel in the DMC meetings.
9.1.11.1
Ophthalmological Evaluation Procedure
An ophthalmologic evaluation will be conducted by a pediatric ophthalmologist or 
neuro-ophthalmologist preferably, although an adult ophthalmologist or an optometrist 
experienced with examining children may be allowed following discussion with the medical 
monitor. The ophthalmologic evaluation may include:
1. Age and developmentally appropriate quantitative visual acuity.
a) If the subject is unable to perform quantitative visual acuity assessment due to age or 
developmental ability, a qualitative assessment should be attempted.
2. Bilateral red reflex test (also known as Bruckner transillumination test), to assess for lens 
abnormalities.
3. Postinstillation of mydriatic eye drop (cyclopentylate is contraindicated in this population with 
epilepsy), slit lamp (portable acceptable) examination for anterior or posterior lens opacities 
concerning for cataracts after adequate pupil dilation. For subjects unable to cooperate with slit 
lamp examination due to age or developmental ability, use of a 20-D double aspheric binocular 
indirect ophthalmoscopy lens or penlight is acceptable.
4. Indirect and or direct ophthalmoscopy of the optic nerve and retina after adequate pupillary 
dilation, preferably with a picture of the fundus.
These evaluations are to be collected at baseline (between the screening and randomization visits) 
and end of the study (before the last visit) for subjects who complete the 16 weeks of double-blind 
treatment or at the early termination visit for those subjects who do not complete (please see 
Appendix A).
9.1.11.2
ECG Procedure
For each subject, 12-lead digital electrocardiograms (ECGs) will be collected according to the 
schedule of study procedures (Appendix A). Subjects must be supine for approximately 5 to 
10 minutes before ECG collection and remain supine but awake during ECG collection.
ECGs may be obtained at additional times, when deemed clinically necessary. Collection of more 
ECGs (more replicates) than expected at a particular time point is allowed when needed to ensure 
high-quality recordings.
ECGs will initially be interpreted by a qualified physician (the investigator or qualified designee) 
at the site as soon after the time of ECG collection as possible, and ideally while the subject is still 
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present at the site, to determine whether the subject meets entry criteria at the relevant visit(s) and 
for immediate subject management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the subject will be assessed by the investigator for symptoms (eg, palpitations, near 
syncope, syncope) and to determine whether the subject can continue in the study, and the medical 
monitor or the sponsor should be contacted. The investigator or qualified designee is responsible 
for determining if any change in subject’s management is needed and must document his/her 
review of the ECG printed at the time of evaluation from at least 1 of the replicate ECGs from each 
time point.
Any clinically significant finding that was not present at screening/baseline will be reported and 
discussed with the medical monitor or the sponsor. When there are differences in ECG 
interpretation between the investigator (or qualified designee) and the site/local cardiologist, the 
investigator (or qualified designee’s) interpretation will be used for study entry and immediate 
subject management. The investigator (or qualified designee) must document his/her review of the 
ECGs printed at the time of collection.
9.1.11.3
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of these 
procedures and specimen handling will be given in the laboratory manual. 
The details for amounts of blood collected per visit and for the study are provided in Appendix G. 
The volumes do not exceed 3 mL/kg of body weight during any 8-week period or at any visit.
Table 9.a lists the tests that will be obtained for each laboratory specimen.
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis a
Erythrocytes
Hemoglobin
Hematocrit
Red blood cell indices
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Red cell distribution width
White blood cell count and 
differential
Neutrophils, segmented
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Mean platelet volume
Sodium
Potassium
Total bilirubin
Direct bilirubin
Indirect bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma glutamyl transferase (GGT)
Blood urea nitrogen (BUN)
Creatinine
Urea
Calcium
Phosphate
Glucose
Albumin
Protein
Carbon dioxide
Magnesium
Chloride
Alpha-1 acidic glycoprotein
pH a
Protein a
Glucose a
Ketones a
Bilirubin a
Nitrite a
Urobilinogen a
Erythrocytes
Leukocyte esterase
Microscopy
Other Serum
Hepatitis B virus surface antigen
Hepatitis B core antibody
Hepatitis C virus antibody
Parathyroid hormone, intact
Vitamin D
Pregnancy test (female subjects only)—choriogonadotropin beta
a Urinalysis is the primary method. Urine dipstick may be used as a backup only. If sufficient volume of urine cannot 
be obtained for either central urinalysis testing or dipstick testing in clinic, per investigator’s discretion, dipstick tests 
can be provided to parents/caregivers for home urine testing and results reported to the site for interpretation.
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results. Local laboratories are allowed before randomization only if a 
screening laboratory value is missing, and after randomization only for emergent reasons, 
including pregnancy tests.
It is anticipated that some laboratory values may be outside of the normal value range due to the 
underlying disease. As in routine practice, the investigators should use their medical judgment 
when assessing clinical significance. Clinical significance is defined as any variation in laboratory 
measurements which has medical relevance, and which results in a change in medical care. If 
clinically significant laboratory changes from baseline are noted, the changes will be documented 
as TEAEs in the eCRF. The investigator will also assess the relationship to study treatment for all 
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clinically significant out of range values. The investigator will continue to monitor the subject with 
additional laboratory assessments until (1) values have reached normal range and/or baseline, or 
(2) in the judgment of the investigator, out of range values are not related to the administration of 
study drug or other protocol-specific procedures.
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase [GGT], and 
INR) should be performed within a maximum of 7 days and preferably within 48 to 72 hours after 
the abnormality was noted. (Refer to Section 7.5 and Section 9.3.1 for the appropriate guidance on 
reporting abnormal liver function tests.)
If ALT or AST remains elevated >3 times the ULN on these 2 consecutive occasions the 
investigator must contact the medical monitor for consideration of additional testing, close 
monitoring, possible discontinuation of study drug, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as a TEAE (please refer to 
Section 9.3.1).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
9.1.12
Documentation of Concomitant (Including ASM and Rescue) Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject/parent or caregiver over the counter. Concomitant 
medication is not provided by the sponsor. At each study visit, the subject/parent or caregiver will 
be asked whether they have taken any medication other than the study drug (used from signing of 
informed consent through the end of the study), and all medications including vitamin 
supplements, over-the-counter medications, and oral herbal preparations must be recorded in the 
eCRF. Documentation will include generic or trade medication name, dose, unit, frequency, route 
of administration, start and end dates, and reason for use.
ASMs treatments, artisanal cannabidiol use, VNS settings, and ketogenic diet should not be altered 
during the study.
9.1.13
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. These include clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening (Visit 1), according to the judgment of the 
investigator. The condition (ie, diagnosis) should be described and recorded in the eCRF.
9.1.14
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed in children aged ≥6 years by use of the C-SSRS. 
The C-SSRS is a 3-part scale that measures suicidal ideation (eg, subject endorses thoughts about a 
wish to be dead or has other thoughts of suicide), intensity of ideation (frequency), and suicidal 
behavior (actually, interrupted, and aborted attempts at suicide) (Posner et al. 2011).
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Two versions of the C-SSRS will be used in this study for all subjects ages 6 through 55 years: the 
C-SSRS Children’s Screening/Baseline (recall period lifetime/12 months) and the C-SSRS 
Children’s Since-Last-Visit.
Children who are <6 years old at the start of the study will have an unscheduled visit after turning 
age 6, at which time the C-SSRS Children’s Screening/Baseline version will be completed. The 
C-SSRS Children’s Since-Last-Visit version will be completed at the end of the study.
Study staff trained in the administration of the C-SSRS will assess subject suicidality using the 
C-SSRS, eliciting answers from the subject/parent or caregiver. Ultimately, the determination of 
the presence of suicidal ideation or behavior depends on the clinical judgment of the investigator.
If a subject exhibits signs of suicidal ideation or behavior, the subject will be withdrawn as 
described in Section 7.5.
9.1.15
Health Outcome/Quality of Life Measures
9.1.15.1
CGI-I (Clinician)
The CGI-I Clinician) is a 7-point Likert scale that the investigator uses to rate a subject’s change 
(improvement) in overall seizure control, behavior, safety and tolerability, after the initiation of 
study drug relative to baseline (before treatment with the study drug). The subject will be rated as 
follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 
(minimally worse), 6 (much worse), and 7 (very much worse). The investigator or designee will 
complete the CGI-I at the timepoints specified in Appendix A.
9.1.15.2
Care GI-I (Caregiver)
The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall 
seizure control, behavior, safety and tolerability after the initiation of study drug relative to 
baseline (before treatment with the study drug). The subject will be rated as follows: 1 (very much 
improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 
(much worse), and 7 (very much worse). The parent/caregiver will complete the Care GI-I via 
interview at the timepoints specified in Appendix A.
9.1.15.3
CGI-I Seizure Intensity and Duration
The CGI-I Seizure Intensity and Duration instrument is used by the parent/caregiver to rate 
changes in intensity and/or duration of the most impactful seizures from the first assessment. The 
subject’s symptoms will be rated as follows: 1 (very much improved), 2 (much improved), 
3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much 
worse). The parent/caregiver will complete the CGI-I seizure intensity and duration at the 
timepoints specified in Appendix A.
9.1.15.4
CGI-I Nonseizure Symptoms
The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the 
investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains 
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(including communication, alertness, and disruptive behaviors) since initiating the study drug. The 
subject will be rated by the investigator as follows: 1 (very much improved), 2 (much improved), 3 
(minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much 
worse). At baseline, a symptoms form is completed by the clinician in collaboration with the 
primary caregiver to assess the subject’s status based on the presence of any nonseizure symptoms. 
The baseline form is intended to serve as a reference for the investigator and caregiver during 
subsequent visits when assessing change in the subject’s condition pertaining to these symptoms.
The investigator or designee will complete the CGI-I Nonseizure Symptoms instrument in 
consultation with the primary caregiver at the timepoints specified in Appendix A.
9.1.15.5
QI-Disability (Parent/Caregiver Version)
The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluates quality of life in 
children with intellectual disabilities (Downs et al. 2019). It contains 32 items covering 6 domains 
of quality of life: physical health, positive emotions, negative emotions, social interaction, leisure 
and the outdoors, and independence.
The parent/caregiver-reported questionnaires will be administered according to the schedule of 
assessments (Appendix A).
9.1.15.6
EQ-5D-5L Quality of Life Scale
The EQ-5D-5L is the 5–response level version of the EQ-5D instrument. It consists of 2 sections, a 
descriptive system questionnaire and the EQ visual analogue scale (EQ VAS). The questionnaire 
provides a descriptive profile across the dimensions of mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. In the EQ-5D-5L version, each dimension has 5 response 
levels: no problems, slight problems, moderate problems, severe problems, and unable to/extreme 
problems. The parents or caregivers are asked to indicate their own health quality of life by ticking 
the box next to the most appropriate statement in each of the dimensions. In addition, the EQ VAS 
is used to indicate the general health status, with 100 indicating the best health status. These 
questionnaires will be administered according to the schedule of assessments (Appendix A).
9.1.16
Contraception and Pregnancy Avoidance Procedure
9.1.16.1
Male Subjects and Their Female Partners
Male subjects are not required to use barrier contraception. Donation of sperm is not allowed 
during the study and within 90 days following the last administration of the study drug.
9.1.16.2
Female Subjects and Their Male Partners
Plasma pregnancy testing at screening and the subject’s last clinic visit will be processed using the 
central laboratory. Additional pregnancy tests (serum or urine) may be performed by a local 
laboratory throughout the study at the investigator’s discretion.
Please refer to Section 7.1 for inclusion criteria for detailed contraception requirements.
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The following definitions apply for contraception and pregnancy avoidance procedures.

A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in 
younger women (eg, those <45 years old) or women who are not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.
For sterilized male partners, at least 1 year should have passed since bilateral vasectomy, and they 
must confirm they have obtained documentation of the absence of sperm in the ejaculate or have 
had bilateral orchidectomy. Subjects and parents/legal guardians will be provided with 
information regarding acceptable methods of contraception as part of the informed consent 
process and will be asked to sign a consent form stating that there is clear understanding (including 
by the parents/legal guardian) of the requirements for avoidance of pregnancy and donation of ova 
during the course of the study and for 30 days after the last dose of study drug. This consent may be 
signed by the legally authorized representative of the subject. 
Female subjects of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at screening (Visit 1). A pregnancy test at randomization 
(Visit 2) is not required for eligibility if performed and confirmed negative at Visit 1 and if the 
investigator does not deem it necessary to repeat pregnancy test at Visit 2. 
During the course of the study, subjects will receive continued guidance with respect to the 
avoidance of pregnancy and ova donation as part of the study procedures. A serum or urine hCG 
pregnancy test will also be performed at Visit 11 (Day 113)/early termination. Additional 
pregnancy tests (serum or urine) may be performed throughout the study at the investigator’s 
discretion.
9.1.16.3
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Assessment of subject compliance through such questions as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit?
–
Are your menses late? (Even in women with irregular or infrequent menstrual cycles, a 
pregnancy test must be performed if the answer is “yes.”)
–
Is there a chance you could be pregnant?
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9.1.17
Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn immediately, and 
the study drug should be immediately discontinued. 
For female subjects, if the pregnancy occurs during administration of active study drug, eg, after 
Visit 2 or within 30 days of the last dose of active study drug, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.1. For partners 
of male subjects, if the pregnancy occurs during the study or within 90 days after the last dose, it 
should be reported following authorization from the subject’s partner.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the 
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted.
9.1.18
Documentation of Screen Failure
Investigators must account for all subjects with a signed informed consent. If the subject is found 
to be ineligible for the study before randomization, the investigator should record the primary 
reason for screen failure in the eCRF. The IWRS should be contacted as a notification of screen 
failure.
The primary reason for screen failure is to be recorded in the IWRS. Subjects may be rescreened 
after consultation with the medical monitor or sponsor.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Pretreatment event (PTE).

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Withdrawal by subject/parent or legal guardian (specify reason).

Study terminated by sponsor.
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
Other (specify reason).
Subjects may be rescreened after consultation with the medical monitor or sponsor.
9.1.19
Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the study.
If the subject is found to be ineligible, the investigator should record the primary reason for failure 
on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
The subject/parent or caregiver will record the study drug taken by subject daily, in the morning 
and evening. This module in the electronic daily seizure and medication diary is only available to 
the subject/parent or caregiver for entry each day, and retroactive entries are not allowed using the 
handheld device or web portal.
Confirmation of study drug intake and dosing will be recorded in the electronic daily seizure and 
medication diary on a daily basis. Any missed doses will be recorded in the electronic daily seizure 
and medication diary by the subject/parent or caregiver and reviewed by the site personnel. The 
subject/parent or caregiver will be required to bring used/unused study drug and the electronic 
daily seizure and medication diary device to each site visit. All subject/parent or caregiver should 
be re-instructed about the dosing requirements during study contacts. The authorized site 
personnel conducting the re-education must document the process in the subject’s source records.
Missed or discrepant entries must be reconciled at the site level and must be accurately reflected in 
the eCRF. Sites will be asked to submit data correction request forms to correct any discrepancies 
regarding study medication that may pose a potential safety concern for the participant. This 
includes potential typographical and/or data entry errors indicating study drug overdose or 
underdose, etc. Sites must ensure the eCRF accurately reflects study drug administration in 
accordance with eCRF completion guidelines.
Subject compliance with study drug will be assessed at each visit.
Compliance will be tracked through the subject electronic daily seizure and medication diary and 
all entries will be reviewed by site personnel, reconciled against returned study medication with 
queries, as necessary.
Subjects who are significantly noncompliant will be discontinued from the study. A subject will be 
considered significantly noncompliant if he or she misses more than 20% of study medication 
during the study duration unless there is a valid reason for interruption in the study medication 
such as hospitalization. These cases should be discussed with the study monitor. Similarly, a 
subject will be considered significantly noncompliant if he or she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.
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9.3
Safety Monitoring
The sponsor’s medical monitor and/or pharmacovigilance physician will monitor safety data 
throughout the course of the study.
9.3.1
Reporting of Abnormal LFTs
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed 
within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Refer to Section 7.5 and Section 10.2.1 for the appropriate guidance on reporting abnormal liver 
function tests.)
If a subject is noted to have elevated ALT or AST >3 times the ULN on 2 consecutive occasions, 
the abnormality should be recorded as a TEAE or SAE. In addition, eCRFs must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed. The investigator must contact 
the medical monitor for discussion of the relevant subject details. and possible alternative 
etiologies. The abnormality should be recorded as a TEAE (please refer to Section 10.2.1).
If a subject is noted to have ALT or AST >3 times the ULN and total bilirubin >2 times the ULN 
for which an alternative etiology has not been identified, a CRF must be completed and transmitted 
with the SAE Report form (as per Section 10.2.2). The investigator must contact the medical 
monitor for discussion of the relevant subject details, possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions, 
and continued participation in the study. Follow-up laboratory tests as described in Table 9.a must 
also be performed.
A consultation with a hepatologist may be considered as per investigator judgement or 
consultation with the medical monitor/sponsor.
9.3.2
Reporting of QTcF Interval Increase
As noted in Section 7.5, if the QTcF is >500 ms or if there is an increase of QTcF >60 msec above 
baseline, study drug should be discontinued immediately, and the subject should be provided with 
appropriate clinical follow-up. The subject’s ECG findings should be confirmed by repeat ECG 
with manual measurement of the QTcF interval.
The investigator must contact the medical monitor for discussion of the relevant subject details, 
possible alternative etiologies, such as medical history/concurrent medical conditions, and 
continued participation in the study.
In addition, the eCRF must be completed and transmitted with the SAE Report form (as per 
Section 10.2.2).
If safety monitoring uncovers an issue that needs to be addressed by unblinding at the group level, 
only members of the DMC (see Section 11.0) can conduct additional analyses of the safety data.
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9.3.3
Reporting of Perampanel Drug-Drug Interaction
To assess the potential interaction of soticlestat with perampanel, the following clinical safety 
monitoring and expanded evaluation will be performed:

Investigators will perform close monitoring of the seizure frequency counts entered into the 
electronic daily seizure and medication diary for all subjects, including those on concomitant 
perampanel.

The medical monitor and sponsor will provide blinded reviews of the electronic daily seizure 
and medication diary for subjects on concomitant perampanel including at the regular medical 
monitoring review meetings. If a significant increase in the blinded review of seizures 
frequency is detected, an ad hoc DMC meeting will be called for an unblinded review (see 
Section 11.0).
9.3.4
Reporting of Cataracts
To assess the potential for developing cataracts (see Sections 4.3 and 10.1.4), an ophthalmological 
evaluation will be performed (see Section 9.1.11.1). If there is a potential finding of cataract, the 
eCRF must be completed and the abnormality should be recorded as an TEAE/SAE of special 
interest following Section 10.2.2. An SAE must be transmitted with the SAE Report form (as per 
Section 10.2.2).
9.3.5
PK and PD Measurements
9.3.5.1
Collection of Plasma Samples for Soticlestat and ASM PK Evaluation
Blood samples for measurement of ASM levels will be collected at Visits 1, 9, and 11.
Blood samples for the measurement of plasma concentrations of soticlestat and its metabolite(s)
(and ASMs) will be collected on the days specified in Appendix A. Serum alpha-1 acidic 
glycoprotein levels will be evaluated as part of the laboratory serum chemistry panel during visits 
when PK samples are obtained.
The exact date, time, and dose of last study drug dose before each scheduled visit will be recorded 
by the subject/parent or caregiver in the electronic daily seizure and medication diary. For subjects 
who are not able to come for the visit during the morning hours, they should be instructed to take 
their morning dose, as usual, and come to the study site during the afternoon hours, as feasible for 
the subject/parent or caregiver. The exact date and time of the PK blood sample collection will be 
recorded in the eCRF.
In addition, before each PK blood sample collection, the exact date, time, and dose of last ASM 
dose will be captured.
Instructions for the collection, handling, and shipping of plasma PK samples are provided in the 
laboratory manual.
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9.3.5.2
Bioanalytical Methods for Soticlestat
Plasma concentrations of soticlestat and its metabolite(s) will be measured by high-performance 
liquid chromatography with tandem mass spectrometry.
9.3.5.3
PK Parameters
The PK parameters of soticlestat will be estimated from the sparse concentration-time data for all 
evaluable subjects using a population PK approach. Actual sampling times will be used in all PK 
computations involving sampling times. Date and time of the last dose of the study drug and 
individual concomitant ASMs must be captured by the subject/parent or caregiver in the electronic 
daily seizure and medication diary.
The population PK/PD/EO model developed for soticlestat based on the data from single- and 
multiple-dose phase 1 through phase 2 studies in healthy subjects and patients will be updated 
using data from this study and used to estimate PK parameters (ie, exposure) and will also be 
updated using data from this study exposure. The detailed population analysis approach will be 
described in a separate data analysis plan before database lock. The results of the population PK 
modeling will be reported separately.
Bioanalytical samples collected to measure study drug concentration will be retained for a 
maximum of 1 year following the last subject visit for the study.
In addition, blood will be drawn for assessment of alpha-1 acidic glycoprotein as part of the 
laboratory serum chemistry panel at each visit where PK samples are obtained.
9.3.5.4
PD Measurements
Blood samples for the measurement of 24HC levels in plasma will be collected according to the 
schedule shown in Appendix A.
Measurements of plasma 24HC levels will be included in this study as a PD biomarker related to 
the mechanism of action of soticlestat. The conversion of cholesterol to 24HC is a mechanism to 
maintain cholesterol homeostasis in the brain and its release into the cerebrospinal fluid and 
plasma (Bretillon et al. 2000; Cartagena et al. 2008; Tian et al. 2010). Evidence suggests that 
plasma 24HC levels are mostly derived from the central nervous system (Lutjohann et al. 1996). 
Data from single-rising dose and multiple-rising dose studies showed a decrease in plasma 24HC 
levels after administration of soticlestat in healthy subjects, which was correlated with the changes 
in EO percentage measured in the brain using the positron emission tomography radioligand 
displacement approach (Study TAK-935-1003). In the current study, baseline and postdose plasma 
24HC levels will be measured to estimate the average 24HC reduction during a dosing interval in 
each subject exposed to soticlestat. As no information is available regarding 24HC levels in 
subjects with epilepsy, baseline data will be collected for possible future comparisons with 
aged-matched healthy subjects.
The date, time, and dose of the last dose of the study drug and any ASMs must be captured by the 
subject/parent or caregiver in the electronic daily seizure and medication diary. The exact date and 
time of the 24HC blood sample collection will be recorded in the eCRF.
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Instructions for the collection, handling, and shipping of plasma PD (24HC) samples are provided 
in the laboratory manual.
The actual plasma level as well as change from baseline in plasma 24HC levels will be 
summarized. Summary statistics will be reported. Additional PD parameters may be calculated, as 
appropriate.
9.4
Biological Sample Retention and Destruction 
If permitted by local regulations and with written consent of the subject/parent or legal guardian, 
the sponsor will store blood left from clinical laboratory tests for potential future research related 
to soticlestat and/or seizure disorders. The samples will be held for up to 15 years after the end of 
the study. The samples will be stored securely at sample storage facilities at the expense of the 
sponsor and only be identified by a unique code such that no one will be able to link the sample to 
a subject. 
Subjects who consented to stored samples for future research can withdraw their consent and 
request disposal of a stored sample at any time. The site will notify sponsor of consent withdrawal. 
If samples have been analyzed, results may not be able to be removed from the study.
9.5
Schedule of Study Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.5.1
Unscheduled Visits
Subjects may return to the study center for unscheduled visits as needed. Unscheduled study visits 
can be performed when the subject has a study-related issue in between regular study visits as per 
investigator discretion.
The following should be performed during this visit:

Documentation of concomitant medications.

TEAE assessment.

Other procedures, including dose adjustments, as deemed appropriate by the investigator.
These visits can also be performed as virtual visits, depending on the planned assessments and per 
the investigator’s judgment (as allowed by local regulations).
9.5.2
Poststudy Care
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies initiated or resumed as 
required. However, following completion of the study, subjects will have the option to enroll in an 
OLE study, as per the OLE study’s inclusion/exclusion criteria.
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10.0
COLLECTION AND REPORTING OF ADVERSE EVENTS
10.1
Definitions
In this study, AE refers to both PTEs and TEAEs. PTEs are AEs that started after the signing of 
informed consent but before receiving any study drug. TEAEs are AEs that started after the first 
dose of study drug.
10.1.1
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
been administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.2
Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, signs or symptoms should be recorded 
appropriately as AEs.
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be AEs if they are judged 
to be clinically significant (ie, if some action or intervention is required, or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory or 
ECG re-test and/or continued monitoring of an abnormal value or finding are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.
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
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased serum creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations (eg, 
laboratory tests, ECG, radiographs) should NOT be recorded as PTEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded appropriately 
as a PTE (worsening or complication occurs before start of study drug) or a TEAE (worsening 
or complication occurs after start of study drug). Investigators should ensure that the event 
term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy), 
any occurrence of an episode should only be captured as an AE if the condition becomes more 
frequent, serious or severe in nature. Investigators should ensure that the event term recorded 
captures the change in the condition from baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a AE if occurring to a greater 
extent to that which would be expected. Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as a TEAE. Investigators should ensure that 
the event term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of a TEAE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in intensity of AEs:

If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be recorded as an AE. Complications resulting from any planned surgery should be 
reported as AEs.
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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded as an 
AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
AEs but instead will be documented on an Overdose page of the (e)CRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF.
10.1.3
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
10.1.4
AEs of Special Interest
An AE of special interest (serious or nonserious) is one of scientific and medical concern specific 
to the compound or program for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda.
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
Potential drug-drug interaction between soticlestat and perampanel leading to increased 
seizure frequency:
A potential drug-drug interaction with perampanel and soticlestat resulting in increased seizure 
frequency was noted in 3 subjects in the TAK-935-2001 study of adult subjects with DEEs. To 
assess this potential interaction, the following clinical safety monitoring and expanded 
evaluation will be performed to closely monitor seizure frequency in these subjects. (Please 
see Section 9.3.3.)

Cataracts:
During nonclinical studies, incipient posterior cortical, subcapsular lenticular cataracts of 
moderate grade were seen in 1 male rat at 300 mg/kg/d and in 1 female rat at 100 mg/kg/d. To 
assess these potential changes, a detailed ophthalmological monitoring and evaluation will be 
performed. (Please see Section 9.1.11.1 and Section 9.3.4.)

Psychosis:
During the phase 1 multiple rising dose study in healthy subjects, episodes of confusion, 
euphoria, and psychosis were seen at the highest dose of 600 mg/d. However, in this study 
subjects were not up-titrated to the target dose. Psychiatric AEs should be monitored closely by 
the investigator and reported based on AE/SAE criteria described in Section 10.1.3.
AEs of special interest must be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor.
10.1.5
Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6
Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments.
10.1.7
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
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The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.8
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.1.9
Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.10
Frequency
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.1.11
Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE (eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE).

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Dose interrupted – the dose was interrupted due to the particular AE.
10.1.12
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
sign/symptom has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, sign/symptom, or laboratory value on the last day of the observed 
study period is worse than when it started; is an irreversible congenital anomaly; the subject 
died from another cause with the particular AE state remaining “not recovered/not resolved.”
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
Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AE is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
AE Collection Period
Collection of PTEs will commence from the time the subject/parent or legal guardian signs the 
informed consent to participate in the study and will continue until the subject is first administered 
study drug (Day 1) or until screen failure. For subjects who discontinue before study drug 
administration, PTEs are collected until the subject discontinues study participation.
Collection of TEAEs will commence from the time that the subject is first administered study drug 
(Day 1). Routine collection of TEAEs will continue until Visit 12 for those who do not roll over to 
the OLE study. For those who do roll over, routine collection of TEAEs will continue to midnight 
on the day of Visit 11.
10.2.1.2
AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing TEAEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until a satisfactory explanation for the changes is 
observed. All AEs will be documented in the AE page of the eCRF, whether or not the investigator 
concludes that the event is related to the drug treatment. The following information will be 
documented for each event:
1. Event term.
2. Start and stop date and time.
3. Frequency.
4. Intensity.
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5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not applicable for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
Subject diary and/or health outcome/quality of life measures will not be used as a primary means 
to collect AEs. However, should the investigator become aware of a potential AE through the 
information collected with this instrument, proper follow-up with the subject for medical 
evaluation should be undertaken. Through this follow-up, if it is determined that an AE not 
previously reported has been identified, normal reporting requirements should be applied.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure:

A sponsor SAE form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event.

Regardless of causality, SAEs must be reported to the sponsor Global Pharmacovigilance 
department or designee, to the attention of the individual identified in the contact information 
list, which will be provided in the study manual, within 24 hours of becoming aware of the 
event. This will be done by transmitting an EDC SAE report. If transmission of an EDC SAE 
report is not feasible within 24 hours, then a facsimile of the completed paper-based SAE form 
should be sent. If SAEs are reported via fax or by email, EDC must be updated as soon as 
possible with the appropriate information.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of serious PTEs will follow the procedure described for SAEs.
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
transmit it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
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10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA, 
investigators, and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor-supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB or IEC.
11.0
STUDY-SPECIFIC COMMITTEES
Details of the DMC are captured in a DMC charter written before the start of the study.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO Drug 
Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent form.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
After submission of the CRFs to the sponsor, any change of, modification of or addition to the data 
on eCRFs should be made by the investigator with use of change and modification records of 
eCRFs (data clarification form) provided by the sponsor. The principal investigator must review 
the data clarification form for completeness and accuracy and must sign and date the form.
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After the lock of the study database, any change of, modification of, or addition to the data on the 
eCRFs should be made by the investigator with the approval from the sponsor. The principal 
investigator must review the data change for completeness and accuracy and must sign and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The following procedure is applicable for all countries except Japan.
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, ICFs, subject authorization 
forms regarding the use of personal health information (if separate from the ICFs), including 
consent to use digital tools and applications, if applicable, electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long term legibility. Furthermore, International Conference on Harmonisation (ICH) E6 
Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the study site agreement between the 
investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The following procedure is applicable for Japanese sites only.
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), and detailed records of drug disposition to enable evaluations or audits 
from regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
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the subject’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator and the head of the study site to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the study site agreement between the 
investigator and/or the head of the study site and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted before unblinding of subject’s treatment assignment. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods.
13.2
Determination of Sample Size
The study will randomize a total of approximately 234 subjects at a 1:1 ratio to receive 1 dose level 
of soticlestat or placebo, resulting in approximately 117 subjects per arm.
The primary endpoint for this study is the percent change from baseline in MMD seizure frequency 
per 28 days. The definition for MMD is different for this study than for ELEKTRA, however, the 
variability of this endpoint is assumed to be the same. This leads to an assumption that the pooled 
SD of the percent change from baseline in MMD seizure frequency is 65%.
A difference of 26.5% in mean percent reduction in MMD seizure frequency between treatments is 
an appropriate target. A sample size of 117 subjects per treatment arm will provide at least 85% 
power at a two-tailed 5% significance level to detect a difference of 26.5% in mean percent 
reduction in seizure frequency between treatments using the Wilcoxon rank-sum test, assuming 
the pooled SD above of 65%.
13.2.1
Analysis Sets
13.2.1.1
ITT Analysis Set
All randomized subjects will be included in the intent-to-treat (ITT) analysis set. All ITT analyses 
will be based on each subject’s randomized treatment assignment.
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13.2.1.2
mITT Analysis Set
All randomized subjects who have received at least 1 dose of study drug and have been assessed 
for seizures for at least 1 day in the treatment period will be included in the mITT analysis set. All 
mITT analyses will be based on each subject’s randomized treatment assignment.
13.2.1.3
Safety Analysis Set
All subjects who take at least 1 dose of study drug will be included in the safety analysis set. Safety 
analyses will be based on the medication that was administered to each subject.
13.2.2
Analysis of Demographics and Baseline Characteristics
Demographic and other baseline characteristics will be summarized and listed for enrolled 
subjects by treatment group and overall. Descriptive statistics will be used to summarize data for 
continuous variables such as age and weight (eg, number of subjects, mean, median, SD, and 
range) and for such categorical variables as sex, ethnicity, and race (number and percentage of 
subjects within each category). Medical history and medication history will be listed by subject.
13.2.3
Subject Disposition
All subjects who discontinue from the study will be identified. If known, a reason for their 
discontinuation will be given.
13.2.4
Efficacy Analysis
The primary efficacy analysis will be performed on the mITT analysis set. The seizure frequency 
will be calculated based on all data collected during the baseline and treatment periods. For all 
efficacy analyses on seizure frequency, baseline refers to the prospective 4- to 6-week baseline 
period. The efficacy endpoints will be summarized for each treatment group, and comparisons will 
be made between the soticlestat and placebo groups. The primary objective of the study is to 
demonstrate that soticlestat is superior to placebo. The primary endpoint (percent change from 
baseline in MMD seizure frequency per 28 days) will be analyzed using rank analysis of 
covariance (ANCOVA) with treatment group as the main effect; age group (≤6 years, >6 years), 
and baseline seizure frequency will be covariates. Sensitivity analyses on the primary endpoint 
will be performed using the van Elteren test and the Wilcoxon rank sum test. Gender will also be 
added to the rank ANCOVA model as a sensitivity analysis.
The proportion of responders will be analyzed using a Cochran-Mantel-Haenszel test stratified by 
age group (≤6 years, >6 years).
The main analysis for CGI-I (clinician), Care GI-I, CGI-I Seizure Intensity and Duration, CGI-I 
Nonseizure Symptoms, and QI-Disability scores will be based on the responses at each subject’s 
last visit where these instruments were utilized. The QI-Disability scores will be analyzed with a 
mixed model for repeated measures, and the other scores will be analyzed using ordinal logistic 
regression. Sensitivity analyses will be performed as specified in the SAP.
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The global type I error will be controlled using a hierarchical gatekeeping procedure on the 
primary and key secondary endpoints. The order of testing will be soticlestat versus placebo for the 
primary endpoint, responder rate, Care GI-I, CGI-I (clinician), CGI-I Nonseizure Symptoms, 
QI-Disability, and CGI-I Seizure Intensity and Duration. All statistical tests will be 2-sided at the 
5% significance level. Techniques for handling missing information with respect to reporting of 
seizures in the treatment period and with respect to subjects who discontinue early will be 
specified in detail in the SAP.
13.2.5
Safety Analysis
Descriptive statistics will be used to summarize all safety endpoints for each of the treatment 
groups. AEs will be summarized using the safety analysis set. All AEs will be coded using 
MedDRA. Data will be summarized using Preferred Terms and primary System Organ Classes.
Two-sided 95% CIs will be presented where meaningful. Data summaries will be displayed for 
incidence of AEs, clinical laboratory variables, vital signs, body weight, and ECG parameters as 
appropriate.
13.2.6
Exploratory/Additional Analyses
Percent change from baseline in each seizure type frequency per 28 days during the full treatment 
period will be compared between soticlestat and placebo using rank ANCOVA adjusting for 
baseline seizure frequency and age stratum. The Hodges-Lehmann estimator and the 
corresponding 95% CI comparing soticlestat and placebo will also be displayed.
Health care resource utilization, including but not limited to emergency room visits and 
hospitalizations, and the effect on the EQ-5D-5L quality of life scale will be analyzed for 
soticlestat and placebo. Descriptive and graphical analyses will be used to summarize results from 
the exploratory endpoints.
Alpha-1 acidic glycoprotein will be analyzed as part of the laboratory serum chemistry panel at 
each visit where PK samples are obtained.
Plasma concentrations of soticlestat and metabolite(s) will be summarized and displayed 
graphically per nominal time points. Mean plasma concentrations over time will be presented 
graphically.
Correlation of change in PD (24HC) exposure and efficacy (change in MMD seizure over the full 
treatment period) will be investigated.
13.3
Other Statistical Issues
13.3.1
Significance Levels
All statistical analyses will be 2-sided and will be tested at the 0.05 level of significance.
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13.3.2
Missing or Invalid Data
Techniques for handling missing information with respect to reporting of seizures in the treatment 
period and with respect to subjects who discontinue early will be specified in detail in the SAP.
13.3.3
Interim Analyses
A blinded interim analysis may be performed to allow for sample re-estimation based on the 
pooled standard deviation of the percent change from baseline in MMD seizure frequency per 
28 days. Details will be provided in the SAP.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
With the exception of visits in China, monitoring visits can be virtual or on site, as indicated in the 
clinical monitoring plan. The investigator guarantees access to source documents by the sponsor or 
its designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process.
In case of prolonged access restrictions to external visits (study monitors) to an investigative site 
due to COVID-19 pandemic and wherever possible by local regulations, remote Source Data 
Verification (rSDV) may be considered for critical data related to subject’s safety and any key 
variables to ensure data accuracy and integrity.
If rSDV is required, full details of the process will be included the Clinical Monitoring Plan 
following any applicable local guidance for secure access to remote source documents and data 
security provisions to protect personal data.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
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required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A protocol deviation form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
The following procedure applies to Japanese sites only: 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the study site of the deviation or change as 
well as its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the study site as soon as possible and an approval from IRB should be obtained.
The investigator should document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States [US] Food and Drug Administration [FDA], 
the United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and study site (or in 
Japan, the head of the study site) guarantee access for quality assurance auditors to all study 
documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual subjects (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix D. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
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has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the US Department of Health and Human 
Services (for studies including TDC Americas).
The sponsor or designee will supply relevant documents for submission to the respective IRB 
or IEC for the protocol’s review and approval. This protocol, the IB, the informed consent form, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB or IEC 
for approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study. 
The IRB or IEC approval must refer to the study by exact protocol title, number, and version date; 
identify versions of other documents (eg, informed consent form) reviewed; and state the approval 
date. The sponsor will notify the site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the study.
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or 
IEC. All IRB and IEC approvals and relevant documentation for these items must be provided to 
the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written and electronic consent documents will embody the elements of informed consent as 
described in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study, including the use of electronic devices and associated technologies (if 
applicable). The informed consent form and the subject information sheet (if applicable) further 
explain the nature of the study, its objectives, and potential risks and benefits, as well as the date 
informed consent is given. The informed consent form will detail the requirements of the subject 
and the fact that he or she is free to withdraw at any time without giving a reason and without 
prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
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form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ballpoint ink in the case of written consent. The 
investigator must also sign and date the informed consent form and subject authorization (if 
applicable) at the time of consent or after the receipt of subject signature (in the case of consent) 
and prior to subject entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable.
Once signed, the original informed consent form or certified copy (if applicable), subject 
authorization form (if applicable), and subject information sheet (if applicable) will be maintained 
by the study site. The investigator must document the date the subject signs the informed consent 
in the subject’s medical record. Copies of the signed informed consent form, the signed subject 
authorization form (if applicable), and subject information sheet (if applicable) shall be provided 
to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials, may be used to verify the subject and accuracy of the subject’s unique 
identification number.
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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 9.1.1).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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16.0
REFERENCES
Bretillon, L., Lutjohann, D., Stahle, L., Widhe, T., Bindl, L., Eggertsen, G., et al. 2000. Plasma 
levels of 24S-hydroxycholesterol reflect the balance between cerebral production and 
hepatic metabolism and are inversely related to body surface. J Lipid Res, 41(5), 840-5.
Cartagena, C. M., Ahmed, F., Burns, M. P., Pajoohesh-Ganji, A., Pak, D. T., Faden, A. I., et al. 
2008. Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. 
J Neurotrauma, 25(9), 1087-98.
Downs, J., Jacoby, P., Leonard, H., Epstein, A., Murphy, N., Davis, E., et al. 2019. Psychometric 
properties of the Quality of Life Inventory-Disability (QI-Disability) measure. Qual Life 
Res, 28(3), 783-94.
Lutjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Siden, A., Diczfalusy, U., et al. 1996. 
Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 
24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A,
93(18), 9799-804.
Nishi, T., Kondo, S., Miyamoto, M., Watanabe, S., Hasegawa, S., Kondo, S., et al. 2020. 
Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for 
neural hyperexcitation in mice. Sci Rep, 10(1), 17081.
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., et al. 2011. 
The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. Am J Psychiatry,
168(12), 1266-77.
Tian, G., Kong, Q., Lai, L., Ray-Chaudhury, A. and Lin, C. G. 2010. Increased expression of 
cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 
association with lipid rafts: a potential role in Alzheimer's disease. J Neurochem, 113(4), 
978-89.
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Appendix A
Schedule of Study Procedures
Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
Informed consent and assent (if 
applicable)
X
Historical seizure calendar 
review
X
Inclusion/exclusion criteria
X
X
Randomization
X
Demographics, medical history, 
medication history
X
Seizure identification and 
diagnostic review form (TESC)
X
Height, weight
X
Weight 
only
X
Serum/urine pregnancy test m
X
X
X
Vital signs
X
X
X
X
Physical examination
X
X
X
X
Neurological examination
X
X
X
X
Ophthalmological examination n
X
X n
12-lead ECG j
X
X
X
X
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Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
Clinical laboratory tests 
(chemistry, hematology, and 
urinalysis)
X
X
X
X
Hepatitis B virus surface antigen
Hepatitis B core antibody 
Hepatitis C virus antibody
X
Concomitant medications review
o
X
X
X
X
X
X
X
X
X
X
X
X
Prior ASM review
X
X
Concomitant ASM and rescue 
medications
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS p
X
X
X
X
Electronic daily seizure and 
medication diary review 
X
X
X
X
X
X
X
X
X
X
X
X
CGI-I (clinician)
X
X
X
Care GI-I
X
X
X
CGI-I Nonseizure Symptoms
X
X
X
CGI-I Seizure Intensity and 
Duration
X
X
X
QI-Disability
X
X
X
EQ-5D-5L quality of life scale
X
X
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Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
Plasma sample for soticlestat 
(and metabolite[s]) PK q
X
X
X
Plasma sample for PD (plasma 
24HC) q
X
X
X
Plasma sample for ASM analysis 
r
X
X
X
Contact IWRS to obtain subject 
ID/medication
ID/subject status s
X
X
X
X
Dispense study drug
X
X
X k
At-home administration of first 
dose of study drug (Dose 1) in 
the morning (continue Dose 1 
through morning dose of Day 8)
X
At-home dose adjustment to 
Dose 2 (continue Dose 2 through 
morning dose of Day 15)
X t
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Study Procedure
Screening/
Baseline 
Period
Double-Blind Treatment Period
Follow-
up 
Period
Ran-do
m-izatio
n
Start 
Dose 1
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 2
Safety 
Check
Dose 
Ti-trati
on
Start 
Dose 3
Safety 
Check
Visit Number (Type) a
V1
(CV)
V2 b
(CV)
NA c
V3 d
(SCP)
V4 c,e
(VV)
NAc
V5 d
(SCP)
V6 c,e
(VV)
NAc
V7 d
(SCP)
V8 f
(VV)
V9 f
(CV)
V10 f
(VV)
V11 f
(CV)
V12
(VV or 
CV)
Study Day
Days -42 
to -1
Day 0
Day 1
Day 3 
Day 8
Day 8 
Day 10 Day 15
Day 15
Day 17 Day 29
Day 57
Day 85
Day 
113/ET
g,h,j,k
Day 134
Follow-
up l
Visit Window (days)
±2
±2
±7
±7
±7
±7
-7
At-home dose adjustment to 
Dose 3 (all subjects continue 
Dose 3 through morning dose of 
V11/ET; subjects rolling over to 
OLE study on same day also take 
Dose 3 in the evening of that 
day)
X u
Optional in-clinic administration 
of study drug 
X
X
Study drug return
X
X
Study drug accountability/
compliance
X
X
X
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
24HC: 24S-hydroxycholesterol; AE: adverse event; ASM: antiseizure medication; Care GI-I: Caregiver Global Impression of Improvement; CGI-I: Clinical Global Impression of 
Improvement; COVID-19: coronavirus disease 2019; C-SSRS: Columbia-Suicide Severity Rating Scale; CV: clinical visit; ECG: electrocardiogram; ET: early termination; 
EQ-5D-5L: EQ-5D 5-Level version; hCG: human chorionic gonadotropin; ID: identification; IWRS: interactive web response system; OLE: open-label extension; PD: 
pharmacodynamic; PK: pharmacokinetic; QI-Disability: Quality of Life Inventory-Disability; SCP: safety check phone call; TESC: The Epilepsy Study Consortium; V#: Visit 
number; VV: virtual visit. 
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a VVs are allowed if aligned with institutional or local guidelines, via phone or via any platforms approved by local regulations, in addition to the communication 
platform offered through the study. V1 (screening) and V11 (Day 113)/ET must be conducted in person; V9 (Day 57) is to be conducted in person if possible, but 
may be conducted virtually (via video or phone) in response to the COVID-19 pandemic and/or based on sponsor approval and if permitted by local regulations. In 
extenuating circumstances, V2 (Day 0/randomization) and V11 (Day 113)/ET can be virtual visits (only via video, not phone), with sponsor approval and if 
permitted by local regulations. In addition, any visit identified as VV in this table may be conducted in clinic and in person if requested by the subject/parent or 
guardian and/or at the investigator’s discretion.
b The minimum duration for screening is 28 days (ie, V2 [Day 0/randomization] cannot occur earlier than 29 days after V1 [screening]). All efforts shall be made to 
complete all procedures at randomization visit (V2 [Day 0/randomization]). If unable to complete, reason should be captured and subject can proceed to 
randomization if there are no clinically significant abnormalities in screening procedures and it is thought appropriate, in the investigator’s judgment. For female 
subjects of childbearing potential, pregnancy test at V2 (Day 0/randomization) is not required for eligibility if performed and confirmed negative at V1 (screening) 
and if the investigator does not deem it necessary to repeat pregnancy test at V2 (Day 0/randomization).
c Dose 1 is started the morning after V2 (Day 0/randomization) or the day after study medication is received. Dose 2 and Dose 3 are started the evening of dose 
titration (V4 [Day 8] and V6 [Day 15], respectively).
d Approximately 2 days after starting Dose 1 and after each dose escalation or taper and before the next visit, subjects will be contacted by phone to monitor study 
drug compliance, to assess the tolerability and safety of the study drug, and to monitor concomitant medication use and treatment-emergent AEs. These safety 
checks at V3 (Day 3), V5 (Day 10), and V7 (Day 17) are calculated as approximately 2 days after starting Dose 1, Dose 2, and Dose 3, respectively.
e Dates of V4 [Day 8] and V6 [Day 15] are calculated from the date of the first dose (Day 1) and the date of titration to Dose 2 (V6 [Day 15]), respectively.
f Dates calculated from V2 (Day 0/randomization).
g Subjects who do not continue into the OLE study will undergo the dose taper procedures and will then proceed to the follow-up period.
h Subjects who withdraw early from the study should complete all final visit procedures at V11 (Day 113)/ET.
(For legibility considerations, footnote i is not used.)
j A 12-lead ECG will be recorded at V1 (Day-42 to -1/screening), V2 (Day 0/randomization), V9 (Day 57), and V11 (Day 113)/ET and will be read locally. ECG at 
V1 needs to be recorded before randomization to evaluate subject’s eligibility.
k At V11 (Day 113)/ET, subjects who do not enroll in the OLE study will be dispensed study drug to taper down. Subjects who enroll in the OLE study should take 
their final dose of double-blind study drug in the evening of the day of V11 (Day 113)/ET.
l The timing of the follow-up phone call, follow-up period, or follow-up visit will depend on the dose taper procedures followed. Visit will be eliminated for subjects 
enrolled in OLE.
m For female subjects of childbearing potential, pregnancy test at V2 (Day 0/randomization) is not required for eligibility if performed and confirmed negative at V1 
(screening) and if the investigator does not deem it necessary to repeat pregnancy test at V2 (Day 0/randomization). A serum or urine hCG pregnancy test will also 
be performed at V11 (Day 113)/ET. Additional pregnancy tests (serum or urine) may be performed throughout the study at the investigator’s discretion.
n Ophthalmological examination at V11 (Day 113)/ET may be conducted within a 14-day window (-14 days) before V11 (Day 113)/ET.
o Subjects on concomitant perampanel will undergo additional safety monitoring as per Section 9.3.3.
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p Two versions of the C-SSRS will be used for all participants ages 6 through 55 years: the C-SSRS Children’s Screening/Baseline (recall period lifetime/12
months) and the C-SSRS Children’s Since-Last-Visit. Children who are <6 years old at the start of the study will have an unscheduled visit after turning age 6, at 
which the C-SSRS Children’s Screening/Baseline version will be completed. The C-SSRS Children’s Since-Last-Visit version will be completed at the end of the 
study.
q PK and PD blood samples for measurement of soticlestat and 24HC levels in plasma will be collected on V1 (screening), V9 (Day 57), and V11 (Day 113)/ET. In 
addition, alpha-1 acidic glycoprotein will be analyzed as part of serum chemistry panel at each visit where PK samples are drawn. An intravenous line may be 
inserted for collection of all blood samples during the visit. 
r Blood samples for measurement of ASM levels in plasma will be collected on V1 (screening), V9 (Day 57), and V11 (Day 113)/ET.
s If additional study drug needs to be dispensed, contact IWRS and enter as an unscheduled visit.
t Subject takes the last dose of Dose 1 on the morning of V4 (Day 8) and the first dose of Dose 2 in the evening.
u Subject takes the last dose of Dose 2 on the morning of V6 (Day 15) and the first dose of Dose 3 in the evening.
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Appendix B
Strong CYP3A Inducers 
Strong inducers of CYP3A are prohibited, except antiseizure medication. Examples of prohibited 
inducers are listed below. (Source: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-ta
ble-substrates-inhibitors-and-inducers, Table 3-3 [inducers], accessed 06 March 2022.)
Strong CYP3A Inducers (examples)
Apalutamide
Enzalutamide
Mitotane
Rifampin
St. John’s wort
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Appendix C
Virtual Visits and Trial Management During COVID-19 Pandemic and Other 
Extenuating Circumstances
The purpose of this section is to safeguard the safety of study subjects, ensure continuation of 
study conduct and uninterrupted maintenance of treatment, and preserve the integrity of the study, 
in case of a general public health crisis or pandemic, such as COVID-19, or other extenuating 
circumstances, such as war or natural disaster. This section addresses situations in which 
scheduled in-person clinic visits are not feasible due to local, regional, or national restrictions.
COVID-19 vaccination of subjects is allowed during the study.
The principal investigator holds the ultimate responsibility for the safety and well-being of study 
subjects and shall maintain compliance with the current local and health authority guidelines and 
recommendations pertaining to the pandemic. The study procedures outlined in this protocol may 
be modified subsequently according to any emerging or revised health authority guidelines during 
conduct of the trial due to the ongoing COVID-19 pandemic.
Due to the COVID-19 pandemic or other extenuating circumstances, such as war or natural 
disaster, study subjects may not be able to attend scheduled in-person clinic visits as per protocol. 
All investigational sites should follow local and country health and government authorities’ 
restrictions and recommendations on conduct of clinical trials during the event. Sites are 
encouraged to discuss subjects and their continued virtual participation with the medical monitor.
In the event an in-person visit is not possible for the planned clinic visits and in alignment with 
institutional or local guidelines, comfort level of site staff, and caregiver/family willingness to 
travel, virtual visits are allowed to monitor subject safety. Additional details around such virtual 
visits are provided in Appendix A.
The virtual visits identified in Appendix A, if aligned with institutional or local guidelines, to 
ensure a point of contact between subjects/parents/caregivers and site staff, can be conducted via 
phone or via any platforms approved by local regulations, besides the communication platform 
offered through the study. This flexibility of communication is not expected to negatively affect 
subject safety or study data integrity.
In addition, the virtual visits included in the study, if aligned with institutional or local guidelines, 
can be converted into clinic visits at the request of subjects or parents/caregivers or at 
investigators’ discretion to lessen the burden of the study and support investigators, subjects, and 
parents/caregivers, particularly during the COVID-19 pandemic or other extenuating 
circumstances such as war or natural disaster. This conversion is not expected to negatively affect 
subjects’ safety or study data integrity.
A decentralized clinical trial platform may be used to conduct the virtual visits, if permitted by 
local regulations. The site will ensure that any related subject data privacy aspects are 
appropriately managed and will obtain subjects’ consent for the use of the platform for virtual 
visits. 
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If necessary and in alignment with institutional or local guidelines and as allowed by local 
regulations, a virtual visit can be conducted as a phone visit instead. Likewise, if necessary, the site 
can use the site’s own platform or phone/tablet social media apps in place of virtual visits. 
In case subjects are not able to attend the planned clinic visits, Direct to Patient (DTP) study drug 
shipment may be considered using a specialized courier vendor, if in alignment with institutional 
or local guidelines and as allowed by local regulations. A process has been put in place to ensure 
shipment traceability, proper temperature control conditions, study drug return and accountability 
should be properly managed to ensure that any related subject data privacy aspects are 
appropriately covered. The investigator will obtain subject’s consent to DTP study drug shipment 
and the use of their personal data to that effect.
Any protocol deviations, missing visits, or missing assessments related to COVID-19 restrictions 
will be recorded and reported in the clinical study report.
In case of prolonged access restrictions to external visits (study monitors) to an investigative site 
due to COVID-19 pandemic and wherever possible by local regulations, remote Source Data 
Verification (rSDV) may be considered for critical data related to subject’s safety and any key 
variables to ensure data accuracy / integrity.
If rSDV is required, full details of the process will be included the Clinical Monitoring Plan 
following any applicable local guidance for secure access to remote source documents and data 
security provisions to protect personal data.
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Appendix D
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each consent form should contain a subject authorization 
section that describes the uses and disclosures of a subject’s personal information (including 
personal health information) that will take place in connection with the study. If a consent form 
does not include such a subject authorization, then the investigator must obtain a separate 
subject authorization form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix E
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written ICF, the subject or the subject’s 
legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative (parent or legal guardian) may discontinue participation at 
any time without penalty or loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative (parent or legal 
guardian) will be informed in a timely manner if information becomes available that may be 
relevant to the subject’s willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for subjects, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use effective or highly effective contraception (as defined in the 
informed consent) from screening throughout the duration of the study, and for 30 days 
following the last dose of study drug. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. If a subject is found to be pregnant 
during study, study drug will be discontinued, and the investigator will offer the subject the 
choice to receive unblinded treatment information.
26. Male partners of female subjects must use effective or highly effective contraception (as 
defined in the informed consent) if required as part of the method (eg, double-barrier, 
vasectomized partner) from signing the informed consent throughout the duration of the study, 
and for a minimum of 30 days following the last dose of study drug. If the partner or wife of the 
subject is found to be pregnant during the study, the investigator will offer the subject the 
choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix F
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix G
Blood Volumes
At any single visit, the amount of blood collected from subjects weighing >45 kg will be 
approximately 9 to 26 mL, as shown in the table. The total blood volume for the scheduled visits 
during the study (including screening and postrandomization treatment period) will be 
approximately 77 mL for subjects weighing >45 kg. Additional blood may be drawn for retests or 
unscheduled visits, if any, and will not exceed 26 mL per visit.
Subject 
Weight
Screening, 
Visit 1 a
Randomization, 
Day 0, 
Visit 2
Day 57, 
Visit 9 a
ET, Visit 11 
(Day 113) a
Total, 
Scheduled 
Visits
Unscheduled/ 
Retest b
10-15 kg
19.1
5.7
14.6
14.6
54.0
19.1
>15-45 kg
23.7
7.4
18.3
20.0
69.4
23.7
>45 kg
26.0
9.0
20.0
21.5
76.5
26.0
See the laboratory manual for details
ET = early termination.
a Blood volumes may vary slightly if performed by a local laboratory or by central antiseizure medication testing 
laboratory in China.
b Unscheduled retests are allowed at investigator discretion. Scheduled and unscheduled blood sample volumes must 
not exceed 3 mL/kg of body weight during any 8-week period or in any single day.
Weight is measured to 1 decimal place for determining dosing bands. Thus 44.9 kg would be in the 30 to <45 mg band.
These volumes represent the approximate maxima for visit and weight. These volumes do not 
exceed 3 mL/kg of body weight during any 8-week period or in any single day.
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Study No. TAK-935-3002
Page 107 of 108
Protocol Incorporating Global Amendment 2
22 April 2022
CONFIDENTIAL
Appendix H
Protocol History
Date
Amendment Number
Amendment Type
Region
22 April 2022
Amendment
Substantial
Global
03 November 2021
Amendment 1 FR-IT-RS v1
Substantial
France, Italy, Serbia
23 March 2021
Initial protocol
Not applicable
Global
Protocol Amendment 1 FR-IT-RS v1 Summary and Rationale
This section describes the changes in reference to the protocol incorporating Amendment 
FR-IT-RS v1. The primary reason for this amendment is to indicate approximate blood volumes 
during the study.
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 FR-IT-RS v1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Section 1.2 Approval
Changed personnel for signatures.
New assignments.
2
Section 2.0 STUDY 
SUMMARY, Study Design, 
Exploratory Objectives
Section 5.1.3 Exploratory 
Objectives
Section 6.2.2 Endpoints
Section 9.1.15.6 EQ-5D-5L 
Quality of Life Scale
Added language to note that the 
EuroQol 5 Dimension 5 Level 
quality of life scale measures the 
parent’s/caregiver’s quality of 
life.
Clarification.
3
Section 6.1.4 End-of-Study
Added definition of end-of-study.
Health authority request.
4
Section 9.1.11.3 Procedures for 
Clinical Laboratory Samples
Indicated the maximum volume 
of blood collected at any single 
visit and the total volume of blood 
collected in the study.
Health authority request.
5
Section 9.3.5.1 Collection of 
Plasma Samples for Soticlestat 
PK Evaluation
Section 9.3.5.2 Bioanalytical 
Methods for Soticlestat
Section 9.3.5.3 PK Parameters
Clarified that pharmacokinetic 
(PK) measurements include 
metabolite(s) of soticlestat.
Clarification.
6
Appendix B Strong CYP3A 
Inducers and CYP3A4 
Inhibitors 
Updated table with additional 
examples of CYP3A 
inducers/CYP3A4 inhibitors.
Correction to maintain 
consistency with protocols 
TAK-935-3001 and 
TAK-935-3003.
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Study No. TAK-935-3002
Page 108 of 108
Protocol Incorporating Global Amendment 2
22 April 2022
CONFIDENTIAL
Protocol Amendment FR-IT-RS v1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
7
Appendix C Trial Management 
During COVID-19 Pandemic
Revised language regarding 
conditions under which virtual 
visits are allowed.
Clarification.
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-935-3002 (SKYWAY) 
Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group 
Study to Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in 
Pediatric and Young Adult Subjects with Lennox-Gastaut Syndrome (LGS) 
Phase 3 
Version: Amendment 1 
Date: 05-MAR-2024 
Prepared by:  
, Ph.D. 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 22 April 2022 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
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Page 2 of 65
Statistical Analysis Plan Amendment 1 
5 Mar 2024
 
CONFIDENTIAL 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original 
29-Mar-22 
Not applicable 
Amendment 1 
8-Mar-2024 
Add updates aligned with protocol amendment 2, clarifications, and 
additional sensitivity and exploratory analyses 
 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................8 
1.1 
Objectives ......................................................................................................................8 
1.1.1 
Primary Objective ..................................................................................................8 
1.1.2 
Secondary Objectives ............................................................................................8 
1.1.3 
Additional Objectives ............................................................................................9 
1.1.3.1 
Exploratory Objectives..................................................................................9 
1.1.3.2 
Safety Objectives ..........................................................................................9 
1.2 
Endpoints .......................................................................................................................9 
1.2.1 
Primary Endpoints .................................................................................................9 
1.2.2 
Secondary Endpoints ...........................................................................................10 
1.2.3 
Exploratory Endpoints .........................................................................................10 
1.2.4 
Safety Endpoints ..................................................................................................11 
1.3 
Estimands .....................................................................................................................11 
1.3.1 
Primary Estimand ................................................................................................11 
1.3.2 
Secondary Estimands ...........................................................................................12 
2.0 
STUDY DESIGN...............................................................................................................14 
2.1 
Overall Study Design ...................................................................................................14 
2.2 
Dose Titration Period (4 Weeks) .................................................................................17 
2.3 
Maintenance Period (12 Weeks) ..................................................................................17 
2.4 
Study Discontinuation/Completion ..............................................................................18 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................18 
3.1 
Statistical Hypotheses ..................................................................................................18 
3.2 
Multiplicity Adjustment ...............................................................................................20 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................20 
5.0 
ANALYSIS SETS .............................................................................................................21 
5.1 
ITT Analysis Set ..........................................................................................................21 
5.2 
mITT Analysis Set .......................................................................................................21 
5.3 
Safety Analysis Set ......................................................................................................21 
5.4 
Pharmacokinetic (PK) Analysis Set .............................................................................21 
5.5 
Pharmacodynamic (PD) Analysis Set ..........................................................................21 
6.0 
STATISTICAL ANALYSIS .............................................................................................21 
6.1 
General Considerations ................................................................................................21 
6.1.1 
Handling of Treatment Misallocations ................................................................22 
6.2 
Disposition of Subjects ................................................................................................22 
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6.3 
Demographic and Other Baseline Characteristics .......................................................23 
6.3.1 
Demographics ......................................................................................................23 
6.3.2 
Baseline Characteristics .......................................................................................23 
6.3.3 
Medical History and Concurrent Medical Conditions .........................................23 
6.4 
Medication History and Concomitant Medications .....................................................24 
6.4.1 
Prior Medications ................................................................................................24 
6.4.2 
Concomitant Medications ....................................................................................24 
6.5 
Efficacy Analysis .........................................................................................................25 
6.5.1 
Primary Endpoint Analysis ..................................................................................25 
6.5.1.1 
Derivation of Endpoint ................................................................................25 
6.5.1.2 
Main Analytical Approach ..........................................................................27 
6.5.1.3 
Sensitivity Analysis .....................................................................................28 
6.5.1.4 
Supplementary Analyses .............................................................................32 
6.5.1.5 
Additional Analyses ....................................................................................32 
6.5.2 
Analysis of Secondary Endpoints Tested in the Gatekeeping Procedure ............32 
6.5.2.1 
Secondary Endpoint Analysis: Proportion of Responders ..........................32 
6.5.2.2 
Secondary Endpoint Analysis: Care GI-I ....................................................33 
6.5.2.3 
Secondary Endpoint Analysis: CGI-I..........................................................36 
6.5.2.4 
Secondary Endpoint Analysis: CGI-I Nonseizure Symptoms ....................37 
6.5.2.5 
Secondary Endpoint Analysis: Change in QI-Disability Score ..................37 
6.5.2.6 
Secondary Endpoint Analysis: CGI-I Seizure Intensity and Duration ........39 
6.5.3 
Other Secondary Endpoints Analysis ..................................................................40 
6.5.3.1 
Percent Change from Baseline in Frequency for all Seizures per 28 
Days ............................................................................................................40 
6.5.3.2 
Responder Analysis .....................................................................................40 
6.5.3.3 
Change from Baseline in Proportion of MMD Seizure-Free Days .............40 
6.5.3.4 
Longest MMD Seizure-free Interval ...........................................................40 
6.5.3.5 
Number of Days when Rescue ASM is Used ...............................................41 
6.5.4 
Exploratory Endpoints Analysis ..........................................................................41 
6.5.4.1 
Percent Change from Baseline in Frequency per 28 Days of Each 
Seizure Type Identified at the Time of Screening or Baseline ...................41 
6.5.4.2 
Change in EQ-5D-5L and Visual Analogue Scale (EQ-VAS) Scores ........42 
6.5.5 
Subgroup Analyses ..............................................................................................43 
6.5.6 
Additional Exploratory Analyses ........................................................................43 
6.6 
Safety Analysis ............................................................................................................44 
6.6.1 
Adverse Events ....................................................................................................44 
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6.6.2 
Adverse Events of Special Interest ......................................................................46 
6.6.3 
Other Safety Analysis ..........................................................................................46 
6.6.3.1 
Clinical Laboratory Evaluations .................................................................46 
6.6.3.2 
Vital Signs ...................................................................................................48 
6.6.3.3 
12-Lead ECG ..............................................................................................48 
6.6.3.4 
C-SSRS .......................................................................................................48 
6.6.3.5 
Ophthalmological Evaluations ....................................................................50 
6.6.3.6 
Physical Examination ..................................................................................51 
6.6.3.7 
New Seizure Types .....................................................................................51 
6.6.4 
Extent of Exposure and Compliance ...................................................................51 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................52 
6.7.1 
Pharmacokinetic Analysis ...................................................................................52 
6.7.1.1 
Plasma Concentrations of Soticlestat and the Soticlestat Metabolite(s) 
at Multiple Time Points ...............................................................................52 
6.7.1.2 
Population Soticlestat PK Modeling Based on Sparse PK .........................52 
6.7.2 
Pharmacodynamic Analysis ................................................................................52 
6.7.2.1 
Percent Change from Baseline in Plasma 24HC .........................................52 
6.7.2.2 
Soticlestat Exposure-PD (Plasma 24HC Level) and Efficacy Response 
Analysis. ......................................................................................................53 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................53 
6.8.1 
Health Care Utilization Analysis .........................................................................53 
6.9 
Interim Analysis ...........................................................................................................53 
6.10 
Data Monitoring Committee ........................................................................................53 
7.0 
REFERENCES ..................................................................................................................53 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................53 
9.0 
APPENDIX ........................................................................................................................54 
9.1 
Changes From the Previous Version of the SAP .........................................................54 
9.2 
Data Handling Conventions .........................................................................................60 
9.2.1 
General Data Reporting Conventions ..................................................................60 
9.2.2 
Definition of Baseline ..........................................................................................61 
9.2.3 
Rules to Select a Post-Baseline Record for Summary .........................................61 
9.2.4 
Handling of Seizure Diary Data ..........................................................................62 
9.3 
Analysis Software ........................................................................................................62 
9.4 
Seizure Classifications Collected in Daily Seizure Diary ............................................63 
9.5 
Health Outcome Scales ................................................................................................63 
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9.5.1 
QI-Disability Domains ........................................................................................63 
 
LIST OF IN-TEXT TABLES 
Table 1.a 
Attributes of the Primary Estimand .......................................................................11 
Table 1.b 
Attributes of Secondary Estimands ........................................................................12 
Table 2.a 
Dosing Schedules by Weight, 10 to <15 kg ...........................................................16 
Table 2.b 
Dosing Schedules by Weight, 15 to <30 kg ...........................................................16 
Table 2.c 
Dosing Schedules by Weight, 30 to <45 kg ...........................................................16 
Table 2.d 
Dosing Schedules by Weight, ≥45 kg .....................................................................17 
Table 3.a 
Statistical Hypotheses ............................................................................................18 
Table 6.a 
Analysis Windows for Care GI-I Summary...........................................................34 
Table 6.b 
Analysis Windows for QI-Disability .....................................................................39 
Table 6.c 
Analysis Windows for EQ-5D-5L .........................................................................42 
Table 6.d 
Analysis Windows for Laboratory Evaluations Summary ....................................47 
Table 6.e 
Severity Rank for C-SSRS Questions ....................................................................49 
Table 9.a 
Summary of changes in SAP .................................................................................54 
 LIST OF IN-TEXT FIGURES 
Figure 2.a 
Schematic of Study Design ....................................................................................15 
 
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CONFIDENTIAL 
ABBREVIATIONS 
24HC 
ADaM 
24S-hydroxycholesterol 
analysis data model 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
ASM 
BID 
antiseizure medication 
twice daily 
Care GI-I 
Caregiver Global Impression of Improvement 
CGI-I 
Clinical Global Impression of Improvement 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
coronavirus disease 2019  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
EQ-VAS 
Visual Analogue Scale 
GCP 
good clinical practice 
IEC 
institutional review board 
IRB 
independent ethics committee 
ITT 
intent-to-treat 
LLOQ 
lower limit of quantification 
LGS 
Lennox-Gastaut syndrome 
LOCF 
last observation carried forward 
MCAR 
missing completely at random 
MedDRA 
MMD 
Medical Dictionary for Regulatory Activities  
major motor drop 
mITT 
modified intent-to-treat 
MNAR 
OLE  
missing not at random 
open-label Extension 
QI-Disability 
Quality of Life Inventory-Disability 
PBO 
placebo 
PD 
pharmacodynamic 
PEG 
percutaneous endoscopic gastrostomy 
PK 
pharmacokinetic 
PT 
Preferred Term  
PTE 
pretreatment event 
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Statistical Analysis Plan Amendment 1 
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CONFIDENTIAL 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
study data tabulation model 
SF 
seizure frequency 
SOC 
standard of care 
SOC 
System Organ Class 
TEAE  
treatment-emergent adverse event 
ULOQ 
upper limit of quantification 
WHO 
World Health Organization 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
• To assess the efficacy of soticlestat in reducing major motor drop (MMD) seizure frequency 
as add-on therapy to standard of care (SOC) as compared with placebo during the full 
treatment period (titration + maintenance). 
For European Medicines Agency (EMA) registration: 
• To assess the efficacy of soticlestat in reducing MMD seizure frequency as add-on therapy to 
SOC compared with placebo during the maintenance period only. 
1.1.2 
Secondary Objectives 
To assess the following in subjects taking soticlestat as compared with placebo during the full 
treatment period, unless otherwise noted: 
• Proportion of treatment responders defined as those with ≥50% reduction in MMD seizures 
from baseline during the maintenance period and the full treatment period. 
• Effect on total seizure frequency of all seizure types during the maintenance period and the 
full treatment period. 
• Change from baseline in proportion of MMD seizure-free days. 
• Longest MMD seizure-free interval. 
• Number of days when rescue antiseizure medications (ASMs) are used. 
• Effect on the Clinical Global Impression of Improvement (CGI-I) (clinician) and Caregiver 
Global Impression of Improvement (Care GI-I). 
• Effect on CGI-I Seizure Intensity and Duration. 
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• Effect on the CGI-I Nonseizure Symptoms completed by clinician with input from the 
caregivers. 
• Effect on Quality of Life Inventory-Disability (QI-Disability). 
1.1.3 
Additional Objectives 
1.1.3.1 
Exploratory Objectives 
To assess the following in subjects receiving soticlestat as compared with placebo during the full 
treatment period: 
• Seizure frequency of each seizure type per 28 days. 
• Health care resource utilization including but not limited to emergency room visits and 
hospitalizations. 
• Population PK and correlation of the population PK exposure parameters with PD (plasma 
24HC levels) in subjects receiving soticlestat. 
• Correlation of change in PD (24HC) exposure and efficacy (change in MMD seizure over the 
full treatment period). 
• Effect on EQ-5D 5-Level version (EQ-5D-5L) quality of life scale for parents’/caregivers’ 
quality of life. 
1.1.3.2 
Safety Objectives 
• To assess the incidence of TEAEs. 
• To assess the incidence of abnormal clinical laboratory values and electrocardiogram 
(ECG) evaluations. 
• To assess change from baseline in clinical laboratory values, vital signs, ECG parameters, 
and Columbia-Suicide Severity Rating Scale (C-SSRS) responses. 
• To assess the incidence of new seizure types arising during soticlestat treatment that are not 
identified at the time of screening (by history) or during prospective baseline. 
1.2 
Endpoints 
1.2.1 
Primary Endpoints 
• Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving 
soticlestat as compared with placebo during the full treatment period.  
For EMA registration: 
• Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving 
soticlestat as compared with placebo during the maintenance period. 
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1.2.2 
Secondary Endpoints 
To assess the following in subjects receiving soticlestat as compared with placebo during the full 
treatment period, unless otherwise noted: 
• Proportion of responders defined as those with ≥50% reduction from baseline in MMD 
seizures during the maintenance period and the full treatment period. 
• Responder analysis of the proportion of subjects with ≤0%, >0% to ≤25%, >25% to 
≤50%, >50% to ≤75%, and >75% to ≤100% reduction from baseline in MMD seizures in a 
cumulative response curve. 
• Care GI-I (caregiver). 
• CGI-I (clinician).  
• CGI-I Nonseizure Symptoms. 
• Change in QI-Disability score. 
• CGI-I Seizure Intensity and Duration. 
• Percent change from baseline in frequency of all seizures per 28 days during the 
maintenance period and the full treatment period. 
• Percent change from baseline in MMD seizure frequency per 28 days during the 
maintenance period. 
• Change from baseline in proportion of MMD seizure-free days. 
• Longest MMD seizure-free interval. 
• Number of days when rescue ASM is used. 
1.2.3 
Exploratory Endpoints 
To assess the following in subjects receiving soticlestat as compared with placebo during the full 
treatment period: 
• Percent change from baseline in frequency per 28 days of each seizure type identified at the 
time of screening or baseline. 
• Health care resource utilization including but not limited to emergency room visits and 
hospitalizations. 
• Soticlestat exposure-PD (plasma 24HC level) and efficacy response analysis. 
• Percent change from baseline in plasma 24HC. 
• Plasma concentrations of soticlestat and the soticlestat metabolite(s) at multiple time points. 
• Population soticlestat PK modeling based on sparse PK. 
• Change in EQ-5D-5L and EQ-5D visual analogue scale (EQ VAS) scores. 
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• 4- to 6-week screening/baseline period. The minimum duration for screening is 28 days (ie, 
Visit 2/Day 0 cannot occur earlier than 29 days after screening). 
• 16-week treatment period. 
4-week titration period. 
12-week maintenance period. 
• 1-week taper period for those discontinuing study drug, followed by a 2-week safety follow-
up visit or phone call. 
This is a 2-arm study. All subjects will be randomized at a 1:1 ratio to receive SOC plus 1 of the 
following adjunctive therapies: soticlestat or placebo. 
Soticlestat or matching placebo added to current antiseizure therapy, will be administered orally 
BID with or without food or via gastrostomy tube (G-tube) or low-profile gastric tube (MIC-KEY 
button). A jejunostomy tube (J-tube) may be considered following approval by the medical 
monitor or sponsor. Note: Study drug will be administered only orally for subjects enrolled in 
sites in jurisdictions where alternative means are not permitted. 
A schematic of the study design is shown in Figure 2.a. A schedule of assessments is listed in 
protocol Appendix A. 
Figure 2.a 
Schematic of Study Design 
 
BID: twice daily; OLE: open-label extension. 
All doses will be blinded and will undergo the same titration scheme, with the same number and 
type of tablets (mini-tablets or tablets). Subjects randomized to placebo will undergo a mock 
titration to ensure the blind is maintained (see tables below). 
The total daily dose of study drug (either placebo or soticlestat) will be calculated based on body 
weight at Visit 1 (screening visit) and given BID starting on the morning after Visit 2/Day 0 (ie, 
on study Day 2) or on the day after receiving study medication. The dosing schedules by weight 
are show in Table 2.a through Table 2.d.. (see tables below). The minimum dose allowed during 
the study is 100 mg BID (weight-based dosing <45 kg.) Subjects who cannot tolerate the 
minimal dose will be discontinued from the study. Subjects weighing <45 kg will be dispensed 20 
mg mini-tablets or matching placebo. Subjects weighing ≥45 kg may be dispensed 20 mg mini-
tablets or 100 mg tablets, or matching placebo. 
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Table 2.a 
Dosing Schedules by Weight, 10 to <15 kg 
Treatment 
Arm 
10 to <15 kg Weight Reference Dose 
Dose 1 (Days 1-7): 
Adult Reference  
100 mg BID 
Dose 2 (Days 8-14): 
Adult Reference  
200 mg BID 
Dose 3 (Days 15-28): 
Adult Reference  
300 mg BID 
(mg/dose) 
No. Tablets/  
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
Soticlestat 
40 mg 
BID 
2 mini tabs soticlestat 
BID 
60 mg 
BID 
3 mini tabs 
soticlestat BID 
100 mg 
BID 
5 mini tabs 
soticlestat 
BID 
PBO 
--- 
2 mini tabs PBO BID 
--- 
3 mini tabs PBO 
BID 
--- 
5 mini tabs 
PBO BID 
BID: twice daily; No.: number; PBO: placebo. 
 
Table 2.b 
Dosing Schedules by Weight, 15 to <30 kg 
Treatment Arm 
15 to <30 kg Weight Reference Dose 
Dose 1 (Days 1-7): 
Adult Reference  
100 mg BID 
Dose 2 (Days 8-14): 
Adult Reference  
200 mg BID 
Dose 3 (Days 15-28): 
Adult Reference  
300 mg BID 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini- tablets 
Soticlestat 
60 mg BID 
3 mini tabs 
soticlestat 
BID 
120 mg 
BID 
6 mini tabs 
soticlestat BID 
200 mg 
BID 
10 mini tabs 
soticlestat BID 
PBO 
--- 
3 mini tabs 
PBO BID 
--- 
6 mini tabs PBO 
BID 
--- 
10 mini tabs 
PBO BID 
BID: twice daily; No.: number; PBO: placebo. 
 
Table 2.c 
Dosing Schedules by Weight, 30 to <45 kg 
Treatment Arm 
30 to <45 kg Weight Reference Dose 
Dose 1 (Days 1-7): 
Adult Reference  
100 mg BID 
Dose 2 (Days 8-14): 
Adult Reference  
200 mg BID 
Dose 3 (Days 15-28): 
Adult Reference  
300 mg BID 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini- tablets 
Soticlestat 
80 mg BID 
4 mini tabs 
soticlestat 
BID 
140 mg 
BID 
7 mini tabs 
soticlestat BID 
200 mg 
BID 
10 mini tabs 
soticlestat BID 
PBO 
--- 
4 mini tabs 
PBO BID 
--- 
7 mini tabs PBO 
BID 
--- 
10 mini tabs 
PBO BID 
BID: twice daily; No.: number; PBO: placebo. 
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Table 2.d 
Dosing Schedules by Weight, ≥45 kg 
Treatment Arm 
≥45 kg Weight Reference Dose 
Dose 1 (Days 1-7): 
Adult Reference  
100 mg BID 
Dose 2 (Days 8-14): 
Adult Reference  
200 mg BID 
Dose 3 (Days 15-28): 
Adult Reference  
300 mg BID 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini-tablets 
(mg/dose) 
No. Tablets/ 
Mini- tablets 
Soticlestat 
100 mg 
BID 
1 tab 
soticlestat BID  
OR 
5 mini tabs 
soticlestat BID 
200 mg 
BID 
2 tabs 
soticlestat BID 
OR 
10 mini tabs 
soticlestat BID 
300 mg 
BID 
3 tabs 
soticlestat BID 
OR 
15 mini tabs 
soticlestat BID 
PBO 
--- 
1 tab PBO BID  
OR 
5 mini tabs 
PBO BID 
--- 
2 tabs PBO BID  
OR 
10 mini tabs 
PBO BID 
--- 
3 tabs PBO 
BID 
OR 
15 mini tabs 
PBO BID 
BID: twice daily; No.: number; PBO: placebo. 
2.2 
Dose Titration Period (4 Weeks) 
Subjects will take the first dose of study drug (Dose 1) the day after the study medication is 
received. Approximately 7 days after initiating study medication, if there are no tolerability 
issues, study drug dose will be increased to Dose 2. After approximately 7 days on Dose 2, if 
there are no tolerability issues, study drug dose will be increased to Dose 3. If the subjects do 
not experience any tolerability issues, they will continue on Dose 3 for the remainder of the 
titration period. Subjects will only be allowed to increase their dose within the 4-week titration 
period before entering the 12-week maintenance period. Decrease in dose level is allowed 
during the titration period if required for safety and tolerability. Subjects who cannot tolerate 
the minimum dose of 100 mg BID (or weight-based equivalent dosing <45 kg) will be 
discontinued from treatment. The maximum allowed dose is 300 mg BID. The subjects/parents or 
caregivers will be contacted by phone within the first 2 days following each dose escalation to 
assess safety and tolerability of the study drug. The final dose tolerated by the end of the 4-week 
titration period should be maintained until the end of the maintenance period, unless tolerability 
issues arise. 
2.3 
Maintenance Period (12 Weeks) 
The dose level at the end of the titration period will be maintained until the end of the 
maintenance period (dose increases are not permitted); however, during the maintenance 
period, the dose may be decreased by 1 dose level to the previous lower dose, for safety and 
tolerability issues. For example, Dose 3 may be reduced to Dose 2, and Dose 2 may be reduced 
to Dose 1. The minimum dose is Dose 1 (100 mg BID adult reference dose; or weight-based 
equivalent dosing for <45 kg); subjects who cannot tolerate the minimum dose of 100 mg BID 
will be discontinued from treatment. Dose changes during the maintenance period are allowed 
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for safety or tolerability reasons as assessed by the investigator; however, if possible, dose 
changes will need to be discussed with the medical monitor and/or the sponsor. 
2.4 
Study Discontinuation/Completion 
At Visit 11/early termination, subjects will have the option to enroll in the OLE study as per that 
study’s inclusion/exclusion criteria.  
Subjects who enroll in the OLE study on the same day as Visit 11/early termination will take 
their final dose of double-blind study drug in the evening of the day of Visit 11/early termination 
and should continue to record seizures in the seizure diary until midnight of the day of Visit 
11/early termination, at which time they will exit the study.  
Subjects who do not roll over to the OLE study on the same day as Visit 11/early termination will 
take their final dose of double-blind study drug in the morning of Visit 11/early termination, 
followed by a taper period. The study drug dose will be tapered down to a lower dose (taper 
Dose 3 to Dose 2, taper Dose 2 to Dose 1) approximately every 3 days until the study drug dose 
is discontinued. The subject/parent or caregiver should continue to record seizures in the seizure 
diary until the safety follow-up phone call, which will occur approximately 14 days after the last 
dose of study drug. After completion of the safety follow-up phone call, the subject will exit the 
study. 
Subjects/parents or caregivers who choose to enroll in the OLE study after Visit 11/early 
termination will continue the taper procedure until the investigator confirms eligibility for the 
OLE study; the subject will then exit the study and roll over to the OLE study. 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES   
3.1 
Statistical Hypotheses 
The study objectives that will be subjected to statistical hypothesis testing are listed below, along 
with corresponding statistical null hypotheses and statistical criteria for a positive outcome for 
each objective. A gatekeeping procedure will be used to test the hypotheses in the order listed 
below. Thus a positive outcome for a hypothesis is contingent on positive outcomes for the 
preceding hypotheses. 
Table 3.a 
Statistical Hypotheses 
Study objective 
Statistical null hypothesis 
Criteria for positive outcome 
Primary: 
To assess the efficacy of soticlestat 
in reducing MMD seizure frequency 
as add-on therapy to standard of 
care (SOC) as compared with 
placebo during the full treatment 
period (titration + maintenance). 
For EMA registration: 
The distribution of percent change 
from baseline in MMD seizure 
frequency per 28 days during the 
Full Treatment Period 
(Maintenance Period for EMA 
registration) is equal between the 
soticlestat and placebo treatment 
populations conditional on age 
stratum (≤6 years, >6 years). 
Statistically significant result from 
the test of no treatment effect based 
on the primary rank ANCOVA 
model including treatment group 
and age stratum as factors, and rank 
of baseline seizure frequency per 28 
days as a covariate. 
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Table 3.a 
Statistical Hypotheses 
Study objective 
Statistical null hypothesis 
Criteria for positive outcome 
To assess the efficacy of soticlestat 
in reducing MMD seizure frequency 
as add-on therapy to SOC 
compared with placebo during the 
maintenance period only. 
Secondary #1: 
Proportion of treatment responders 
defined as those with ≥50% 
reduction in MMD seizures from 
baseline during the full treatment 
period. 
For EMA registration: 
Proportion of treatment responders 
defined as those with ≥50% 
reduction in MMD seizures from 
baseline during the maintenance 
period. 
The odds of treatment response are 
equal between the soticlestat and 
placebo treatment populations 
conditional on age stratum. 
Statistically significant result from 
the test of no treatment effect based 
on the Cochran-Mantel-Haenszel 
test stratified by age stratum. 
Secondary #2 
Effect on the Caregiver Global 
Impression of Improvement (Care 
GI-I). 
The cumulative odds of a response 
in each Care CG-I ordinal response 
category at the end of the Full 
Treatment Period is equal between 
the soticlestat and placebo 
treatment populations conditional 
on age stratum. 
Statistically significant result from 
the test of no treatment effect based 
on a cumulative logit model with 
treatment group and age stratum as 
factors. 
Secondary #3 
Effect on the Clinical Global 
Impression of Improvement (CGI-I) 
(clinician). 
The cumulative odds of a response 
in each CCG-I ordinal response 
category at the end of the Full 
Treatment Period is equal between 
the soticlestat and placebo 
treatment populations conditional 
on age stratum 
Statistically significant result from 
the test of no treatment effect based 
on a cumulative logit model with 
treatment group and age stratum as 
factors. 
Secondary #4 
Effect on the CGI-I Nonseizure 
Symptoms completed by clinician 
with input from the caregiver. 
The cumulative odds of a response 
in each CGI-I Nonseizure 
Symptoms ordinal response 
category in the Alertness domain, 
Communication domain, and the 
Disruptive Behaviors domain at the 
end of the Full Treatment Period is 
equal between the soticlestat and 
placebo treatment populations 
conditional on age stratum. 
Statistically significant results from 
the tests of no treatment effect in all 
three domains based on a separate 
cumulative logit model for each 
domain with treatment group and 
age stratum as factors. Testing 
(sequential) order will be as 
follows: alertness, communication, 
and disruptive behaviors. Statistical 
significance of individual domains 
within the hierarchy can be asserted 
with global type 1 error control 
provided all preceding tests are 
significant, but statistical 
significance of the full endpoint 
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Table 3.a 
Statistical Hypotheses 
Study objective 
Statistical null hypothesis 
Criteria for positive outcome 
consisting of all 3 domains of CGI-I 
Nonseizure Symptoms, can only be 
asserted if all 3 domains are 
statistically significant. 
Secondary #5 
Effect on Quality of Life Inventory-
Disability (QI-Disability). 
The change from baseline in QI-
Disability total score at the end of 
the Full Treatment Period is equal 
between the soticlestat and placebo 
treatment populations conditional 
on age stratum. 
Statistically significant result from 
the test of no treatment effect at the 
end of treatment visit based on an 
MMRM model with treatment 
group, visit, age stratum, and 
treatment by visit interaction as 
fixed effects. 
Secondary #6 
Effect on CGI-I Seizure Intensity 
and Duration. 
The cumulative odds of a response 
in each CGI-I Seizure Intensity and 
Duration ordinal response category 
at the end of the Full Treatment 
Period is equal between the 
soticlestat and placebo treatment 
populations conditional on age 
stratum. 
Statistically significant result from 
the test of no treatment effect based 
on a cumulative logit model with 
treatment group and age stratum as 
factors. 
3.2 
Multiplicity Adjustment 
The global type 1 error will be controlled at 2-sided 5% level using a hierarchical gatekeeping 
procedure on the primary and the secondary endpoints mentioned in Sections 1.3.2 and 3.1. 
Hypotheses will be tested in the order described in Section 3.1. The gatekeeping procedure only 
requires testing hypotheses for the corresponding regulatory agencies. For example, the 
gatekeeping procedure does not require testing EMA registration hypotheses for other regulatory 
agencies.  
4.0 
SAMPLE-SIZE DETERMINATION 
The study will randomize a total of approximately 234 subjects at a 1:1 ratio to receive 1 dose 
level of soticlestat or placebo, resulting in approximately 117 subjects per arm.  
The primary endpoint for this study is the percent change from baseline in MMD seizure 
frequency per 28 days. The definition for MMD is different for this study than for ELEKTRA, 
however, the variability of this endpoint is assumed to be the same. This leads to an assumption 
that the pooled SD of the percent change from baseline in MMD seizure frequency is 65%.  
A difference of 26.5% in mean percent reduction in MMD seizure frequency between treatments 
is an appropriate target. A sample size of 117 subjects per treatment arm will provide at least 
85% power at a two-tailed 5% significance level to detect a difference of 26.5% in mean percent 
reduction in seizure frequency between treatments using the Wilcoxon rank-sum test, assuming 
the pooled SD above of 65%. 
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5.0 
ANALYSIS SETS 
5.1 
ITT Analysis Set 
All randomized subjects will be included in the intent-to-treat (ITT) analysis set. 
5.2 
mITT Analysis Set 
All randomized subjects who have received at least 1 dose of study drug and have been assessed 
for seizures for at least 1 day in the treatment period will be included in the modified ITT 
(mITT) analysis set.  
The mITT analysis set will be used for all efficacy analyses. 
5.3 
Safety Analysis Set 
All subjects who take at least 1 dose of study drug will be included in the safety analysis set. 
5.4 
Pharmacokinetic (PK) Analysis Set  
All subjects in the safety analysis set who have at least one measurable soticlestat or metabolite 
plasma concentration will be included in the PK analysis set. 
5.5 
Pharmacodynamic (PD) Analysis Set 
All subjects in the safety analysis set who have at least one measurable plasma 24HC 
concentration will be included in the PD analysis set. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
All hypothesis tests and confidence intervals (CIs) will be 2-sided. A significance level of 0.05 
will be used for all statistical testing, unless otherwise stated. All p-values reported will be 2-
tailed and rounded to 3 decimal places prior to assessment of statistical significance.  
Where applicable, variables will be summarized descriptively by study visit. 
For categorical variables, the count (n) and percent (%) will be displayed. Unless otherwise 
stated, the denominator for percentages is the number of subjects in the treatment group within 
that analysis set. For any summary by subgroups (e.g. by sex), the denominator is the number of 
subjects in that subgroup/treatment group within that analysis set. Generally, “Missing” will be 
displayed as a category to represent missing data, where applicable. If missing is not a category, 
then the denominator is the number of subjects with non-missing values. 
For continuous variables, the number of subjects with non-missing values, mean, median, SD, 
minimum, and maximum values will be tabulated. 
Descriptive summaries for efficacy, PK, and PD endpoints will be provided by treatment group 
unless indicated otherwise. Descriptive summaries for safety endpoints will be provided by 
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treatment group and overall unless indicated otherwise. Descriptive summaries of demographic 
characteristics, baseline characteristics, medical history and concurrent medical conditions, 
concomitant medications, ASMs, and concomitant rescue medications will be based on the safety 
analysis set. The mITT analysis set may also be used if it differs from the safety analysis set. 
Generally, the ITT analysis set will be used for listings unless indicated otherwise.   
All log transformations will be based on natural logarithms. 
If a subject is assigned to the wrong age stratum during randomization, the actual age, collected 
as a part of demographic information, will be used to identify the correct age stratum (≤6 or >6 
years) for all summaries and analyses that reference age stratum. 
6.1.1 
Handling of Treatment Misallocations 
If a subject is randomized but takes incorrect treatment, the planned randomized treatment 
assignment will be used in analyses that are based on the ITT or mITT analysis sets, but the 
actual treatment the subject received will be used in analyses that are based on the safety, PK, or 
PD analysis sets. 
6.2 
Disposition of Subjects 
Disposition of all randomized subjects will be tabulated: 
• Subjects randomized  
• Subjects randomized but not treated 
• Subjects received at least one dose of study drug (denominator) 
• Subjects who completed V11 
• Subjects who did not roll over to the OLE study 
• Subjects who rolled over to the OLE study 
• Subjects who prematurely discontinued the study drug 
• Subjects who prematurely discontinued study 
Primary reasons for discontinuation of study drug or study will be tabulated. 
Summaries will be presented by treatment groups (placebo and soticlestat) and overall. 
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be listed. If known, a reason for their discontinuation will be listed. 
A separate summary of disposition may be presented for patients whose participation of the trial 
is affected by COVID-19 in anyway (visit schedule, discontinuation, etc.).  
Significant protocol deviations will be summarized by site and treatment group and overall based 
on the ITT analysis set, and all protocol deviations will be listed. A separate listing will be 
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created for protocol deviations due to COVID-19 and a listing of visits affected by COVID-19 
will be presented. 
Screen failure subjects will be summarized descriptively. Primary reasons for failure will be 
summarized and will be presented in a data listing.  
A summary table for all analysis sets will be created. Patients excluded from an analysis set will 
be listed. 
A table will be created summarizing the number of subjects randomized to each country and site. 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
Demographic characteristics will be summarized and listed. Variables to be presented include 
age, stratification age category, sex, ethnicity, and race. 
6.3.2 
Baseline Characteristics 
Baseline characteristics including disease characteristics and interventions related to DS will be 
summarized and listed. Variables to be presented include: 
• Weight, height, body mass index (BMI) 
• Years since diagnosis 
• Number of ASMs: categorized as 0, 1, 2, 3 etc. 
• MMD seizure frequency during Baseline Period 
• All seizure frequency during Baseline Period 
• Ketogenic/ modified Atkins Diet 
• Vagus nerve stimulation 
6.3.3 
Medical History and Concurrent Medical Conditions 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
protocol Section 9.1.13).  
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 judgement of 
the investigator. The condition (ie, diagnosis) should be described and recorded in the eCRF. 
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 24.0 or higher) and will be summarized by 
treatment group and overall using System Organ Class (SOC) and MedDRA preferred term. The 
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actual version of the MedDRA coding dictionary will be noted in the clinical study report. The 
table will include number and percentages of subjects. SOCs will be sorted using alphabetical 
order, while preferred terms will be sorted in decreasing frequency based on the total number of 
subjects. A subject will only be counted once within a particular class even if he/she has multiple 
conditions/symptoms. 
Medical history and concurrent medical conditions will be summarized and listed. 
6.4 
Medication History and Concomitant Medications  
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 6 months before signing of informed 
consent. 
All ASMs stopped prior to signing of informed consent should be recorded. 
6.4.1 
Prior Medications 
Any medication stopped prior to first dose of study drug will be considered prior medication. 
Prior medication will not be summarized but will be listed with concomitant medications and be 
identified as “prior” in the listing. 
6.4.2 
Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject/parent or caregiver over the counter. 
Concomitant medication is not provided by the sponsor. At each study visit, the subject/parent or 
caregiver will be asked whether they have taken any medication other than the study drug (used 
from signing of informed consent through the end of the study), and all medications including 
vitamin supplements, over-the-counter medications, and oral herbal preparations must be 
recorded in the eCRF. Documentation will include generic or trade medication name, dose, unit, 
frequency, route of administration, start and end dates, and reason for use.  
ASMs treatments, artisanal cannabidiol use, VNS settings, and ketogenic diet should not be 
altered during the study. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. A by-subject listing of concomitant medications will include all medications 
(including vaccinations) taken during the study regardless of the timing for the start of the 
medication. Only the concomitant medication use will be summarized. 
The number and percentage of subjects who took at least 1 medication during the double-blind 
period as well as the number and percentage of subjects who took each type of medication will 
be presented for each treatment group. Medications will be listed according to their WHO Drug 
Dictionary Anatomic Therapeutic Chemical (ATC) class level 4 and preferred drug name within 
ATC class level 4 by decreasing frequency of incidence for all active treatment groups combined.  
The list of excluded medications and procedures is provided in protocol Appendix B. 
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Concomitant medications, concomitant ASMs, and concomitant rescue medications will be 
summarized. The number and percentage of patients receiving each ASM concomitantly, and 
each rescue medication concomitantly will be presented as well as the number and percentage of 
patients with at least 1 concomitant ASM and concomitant rescue medication. ASM listing will 
also be presented. Summaries and analyses will be based on the data available in electronic data 
capture (EDC). 
Missing or partial dates will not be imputed. Conservatively, a medication or procedure will be 
classified as concomitant if the available information about the end date is insufficient to 
determine whether it was stopped before first dose of study drug. 
6.5 
Efficacy Analysis 
The mITT analysis set will be used for all efficacy analyses. 
6.5.1 
Primary Endpoint Analysis 
6.5.1.1 
Derivation of Endpoint 
The primary endpoint is: 
• Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving 
soticlestat as compared with placebo during the full treatment period. 
For EMA registration: 
• Percent change from baseline in MMD seizure frequency per 28 days in subjects receiving 
soticlestat as compared with placebo during the maintenance period. 
Seizure frequency (SF) per 28 days during a given period is calculated using only available data 
during the period as follows: 
SF per 28 days =
Number of seizures during period
Number of non-missing seizure diary days in period × 28 
Percent change from baseline in seizure frequency per 28 days during a period is defined as 
(SF per 28 days during period) −(SF per 28 days during Baseline Period)
SF per 28 days during Baseline Period
× 100 
For calculation of seizure frequency per 28 days, time periods are defined as follows. These 
periods are only defined for subjects who took at least one dose of study drug. 
The Baseline Period for the purpose of change from baseline analysis of seizure frequencies 
includes the first day of screening (V1) and all days up to and including the day before first dose 
of study drug. 
The Full Treatment Period includes the day of first dose of study drug and all days up to and 
including the day before visit V11 for subjects who completed that visit. If that visit did not 
occur, the Full Treatment Period will include all days up to and including the day before the last 
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study visit or the day of first dose of study drug + 111 days, whichever is earlier. By this 
definition, the Full Treatment Period may include dose tapering and follow-up days for subjects 
who prematurely discontinue from the study. 
The Maintenance Period starts 28 days after the first dose of study drug and includes all days 
up to and including the last day of the Full Treatment Period. Subjects who discontinue study 
drug or initiate tapering due to discontinuation during the first 28 days beginning with the day of 
first dose of study drug do not have a Maintenance Period. 
Seizure frequency will be collected via an electronic daily seizure and medication diary. The 
electronic diary will allow a 7-day window for data entry/correction by the subject/parent or 
caregiver. 
The electronic daily seizure and medication diary is an observer-reported clinical outcome 
assessment measure that captures seizures noted as occurring as individual seizures and seizures 
occurring in a cluster. Countable and uncountable seizures occurring within a cluster will be 
captured. Subject/parent or caregiver will be the observers and reporters in the current study. 
All seizure events will be recorded starting at the screening/baseline period up until the follow-
up visit. 
Only seizure classification/descriptions approved by The Epilepsy Study Consortium (TESC) 
will be collected in the electronic daily seizure and medication diary for this study. 
MMD seizures include the following 8 seizure types noted in the table below, which are among 
the seizure classifications approved for this study by TESC. For the efficacy analyses by seizure 
type, any seizure type lasting less than 30 mins will be captured under the specific seizure type 
(e.g., Hemiclonic or Focal Clonic; Focal to Bilateral Tonic-Clonic; Generalized Tonic-Clonic; 
Bilateral Clonic; Tonic) rather than under the category of Convulsive Status Epilepticus. Any 
seizure type lasting 30 minutes or longer will be captured under the category of Convulsive 
Status Epilepticus which is also included in the MMD definition, as noted below. 
Primary Outcome Seizure Types: Major Motor Drop (MMD) 
A - Hemiclonic or Focal Clonic 
B - Focal to Bilateral Tonic-Clonic 
C - Generalized Tonic-Clonic 
D - Bilateral Clonic 
E - Convulsive Status Epilepticus 
F - Focal with Major Motor Signs (e.g., Hypermotor 
Seizures or Involving Major Body Areas such as 
Lower Extremities or Trunk) Leading to Fall or 
Likely Fall 
G - Tonic Seizures Involving Major 
Body Areas such as Lower Extremities 
or Trunk Leading to Fall or Likely Fall 
H - Atonic Seizures Involving Major 
Body Areas such as Lower Extremities 
or Trunk Leading to Fall or Likely Fall  
 
 
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A complete list of seizure classifications approved for this study is provided in Appendix 9.4. 
Definitions of seizure types are provided in the Study Manual. For each patient, any existing or 
new seizure types entered in the seizure diary will be adjudicated by the TESC. 
For all seizure frequency calculations in this study, the number of seizures on a given day is the 
sum of the number of countable or repetitive countable seizures, plus a count of 1 for each 
reported uncountable seizure event. The primary endpoint for this study is based on the number 
of MMD seizures. Refer to Section 9.2.4 for details of seizure data handling. 
6.5.1.2 
Main Analytical Approach 
The primary efficacy analysis will compare percent change from baseline in frequency of MMD 
seizure per 28 days during the Full Treatment Period between the soticlestat and placebo groups, 
based on the mITT analysis set using a rank ANCOVA model. The model will have rank of 
percent change from baseline in frequency of MMD seizures per 28 days during the Full 
Treatment Period (Maintenance Period for EMA registration) as the outcome variable and 
treatment group, stratification age group (≤6 years, >6 years), and rank of baseline seizure 
frequency per 28 days as predictors. Rank transformation on the outcome and baseline will be 
done on the combined data from soticlestat and placebo subjects. Tied ranks will be assigned 
their mean value. The null hypothesis that the coefficient of the treatment group term in the 
model is 0 will be tested and the p-value will be reported. 
The Hodges-Lehmann estimator will be used as the primary estimator of the treatment effect. 
The resulting estimate will be interpreted as the location shift of percent change from baseline in 
MMD seizure frequency per 28 days during the Full Treatment Period (Maintenance Period for 
EMA registration) between the soticlestat and placebo treatment groups. The asymptotic (Moses) 
95% confidence interval will be presented. 
The method of calculating seizure frequency per 28 days for the primary analysis is described in 
Section 6.5.1.1. In accordance with the treatment policy strategy for handling intercurrent events, 
all seizure diary data collected during the Full Treatment Period will be used even if collected 
after an intercurrent event. For the primary analysis, only available seizure diary data (i.e., non-
missing seizure diary days) are used in the calculation of seizure frequency. This approach 
assumes that the seizure frequency during the missing seizure diary days is equal to the seizure 
frequency during the non-missing seizure diary days. 
The primary analysis for EMA registration will include all subjects in the mITT set who have at 
least one non-missing seizure diary day during the Maintenance Period. This analysis is based on 
principal stratum of subjects who would not discontinue study drug or initiate tapering due to 
discontinuation during the first 28 days regardless of assigned treatment. A principal 
stratification framework that allows for interpretation of the primary analysis in terms of causal 
effects is described in Section 6.5.1.3.5, along with a tipping point sensitivity analysis. 
Descriptive summaries of MMD seizure frequency per 28 days during the Baseline Period, Full 
Treatment Period, and Maintenance Period will be provided. Descriptive summaries will also be 
provided for percent change from baseline in MMD seizure frequency per 28 days during the 
Full Treatment Period and the Maintenance Period. 
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6.5.1.3 
Sensitivity Analysis 
All sensitivity analyses will evaluate the primary estimand. For brevity, the term “seizure 
frequency” will indicate “MMD seizure frequency”. Sensitivity analyses are performed on the 
mITT analysis set unless indicated otherwise. 
6.5.1.3.1 
Sensitivity Analysis Considering Multiple Imputations with a Missing not at 
Random Mechanism 
The Full Treatment Period will be divided into the following periods, and multiple imputations 
will be implemented based on a pattern mixture modeling approach using a control-based pattern 
imputation to impute seizure frequency during periods where data is missing, under the 
assumption that data are missing not at random: 
• Period 1 consists of the first 28 days beginning with the day of first dose of study drug. 
• Period 2 consists of the subsequent 28 days after Period 1.  
• Period 3 consists of the subsequent 28 days after Period 2. 
• Period 4 consists of the subsequent 28 days after Period 3 for subjects who did not complete 
visit V11. For subjects who completed that visit, the last day of Period 4 is the day before the 
visit. 
Let 𝑌𝑘= log(1 + seizure frequency per 28 days during the Period 𝑘) for 𝑘= 1, 2, 3, 4. Define 𝑌𝐵 
similarly for the Baseline Period. Subjects who have no seizure diary data during Period 𝑘 will 
have 𝑌𝑘 missing. Early study discontinuations will induce a monotone missing data pattern on 
𝑌1, 𝑌2, 𝑌3, 𝑌4. It is assumed that after discontinuation, subjects in the soticlestat group will 
experience a similar rate of MMD seizures as subjects in the placebo group. Sequential 
monotone regression will be applied using the imputation model where 𝑌𝑘 depends linearly in 
expectation on 𝑌𝐵, 𝑌1, … , 𝑌𝑘−1, and age stratum. The imputation model will be fitted to available 
data from placebo subjects only, and the missing values from both placebo and soticlestat groups 
will be imputed from the fitted model sequentially by Period until all missing values have been 
imputed. A total of 100 imputed datasets will be generated via PROC MI in SAS using a pre-
specified seed. 
In case the missing pattern is not monotone (e.g., a subject has seizure diary data during Periods 
2 and 4 but not Period 3), imputation will be applied first to restore data to monotonicity using 
the MCMC method using PROC MI with IMPUTE=MONOTONE statement. Then monotone 
regression imputation will be applied once on each dataset, resulting in 100 complete datasets. A 
seed value of 14823 will be used for multiple imputation analysis. 
Each subject’s seizure frequency per 28 days during the Full Treatment Period or Maintenance 
Period is derived from their completed, possibly imputed, data 𝑌1, 𝑌2, 𝑌3, 𝑌4  as the weighted sum 
∑𝑤𝑘max{0, exp(𝑌𝑘) −1}
𝑘
 with 𝑘 ranging from 1 to 4 for the Full Treatment Period, and from 2 
to 4 for the Maintenance Period. The weights are defined as 
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𝑤𝑘=
Number of non-missing seizure diary days during Period k
Number of non-missing seizure diary days during Treatment (or Maintenance) Period 
If 𝑌𝑘 was imputed, the number of non-missing diary seizure days during Period 𝑘 is set to the 
number of days in Period 𝑘, and this number of days is added to the denominator. Percent change 
from baseline in seizure frequency per 28 days will subsequently be derived per the formula in 
Section 6.5.1.1. 
For each completed dataset, the rank ANCOVA model will be fitted, and the 100 estimated 
coefficients of the treatment group term and their standard errors will be combined via Rubin’s 
rule to generate an overall treatment effect estimate and standard error, which in turn will be 
used to calculate a p-value to test the null hypothesis of no treatment effect. Similarly, the 
Hodges-Lehmann estimate and asymptotic standard error will be calculated for each completed 
dataset and combined via Rubin’s rule to generate an overall estimate of location shift and 
standard error. The asymptotic 95% CI will be derived in turn. 
6.5.1.3.2 
Sensitivity Analysis with Van Elteren Test 
Percent change from baseline in MMD seizure frequency per 28 days during the Full Treatment 
Period (Maintenance Period for EMA registration) will be compared between treatment groups 
using the van Elteren test stratified by age stratum. The p-value will be presented. Only subjects 
who have at least one non-missing seizure diary day during the Maintenance Period will be 
included in the Maintenance Period analysis. 
6.5.1.3.3 
Sensitivity Analysis with Wilcoxon Rank Sum Test 
Percent change from baseline in MMD seizure frequency per 28 days during the Full Treatment 
Period (Maintenance Period for EMA registration) will be compared between treatment groups 
using the Wilcoxon rank sum test. The p-value will be presented. Only subjects who have at least 
one non-missing seizure diary day during the Maintenance Period will be included in the 
Maintenance Period analysis. 
6.5.1.3.4 
Sensitivity Analysis with Sex Added to the Rank ANCOVA Model 
The primary analysis as described in Section 6.5.1.2 will be repeated using a rank ANCOVA 
model with sex included as a factor. 
6.5.1.3.5 
Sensitivity Analysis on the Principal Stratification Strategy for EMA Registration 
If >5% of subjects discontinue study drug or initiate tapering due to discontinuation during the 
first 28 days beginning with the day of first dose of study drug in either treatment group, a 
tipping point sensitivity analysis will be performed for EMA registration. A potential outcomes 
and principle stratification method [2] is provided here to allow interpretation of the primary 
estimate as a causal effect. Then a procedure for a tipping point sensitivity analysis is described. 
Let Y = Percent change from baseline in MMD seizure frequency per 28 days for a subject 
during maintenance period 
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Let S = Status indicating whether a subject experienced the intercurrent event of discontinuing 
drug or initiating tapering due to discontinuation during the first 28 days (D=discontinued drug 
or initiated tapering during the first 28 days, C=continued drug into maintenance period) 
Potential outcomes: 
• 𝑌1 and 𝑌0  denote potential outcomes for a subject if assigned to soticlestat or placebo, 
respectively. 
• 𝑆1 and 𝑆0 denote the potential intercurrent event status for a subject if assigned to 
soticlestat or placebo, respectively. 
Following the principal stratification approach, let U denote the principal stratum defined by the 
joint potential status (𝑆1, 𝑆0) of a subject. There are four principal strata defined by the 4 possible 
joint values (𝑆1, 𝑆0) = 𝐶𝐶, 𝐷𝐶, 𝐶𝐷, 𝐷𝐷. 
• “Always continue” (𝑈= 𝐶𝐶): Participant would always continue drug into maintenance 
regardless of treatment assignment. 
• “Continue with placebo only” (𝑈= 𝐷𝐶): Participant would continue drug under placebo 
but not soticlestat. 
• “Continue with soticlestat only” (𝑈= 𝐶𝐷): Participant would continue drug with 
soticlestat but not placebo. 
• “Never continue” (𝑈= 𝐷𝐷): Participant would never continue drug regardless of 
treatment assignment. 
The primary estimand for EMA registration is the treatment effect in the principal stratum of 
subjects who would always continue drug into maintenance regardless of treatment assignment. 
That is, the primary estimand is the causal effect 
𝜃= 𝐸(𝑌1| 𝑈= 𝐶𝐶) −𝐸(𝑌0| 𝑈= 𝐶𝐶) 
Note that if the distributions 𝑌0 and 𝑌1 shifts of each other, then the difference in expectation is 
equal to the location shift, which is the treatment effect summary measure of interest. 
The primary analysis will use rank ANCOVA to calculate a p-value and the Hodges-Lehmann 
estimator along with 95% asymptotic confidence interval to estimate the treatment effect 
(location shift) using only the observed outcomes from subjects who continued drug into the 
Maintenance Period. Hence the primary analysis provides an unbiased estimate of the estimand 
𝜃0 = 𝐸(𝑌1 | 𝑆1 = 𝐶) −𝐸(𝑌0 | 𝑆0 = 𝐶) 
In general 𝜃0 is not a causal effect and does not equal the target estimand 𝜃. Their difference 
(“Bias”) has an exact expression provided by [4]: 
𝜃−𝜃0 = 𝐵𝑖𝑎𝑠= 𝜋𝐷𝐶
𝑝0  𝛽0 −𝑝1−𝑝0+𝜋𝐷𝐶
𝑝1
 𝛽1 
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Where 
• 𝑝1 = 𝑃(𝐶𝐶, 𝐶𝐷) = Probability of continuing drug if assigned to soticlestat  
• 𝑝0 = 𝑃(𝐶𝐶, 𝐷𝐶) = Probability of continuing drug if assigned to placebo 
• 𝜋𝐷𝐶= 𝑃(𝐷𝐶) = Probability of continuing drug under placebo but not soticlestat 
• 𝛽0 = 𝐸(𝑌0 | 𝑈= 𝐷𝐶) −𝐸(𝑌0 | 𝑈= 𝐶𝐶) = Difference in average potential outcomes 
under placebo between the “continue with placebo only” and “always continue” strata. 
• 𝛽1 = 𝐸(𝑌1 | 𝑈= 𝐶𝐷) −𝐸(𝑌1 | 𝑈= 𝐶𝐶) = Difference in average potential outcomes 
under soticlestat between the “continue with soticlestat only” and “always continue” 
strata. 
The base case assumption for the primary analysis is 𝛽0 = 𝛽1 = 0; i.e. the placebo effect is the 
same in the “continue with placebo only” and “always continue” strata, and the soticlestat effect 
is the same in the “continue with soticlestat only” and “always continue” strata. With this set of 
base case assumptions, we have 𝜃= 𝜃0, and the primary analysis will provide an unbiased 
estimate of the primary estimand. 
A tipping point sensitivity analysis will be performed to evaluate the robustness of the primary 
estimate. This will be done by varying the sensitivity parameters 𝜋𝐷𝐶, 𝛽0, 𝛽1 until the upper 
bound of the two-sided 95% confidence interval for 𝜃 equals 0; i.e. until the results are 
borderline statistically significant in favor of soticlestat. For the purpose of the tipping point 
analysis, “statistical significance favoring soticlestat” means that the upper bound of the two-
sided 95% CI for the treatment difference is <0.  
The parameters 𝑝0 and 𝑝1 will be estimated directly from the data as the proportion of subjects 
on placebo and soticlestat, respectively, who continue drug into the Maintenance Period. The 
sensitivity parameters 𝜋𝐷𝐶, 𝛽0, and 𝛽1 cannot be estimated directly. It can be shown [3] that 𝜋𝐷𝐶 
is bounded between max (0, 𝑝0 −𝑝1) and min(𝑝0, 1 −𝑝1). However, 𝛽0 and 𝛽1 are unrestricted. 
The tipping point analysis will proceed as follows. 
1. The 95% CI for 𝜃 will first be calculated from the primary estimate under the base case 
assumption with Bias=0. Let the 𝜃̂0 −𝐴 and 𝜃̂0 + 𝐴 be the lower and upper limits of this 
CI. 
2. In general, to calculate the 95% CI for 𝜃 when the base case assumption may not hold, 
i.e., when Bias≠0, the Bias term will be added to the lower and upper bounds of the base 
case CI to obtain a bias-corrected 95% CI from 𝜃̂0 −𝐴+ 𝐵𝑖𝑎𝑠 to 𝜃̂0 + 𝐴+ 𝐵𝑖𝑎𝑠. 
3. Define a grid of equally spaced values spanning the interval [max(0, 𝑝0 −
𝑝1) , min(𝑝0, 1 −𝑝1)]. The default number of grid points will be 4, but more or fewer 
points may be considered depending on the observed width of the interval. 
4. Assign 𝜋𝐷𝐶 iteratively to each value in the grid. For each value of 𝜋𝐷𝐶, let 𝑤0 =
𝜋𝐷𝐶
𝑝0  and 
𝑤1 =
𝑝1−𝑝0+𝜋𝐷𝐶
𝑝1
, so the equation 𝜃̂0 + 𝐴+ 𝑤0𝛽0 −𝑤1𝛽1 = 0 defines the set of tipping 
point pairs (𝛽0, 𝛽1) at which the conclusion changes from favoring soticlestat to not 
favoring soticlestat. This linear equation will be plotted with 𝛽0 on the horizontal axis 
and 𝛽1 on the vertical axis. The area representing values (𝛽0, 𝛽1) for which the 
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conclusion does not favor soticlestat (i.e., the region of non-significance 𝜃̂0 + 𝐴+
𝑤0𝛽0 −𝑤1𝛽1 ≥0) will be shaded. 
5. Clinical plausibility of parameter values (𝛽0, 𝛽1) in the region of non-significance will be 
discussed. 
6.5.1.3.6 
Sensitivity Analysis on the Use of J-tube 
A sensitivity analysis may be performed to evaluate the impact of J-tube use when appropriate.  
6.5.1.3.7 
Sensitivity Analysis to Exclude Subjects from Ukraine 
A sensitivity analysis to explore the potential impact of the Russia-Ukraine crisis may be 
performed. The main analytical approach described in Section 6.5.1.2 would be used with 
subjects from Ukraine excluded from the analysis. Results will be reported for both the Full 
Treatment Period and the Maintenance Period. 
6.5.1.4 
Supplementary Analyses 
Not applicable. 
6.5.1.5 
Additional Analyses 
The percent change from baseline in frequency of MMD seizure per 28 days will be summarized 
by treatment group every 4 weeks using the time intervals Period 1 (weeks 1-4), Period 2 (weeks 
5-8), Period 3 (weeks 9-12), and Period 4 (weeks 13-16/V11) as defined in Section 6.5.1.3.1, based 
on the mITT analysis set. The Hodges-Lehmann estimator of location shift of percent change from 
baseline in MMD seizure frequency per 28 days will be used as the primary estimator of the 
treatment effect in each of the 4 periods. The asymptotic (Moses) 95% confidence interval will be 
presented. 
6.5.2 
Analysis of Secondary Endpoints Tested in the Gatekeeping Procedure 
6.5.2.1 
Secondary Endpoint Analysis: Proportion of Responders 
6.5.2.1.1 
Derivation of Endpoint 
Subjects with ≥50% reduction from baseline in MMD seizure frequency per 28 days during the 
Full Treatment Period are considered responders.  
For EMA registration: 
Subjects with ≥50% reduction from baseline in MMD seizure frequency per 28 days during the 
Maintenance Period are considered responders. 
The method of calculating percent change from baseline in MMD seizure frequency per 28 days 
is explained in Section 6.5.1.1. 
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6.5.2.1.2 
Main Analytical Approach 
The Cochran-Mantel-Haenszel (CMH) test stratified by age stratum (≤6 years, >6 years) will be 
used to compare the proportion of responders during the Full Treatment Period in the soticlestat 
vs placebo groups. 
For EMA registration: 
The proportion of responders during the Maintenance Period will be compared between 
treatment groups using the CMH test stratified by age stratum. This analysis will include all 
subjects in the mITT analysis set who have at least one non-missing seizure diary day during the 
Maintenance Period. 
The Mantel-Haenszel estimator of the common odds ratio will be presented along with 95% CIs 
based on the Robins, Breslow, and Greenland variance estimate, using the SAS PROC FREQ. 
Descriptive statistics for proportions of responders will also be presented by treatment group. 
6.5.2.1.3 
Sensitivity Analysis 
A sensitivity analysis to evaluate the impact of missing data will be performed using multiple 
imputations following the same control-based pattern imputation approach used for sensitivity 
analysis of the primary endpoint, as described in Section 6.5.1.3.1.  
After 100 completed datasets have been generated and percent change from baseline in MMD 
seizure frequency per 28 days during the Full Treatment Period and the Maintenance Period has 
been calculated for each dataset, the responder status (≥50% reduction) for each subject will be 
derived in each dataset, then the CMH test will be performed on each dataset separately for the 
Full Treatment Period and for the Maintenance Period. The Mantel-Haenzel estimator of the 
common odds ratio and the Robins, Breslow, and Greenland variance estimate of the log odds 
ratio will also be calculated, using the FREQ procedure in SAS. 
The estimated log odds ratios and corresponding standard errors will be combined via Rubin’s 
rule and the pooled estimate and standard error will be calculated. An asymptotic 95% CI for the 
log odds ratio will be derived from the pooled estimates. The estimated odds ratio and 95% CI 
derived by anti-log transformation will be presented. 
The chi-squared statistics from the CMH tests of the 100 datasets will be combined via the chi 
squared pooling method described in [1] (see also [5]), and the corresponding p-value derived 
from the pooled statistic will be reported. 
Results will be reported for both the Full Treatment Period and the Maintenance Period. 
6.5.2.2 
Secondary Endpoint Analysis: Care GI-I 
6.5.2.2.1 
Derivation of Endpoint 
The Care GI-I is a 7-point Likert scale that the caregiver uses to rate improvement in overall 
seizure control, behavior, safety and tolerability after the initiation of study drug relative to 
baseline (before treatment with the study drug). The subject will be rated as follows: 1 (very 
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much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally 
worse), 6 (much worse), and 7 (very much worse). The parent/caregiver will complete the Care 
GI-I via interview at visit V8 and visit V11/ET. At the baseline visit, with input from the 
parent/caregiver, the investigator or designee documents a description of the participant’s overall 
condition over the past month with respect to seizure control as well as non-seizure symptoms 
and behavior. The Care GI-I scale is then completed by the caregiver at designated post baseline 
visits while referencing the baseline description.  
6.5.2.2.2 
Main Analytical Approach 
The main analysis of Care GI-I will compare the ordinal responses at the end of the Full 
Treatment Period between the soticlestat and placebo groups. For the purpose of Care GI-I 
analysis and other caregiver or clinician reported scales, the end of the Full Treatment Period is 
defined as visit V11. If that visit did not occur for a subject, then a last-observation carried 
forward (LOCF) approach will be used to impute the subject’s score. 
Let 𝑌 be the response at the end of the Full Treatment Period. The following cumulative logit 
model will be used for analysis: 
𝑙𝑜𝑔𝑖𝑡(𝑃(𝑌≤𝑗| 𝑇𝑅𝑇, 𝐴𝐺𝐸𝐺𝑃)) = α𝑗+ β1𝑇𝑅𝑇+ β2𝐴𝐺𝐸𝐺𝑃,   𝑗= 1, … ,6 
Set TRT=0 for the placebo group and TRT=1 for the soticlestat group, and set AGEGP=0 for 
subjects ≤6 years old and AGEGP=1 for subjects >6 years old. The null hypothesis that β1 = 0 
will be tested. The anti-log transform of the treatment effect estimate β̂1 and corresponding 95% 
CI will be reported. The transformed value 𝑒𝑥𝑝(β̂1) will be interpreted as the odds ratio of 
obtaining a response in category 𝑗 or better in the soticlestat group vs placebo group. 
The proportion of responses in each category will be summarized by treatment group and by 
study visit.  
A window approach (see Table 6.a) will be used to define the timepoints included in the 
summary. Refer to Section 9.2.3 for rules to select a record from analysis visit windows. 
Table 6.a 
Analysis Windows for Care GI-I Summary 
Analysis Visit  
Analysis Visit Window 
V8  
The day after the initial dose – the midpoint between the V8 
and V11 per protocol (inclusive) 
V11  
• For subjects who rolled over to the OLE study and OLE 
V1 date is available, the window is: the midpoint 
between V8 and V11 per protocol (not inclusive) – V1 of 
OLE study (inclusive).  
• For subjects who rolled over to the OLE study and OLE 
V1 date is not available, the window is: midpoint 
between V8 and V11 per protocol (not inclusive) – 
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Table 6.a 
Analysis Windows for Care GI-I Summary 
Analysis Visit  
Analysis Visit Window 
min(V11, last scheduled visit including ET if available) 
(inclusive). 
• For subjects who did not roll over to the OLE study, the 
window is: > the midpoint between V8 and V11 per 
protocol. 
6.5.2.2.3 
Sensitivity Analysis 
A sensitivity analysis will be performed using the van Elteren test, stratified by age stratum. This 
nonparametric approach does not make assumptions about proportional odds. This analysis will 
use the same population (with LOCF) as the main analytical approach (Section 6.5.2.2.2). 
An additional sensitivity analysis will be performed based on responses for completers only, i.e., 
subjects who were assessed at visit V11. This analysis will be performed using the same 
cumulative logit model as the main analysis. The estimated odds ratio, 95% CI, and p-value for 
the test of no treatment effect will be reported. Descriptive summaries of responses by treatment 
group and visit will also be provided. 
6.5.2.2.4 
Sensitivity Analysis Using Multiple Imputation 
A sensitivity analysis will be conducted using multiple imputation under the assumption of a 
missing not at random (MNAR) mechanism, as an alternative to the last-observation-carried-
forward (LOCF) method in the main analytic approach, for imputing missing visit V11 scores. 
The imputation model for visit V11 scores (visit V8) will include visit V8 (visit V11), treatment 
group (placebo or soticlestat), and age stratum (≤6 or >6 years old) as covariates. The fully 
conditional specification (FCS) method will be applied using cumulative logit models for both 
visits V8 and V11. For missing assessments due to confirmed early discontinuation for any 
reason or death, a control-based pattern multiple imputation will be used, operating under the 
assumption that responses in the soticlestat group would mirror those in the placebo group post-
discontinuation. For missing assessments due to all other reasons, imputation will be based on 
the subject’s randomized treatment arm. 
The imputation process will proceed sequentially, beginning with the imputation of missing data 
from analysis visit 8, followed by analysis visit 11. A total of 100 imputed datasets will be 
generated using PROC MI in SAS, with a fixed seed of 35980 to ensure reproducibility. For each 
imputed dataset, the analysis will employ the same cumulative logit model used in the main 
analysis. This model estimates the log odds ratio β̂1 and its standard error for the treatment 
effect. The results from these 100 imputed datasets will be aggregated using Rubin's rules to 
derive an overall estimate of the treatment effect and its standard error. This will then be used to 
calculate a p-value for the test of no treatment effect. Furthermore, the exponentiated form of the 
overall treatment effect (odds ratio) and its 95% confidence interval will be reported.  
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6.5.2.2.5 
Supplementary Analysis 
A supplementary analysis of Care GI-I will be done to compare the combined responses 
improvement (scores 1, 2 and 3) versus no change or worse (scores 4, 5, 6, and 7) at the end of 
the Full Treatment Period between the soticlestat and placebo groups.  
The combined responses of Care GI-I at visit V11 will be analyzed using a Cochran-Mantel-
Haenszel (CMH) test, stratified by age stratum. If V11 did not occur for a subject, then an LOCF 
approach will be used to impute the subject’s combined response. The Mantel-Haenszel 
estimator of the common odds ratio will be presented along with 95% CIs based on the Robins, 
Breslow, and Greenland variance estimate, using the SAS procedure FREQ. 
The number and percentage of patients with the combined responses of improvement and no 
change or worse will be summarized by treatment group and visit. 
6.5.2.3 
Secondary Endpoint Analysis: CGI-I 
6.5.2.3.1 
Derivation of Endpoint 
The CGI-I (Clinician) is a 7-point Likert scale that the investigator uses to rate a subject’s 
change (improvement) in overall seizure control, behavior, safety and tolerability, after the 
initiation of study drug relative to baseline (before treatment with the study drug). The subject 
will be rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 
(no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The investigator or 
designee will complete the CGI-I at visit V8 and visit V11/ET. The baseline visit for this 
assessment occurs on visit V2. At the baseline visit, with input from the parent/caregiver, the 
investigator or designee documents a description of the participant’s overall condition over the 
past month with respect to seizure control as well as non-seizure symptoms and behavior. The 
CGI-I scale is then completed by the investigator at designated post baseline visits while 
referencing the baseline description.  
6.5.2.3.2 
Main Analytical Approach 
The main analysis of CGI-I will compare the ordinal responses at the end of the Full Treatment 
Period between the soticlestat and placebo groups. The analysis and data summaries will follow 
the same approach as for the Care GI-I analysis, per Section 6.5.2.2.2. 
6.5.2.3.3 
Sensitivity Analysis 
The sensitivity analyses described for Care GI-I in Section 6.5.2.2.3 and Section 6.5.2.2.4 will be 
repeated for CGI-I. 
6.5.2.3.4 
Supplementary Analysis 
Similar supplementary analysis as described for Care GI-I (Section 6.5.2.2.5) will be repeated for 
CGI-I. For CGI-I, the combined responses will be defined as improvement (scores 1, 2 and 3) 
and no change or worse (scores 4, 5, 6 and 7). 
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6.5.2.4 
Secondary Endpoint Analysis: CGI-I Nonseizure Symptoms 
6.5.2.4.1 
Derivation of Endpoint 
The CGI-I nonseizure symptoms instrument is a series of single-item assessments that the 
investigator uses to rate improvement in the symptoms and impacts in select nonseizure domains 
(including communication, alertness, and disruptive behaviors) since initiating the study drug. 
The subject will be rated by the investigator as follows: 1 (very much improved), 2 (much 
improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 
(very much worse). At baseline, a symptoms form is completed by the clinician in collaboration 
with the primary caregiver to assess the subject’s status based on the presence of any nonseizure 
symptoms. The baseline form is intended to serve as a reference for the investigator and 
caregiver during subsequent visits when assessing change in the subject’s condition pertaining 
to these symptoms. 
The investigator or designee will complete the CGI-I Nonseizure Symptoms instrument in 
consultation with the primary caregiver at visit V8 and visit V11/ET. The baseline visit for this 
assessment occurs on visit V2. 
6.5.2.4.2 
Main Analytical Approach 
The main analysis of CGI-I Non-Seizure Symptoms will compare the ordinal responses at the 
end of the Full Treatment Period between the soticlestat and placebo groups. The analysis will be 
done separately in each of the three domains: alertness, communication and disruptive behaviors 
(the testing order will be: alertness, communication, and disruptive behaviors). The analysis and 
data summaries for each domain will follow the same approach as for the Care GI-I analysis, per 
Section 6.5.2.2.2. 
6.5.2.4.3 
Sensitivity Analysis 
The sensitivity analyses described for Care GI-I in Section 6.5.2.2.3 will be repeated for each of 
the three domains in CGI-I Non-Seizure Symptoms. 
6.5.2.4.4 
Supplementary Analysis 
Similar supplementary analysis as those described for Care GI-I in Section 6.5.2.2.5 will be done 
for each of the three domains in CGI-I Non-Seizure Symptoms. For each domain, the combined 
responses will be defined as improvement (scores 1, 2 and 3) and no change or worse (scores 4, 
5, 6 and 7). 
6.5.2.5 
Secondary Endpoint Analysis: Change in QI-Disability Score 
6.5.2.5.1 
Derivation of Endpoint 
The QI-Disability tool is a parent/caregiver-reported questionnaire that evaluates quality of life 
in children with intellectual disabilities. It contains 32 items covering 6 domains of quality of 
life: physical health, positive emotions, negative emotions, social interaction, leisure and the 
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outdoors, and independence. The parent/caregiver-reported questionnaires will be administered 
at visits V2 (Baseline), V8, and V11/ET in countries where the questionnaires have been 
translated into the native language of the region and linguistically validated. 
Each QI-Disability item is rated on a Likert scale of: Never, Rarely, Sometimes, Often, and Very 
Often. Responses in the negative emotions domain will be scored on a 0-100 point scale with 
0=Very often; 25=Often; 50=Sometimes; 75=Rarely; 100=Never. For all other domains, the 
opposite convention is used: 0=Never; 25=Rarely; 50=Sometimes; 75=Often; 100=Very often. 
See Appendix 9.5.1 for the grouping of items into domains. The domain score is the sum of the 
non-missing items in the domain divided by the number of non-missing items, and the total score 
for the QI-Disability questionnaire is the sum of the domain scores divided by 6. The domain 
score is considered non-missing provided at least one item received a score. The total score is 
considered non missing if all domain scores are non-missing. A higher score implies a better 
outcome. 
6.5.2.5.2 
Main Analytical Approach 
The main analysis of QI-Disability will compare the change from baseline to the end of the Full 
Treatment Period between the soticlestat and placebo groups. A windowing approach will be 
used to define analysis timepoints. For this purpose, Analysis Day 1 is defined as the date of first 
dose. A mixed model for repeated measures (MMRM) will be fitted under a missing at random 
assumption, with change from baseline as the outcome and baseline score as a fixed continuous 
effect, and treatment group, age stratum, Analysis Visit, and Analysis Visit by treatment group 
interaction as fixed categorical effects. An unstructured covariance model will be used. If there 
are convergence issues, an AR(1) autoregressive model will be used. If there are convergence 
issues with the AR(1) model, other covariance structures will be considered, as appropriate. A 
test of the contrast between soticlestat and placebo groups and at Analysis V11 will be the 
primary basis for inference. The model estimated means by treatment group and difference in 
means between treatment groups at each Analysis Visit will be provided along with 95% CIs. In 
addition, observed descriptive statistics at Baseline and Analysis Visits will be provided by 
treatment group. 
A window approach (see Table 6.b) will be used to define the timepoints included in the 
summary. Refer to Section 9.2.3 for rules to select a record from analysis visit windows. 
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Table 6.b 
Analysis Windows for QI-Disability 
Analysis Visit  
Analysis Visit Window 
V8 
Day after first dose day - Day before Analysis Day 57 (inclusive) 
V11 
• For subjects who rolled over to the OLE study, if V1 date of 
OLE is available, the window is: Analysis Day 57 (inclusive) 
– V1 of OLE study (inclusive). If V1 date of OLE is not 
available, use min(V11, last scheduled visit including ET if 
available) (inclusive) as upper the bound. 
• For subjects who did not roll over to the OLE study, the 
window is: ≥Analysis Day 57. 
6.5.2.6 
Secondary Endpoint Analysis: CGI-I Seizure Intensity and Duration 
6.5.2.6.1 
Derivation of Endpoint 
The CGI-I Seizure Intensity and Duration instrument is used by the parent/caregiver to rate 
changes in intensity and duration of MMD seizures from the first assessment. The subject’s 
symptoms will be rated as follows: 1 (very much improved), 2 (much improved), 3 (minimally 
improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). The 
parent/caregiver will complete the CGI-I seizure intensity and duration at visit V8 and visit 
V11/ET. The baseline visit for this assessment occurs on visit V2. At the baseline visit, with 
input from the parent/caregiver, the investigator or designee documents the caregiver’s 
description of the intensity and/or duration of the participant’s most impactful seizures over the 
past month (excluding status epilepticus). The CGI-I Seizure Intensity and Duration scale is then 
completed by the parent/caregiver at designated post baseline visits while referencing the 
baseline description. 
6.5.2.6.2 
Main Analytical Approach 
The main analysis of CGI-I Seizure Intensity and Duration will compare the ordinal responses at 
the end of the Full Treatment Period between the soticlestat and placebo groups. The analysis 
and data summaries will follow the same approach as for the Care GI-I analysis, per 
Section 6.5.2.2.2. 
6.5.2.6.3 
Sensitivity Analysis 
The sensitivity analyses described for Care GI-I in Section 6.5.2.2.3 will be repeated for CGI-I 
Seizure Intensity and Duration. 
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6.5.2.6.4 
Supplementary Analysis 
Similar supplementary analysis as those described for Care GI-I (Section 6.5.2.2.5) will be done 
for CGI-I Seizure Intensity and Duration. For CGI-I Seizure Intensity and Duration, the 
combined responses will be defined as improvement (scores 1, 2 and 3) and no change or worse 
(scores 4, 5, 6 and 7). 
6.5.3 
Other Secondary Endpoints Analysis 
6.5.3.1 
 Percent Change from Baseline in Frequency for all Seizures per 28 Days 
Percent change from baseline in frequency per 28 days of all seizures during the Full Treatment 
Period and Maintenance Period will be analyzed using the main analytic approach for the 
primary efficacy analysis per Section 6.5.1.2. Per the main analytic approach, Hodges-Lehmann 
estimators and 95% CIs will be reported. P-values and summary statistics by treatment group 
will be reported for descriptive purposes. 
6.5.3.2 
Responder Analysis 
The number and proportion of subjects with ≤0%, >0% to ≤25%, >25% to ≤50%, >50% to 
≤75%, and >75% to ≤100% reduction from the baseline in MMD seizure frequency per 28 days 
during the Full Treatment Period will be summarized by treatment group. Seizure frequency 
reduction of >X% is equivalent to percent change from baseline in seizure frequency of < -X%. 
A cumulative response curve will be plotted showing the proportion of subjects with >X% 
reduction from baseline in MMD seizure frequency per 28 days as a function of X, with separate 
curves for each treatment group. 
For EMA registration, the same analysis will be done for the Maintenance Period. 
6.5.3.3 
Change from Baseline in Proportion of MMD Seizure-Free Days 
The proportion of MMD seizure-free days during a period is defined as the number of non-
missing seizure diary days when no MMD seizures occurred during the period divided by the 
number of non-missing seizure diary days during the period. The proportion of MMD seizure-
free days will be summarized descriptively for the Baseline Period and Full Treatment Period by 
treatment group. The change from baseline in proportion of MMD seizure-free days, defined as 
the proportion of seizure-free days during the Full Treatment Period minus the proportion of 
seizure-free days during the Baseline Period, will be summarized descriptively by treatment 
group. The treatment effect on change from baseline in proportion of MMD seizure-free days 
will be estimated using a linear model with treatment group and age stratum as factors and 
baseline proportion as a covariate. The estimated main effect of treatment group, interpreted as 
the adjusted difference in group means, will be reported along with 95% CI. 
6.5.3.4 
Longest MMD Seizure-free Interval 
The longest MMD seizure-free interval is defined as the longest consecutive number of days 
during the Full Treatment Period on which there were no MMD seizures. 
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If a subject has one or more consecutive days of missing seizure diary data, the first day of 
missing seizure diary data will be considered as MMD seizure-free provided it is preceded by an 
MMD seizure-free day, and all other subsequent days, starting from the second day with missing 
seizure data, will be assumed to have MMD seizure occurrence, until the next non-missing 
seizure data are available. Identification of seizure free days will be based on the rules described 
in Section 9.2.4. 
The longest MMD seizure-free interval will be summarized descriptively by treatment group. 
The treatment effect on the longest MMD seizure-free intervals will be estimated using a linear 
model with treatment group and age stratum as factors. The estimated main effect of treatment 
group, interpreted as the adjusted difference in group means, will be reported along with 95% CI. 
6.5.3.5 
Number of Days when Rescue ASM is Used 
Use of rescue anti-seizure medications (ASM) is to be recorded in the CRF in the Concomitant 
Medications (Rescue Anti-Seizure) folder along with start and end date of medication. Based on 
the start and end dates for all rescue ASMs taken by a subject, the number of days during the Full 
Treatment Period when rescue ASM is used can be derived, where Full Treatment Period is as 
defined in Section 6.5.1.1. The proportion of days during the Full Treatment Period will also be 
calculated, using the number of days during the Full Treatment Period as the denominator. The 
number of days when rescue ASM is used will be summarized descriptively. The treatment 
effect on the proportion of days when rescue ASM is used will be estimated using a linear model 
with treatment group and age stratum as factors. The estimated main effect of treatment group, 
interpreted as the adjusted difference in group means, will be reported along with 95% CI. 
For this analysis, missing start dates for rescue ASM will be imputed to the first day of the 
month if day is missing but month and year are known, and to the first day of the year if day and 
month are missing but year is known. If year is missing, the rescue ASM will conservatively be 
assumed to have started on the first day of the Full Treatment Period. Missing end dates for 
rescue ASM will be imputed to the last day of the month if day is missing but month and year are 
known, and to the last day of the year if day and month are missing but year is known. If year is 
missing, the rescue ASM will conservatively be assumed to have ended on the last day of the 
Full Treatment Period. Analyses will be based on the data available in EDC. 
6.5.4 
Exploratory Endpoints Analysis 
6.5.4.1 
Percent Change from Baseline in Frequency per 28 Days of Each Seizure Type 
Identified at the Time of Screening or Baseline 
Percent change from baseline in frequency per 28 days of each seizure type during the Full 
Treatment Period will be compared between soticlestat and placebo groups using the main 
analytic approach for the primary efficacy analysis per Section 6.5.1.2. The list of seizure types 
collected in the daily diary is provided in Appendix 9.4. For each seizure type, only subjects who 
experience at least 1 seizure of that type during the baseline period (as defined in Section 6.5.1.1) 
will be included in the analysis. Per the main analytic approach, Hodges-Lehmann estimators 
and 95% CIs will be reported. P-values and summary statistics by treatment group will be 
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reported for descriptive purposes. Note that seizure types O (Infantile Spasms [Under 3 Years of 
Age]) and P (Epileptic Spasms [3 Years of Age and Older]) will be grouped into single type in 
the summary outputs. 
6.5.4.2 
Change in EQ-5D-5L and Visual Analogue Scale (EQ-VAS) Scores 
The EQ-5D-5L is the 5–response level version of the EQ-5D instrument. It consists of 2 sections, 
a descriptive system questionnaire and the EQ visual analogue scale (EQ VAS). The 
questionnaire provides a descriptive profile across the dimensions of mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. In the EQ-5D-5L version, each dimension 
has 5 response levels: no problems, slight problems, moderate problems, severe problems, and 
unable to/extreme problems. The parents or caregivers are asked to indicate their own health 
quality of life by ticking the box next to the most appropriate statement in each of the dimensions. 
In addition, the EQ-VAS is used to indicate the general health status, with 100 indicating the best 
health status. These questionnaires will be administered at baseline and at visit V11/ET. 
EQ-5D-5L responses are coded as: 1=no problems; 2=slight problems; 3=moderate problems; 
4=severe problems; 5=unable to/extreme problems. EQ-5D-5L will be summarized descriptively 
by presenting the number and percentage of responses in each level within each dimension. In 
addition, a dichotomization based on ‘no problems’ (level = 1) vs ‘any problems’ (levels = 2, 3, 
4, and 5) will be summarized using a shift table to assess change from baseline to V11/ET. EQ-
VAS scores will be summarized descriptively by visit and treatment group. Change in EQ-VAS 
from baseline to post-baseline will be summarized descriptively by treatment group. A higher 
EQ-VAS score implies a better outcome. 
The change from baseline on the EQ-VAS score will be analyzed using an ANCOVA with 
baseline as a covariate, treatment and age stratum as fixed factors. The analysis will be 
performed using observed cases only. Only assessments pertaining to the caregivers’ own health 
quality of life will be included in the analysis.  
A window approach (see Table 6.c) will be used to define the timepoints included in the 
summary. Refer to Section 9.2.3 for rules to select a record from analysis visit windows. 
Table 6.c 
Analysis Windows for EQ-5D-5L 
Analysis Visit  
Analysis Visit Window 
V11 
• For subjects who rolled over to the OLE study, the window 
is: Day after first dose day (inclusive) – V1 of OLE 
(inclusive) study if V1 date of OLE is available. If V1 date of 
OLE is not available, the upper bound is min(V11, last 
scheduled visit including ET if available) (inclusive) 
• For subjects who did not roll over to the OLE study, the 
window is: ≥ Day after first dose day 
 
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6.5.5 
Subgroup Analyses 
The main analytic approach for the primary analysis will be conducted for the following 
subgroups: 
• Age stratum subgroups (subjects of age ≤6 years; subjects of age >6 years) with the 
modification of not including age stratum as a predictor in the rank ANCOVA model. 
6.5.6 
Additional Exploratory Analyses 
Analyses may be performed to explore efficacy endpoints in these subpopulations: 
• Pediatric subjects (<18 years old) and adult subjects (18 years or older) 
• Subgroups based on disease etiology or history, specifically: 
o Structural. This subgroup includes subjects for whom any of the following were 
reported as definite or possible etiologies: intraventricular hemorrhage; 
malformations of cortical or other brain development with or without known 
genetic determinants; mesial temporal sclerosis; neoplasia; neurocutaneous 
syndromes; stroke; traumatic brain injury. 
o Genetic. This subgroup includes subjects for whom any of the following were 
reported as definite or possible etiologies: genetic and chromosomal development 
encephalopathies; genetic or presumed genetic. 
o Unknown. This subgroup includes subjects for whom any of the following were 
reported as definite or possible etiologies: developmental encephalopathy of 
unknown cause; epilepsy of unknown cause. 
o History of infantile spasms. This subgroup includes subjects for whom infantile 
spasms was reported on medical history. 
• Subgroups defined according to the number of prior or baseline ASMs. 
• Subjects who took rescue medication during the treatment period and subjects who did 
not take rescue medications during the treatment period. 
• Subgroups defined according to whether any CYP3A4 inducers were used as 
concomitant ASMs. CYP3A4 inducers include carbamazepine, phenobarbital, phenytoin, 
and primidone. 
Analyses may be performed to explore efficacy endpoints under the following alternative 
definitions of drop seizures (refer to Section 9.4 for a complete list of seizure classifications 
collected in the daily diary): 
• Alternative definition 1: Drop seizures as defined by seizures of these types:  
o Generalized Tonic-Clonic 
o Tonic Seizures Involving Major Body Areas such as Lower Extremities or Trunk 
Leading to Fall or Likely Fall 
o Tonic Seizures Without Fall or Without Likely Fall (e.g., Head Drop or Upper 
Extremities Only) 
o Atonic Seizures Involving Major Body Areas such as Lower Extremities or Trunk 
Leading to Fall or Likely Fall 
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o Atonic Seizures Without Fall or Without Likely Fall (e.g., Head Drop or Upper 
Extremities Only) 
• Alternative definition 2: Drop seizures as defined by the seizures of these types: 
o Focal to Bilateral Tonic-Clonic 
o Generalized Tonic-Clonic 
o Tonic Seizures Involving Major Body Areas such as Lower Extremities or Trunk 
Leading to Fall or Likely Fall 
o Tonic Seizures Without Fall or Without Likely Fall (e.g., Head Drop or Upper 
Extremities Only) 
6.6 
Safety Analysis 
Descriptive statistics will be used to summarize all safety endpoints for each of the treatment 
groups and overall. AEs will be summarized using the safety analysis set. All AEs will be coded 
using MedDRA. Data will be summarized using Preferred Terms and primary System Organ 
Classes. 
Two-sided 95% CIs will be presented where meaningful. Data summaries will be displayed for 
incidence of AEs, clinical laboratory variables, vital signs, body weight, and ECG parameters as 
appropriate.  
All data will be listed.  
6.6.1 
Adverse Events 
In this study, Adverse Event (AE) refers to both pretreatment events (PTEs) and treatment-
emergent adverse events (TEAEs). PTEs are AEs that started after the signing of informed 
consent but before receiving any study drug.  
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
been administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
o The term “life threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
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5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
o May require intervention to prevent items 1 through 5 above. 
o May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
A TEAE is defined as any AE that starts or increases in severity during or after the first dose of 
study drug of this study and prior to the first dose of study drug of the OLE for subjects rolling 
over to the OLE, or through the last study visit for subjects not rolling over to the OLE. Events 
where the onset date is the same as the study drug start date are assumed to be treatment 
emergent, unless the investigator indicates on the CRF that the event occurred before the first 
dose. 
AE dates that are partially or completely missing will be presented as they are in the listings, 
although incomplete adverse event (AE) start dates will be imputed to determine the relationship 
between the start date and the informed consent date, as well as the start date and the first dose 
date of the double-blind study medication (except when the event end date was prior to the study 
drug start date).  
The following methods will be used to impute incomplete start dates of AEs: 
• If only the month and year of the start date are available and the month and year are different 
than the month and year of the first dose of double-blind study medication or the stop date is 
prior to the first dose of study medication, then the first day of the month will be used for the 
start date. If only the month and year of the start date are available and the month and year 
are the same as the month and year of the first dose of double-blind study medication and the 
stop date is not prior to the date of first dose, then the date of first dose will be used for the 
start date. 
• If only the year of the start date is available and the year is different than the year of the first 
dose of double-blind study medication or the stop date is prior to the first dose of study 
medication, then January 1st will be used for start date. If only the year of the start date is 
available and the year is the same as the year of the first dose of double-blind study 
medication and the stop date is not prior to the date of first dose, then the date of first dose 
will be used for start date. 
When calculating the frequency and percentage of subjects who reported AEs, a subject will be 
counted only once for each SOC or PT when multiple AEs are coded to the same SOC or PT. For 
the severity or relatedness summaries, if a subject reports multiple AEs coded to the same SOC 
or PT, the AE with maximum severity or strongest relationship will be included in the summary. 
AEs with missing severity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. The tables will include number of events, as appropriate. If the 
relationship of an event is missing, the relationship for the event will be considered to have been 
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In general, AEs will be tabulated by treatment group and overall. The tables will include the 
number and percentage (N[%]) of subjects. Summary tables that will be generated will include, 
but may not be limited to:  
• Overall TEAEs  
• TEAEs by SOC and PT 
• Frequently occurring (≥ 5% of subjects in either one of the treatment groups) TEAEs by PT: 
the 5% cut-off value will be applied before rounding 
• TEAEs by Maximum Severity, SOC and PT 
• Drug-Related TEAEs by SOC and PT  
• TEAEs leading to Study Drug Discontinuation by SOC and PT 
• Serious TEAEs by SOC and PT  
• Non-serious TEAEs by SOC and PT 
• Relationship of TEAEs to Study Drug by SOC and PT 
• Serious Drug-Related TEAEs by SOC and PT 
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
SAEs, and TEAEs that resulted in death.  
6.6.2 
Adverse Events of Special Interest 
This study has 3 types of AEs of special interest, as described in detail in the protocol. 
• Potential drug-drug interaction between soticlestat and perampanel leading to increased 
seizure frequency 
• Cataracts 
• Psychosis 
AEs of special interest must be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor. 
The number and percentage of TEAEs of special interest and number of subjects will be 
tabulated by treatment group and overall. Each type of adverse event of special interests will be 
listed. 
6.6.3 
Other Safety Analysis 
6.6.3.1 
Clinical Laboratory Evaluations  
Clinical laboratory tests will be assessed using the Safety Analysis Set and will be evaluated and 
presented using International System of Units (SI) units unless otherwise stated. Refer to 
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Protocol Section 9.1.11.3 as well as the schedule of the events for a list of all clinical laboratory 
tests. 
All laboratory test parameters will be displayed in individual subject data listings in SI units. If 
necessary, SI units from the central laboratory may be converted to Takeda’s preferred SI units 
in the derived Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM) 
datasets. All summaries and analyses will be based on the values using these preferred SI units. 
No inferential statistics will be presented unless otherwise stated. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values will be presented for quantitative data. Study baseline will be used 
for change from baseline. Measurements will be summarized by nominal timepoints. Only 
central lab data will be used for the descriptive summary table, and lab results below or equal to 
lower limit of quantification (LLOQ) will be set to LLOQ/2; lab results above or equal to upper 
limit of quantification (ULOQ) will be set to ULOQ. For details, refer to Section 9.2.3. 
A window approach (see Table 6.d) will be used to define the timepoints included in the 
summary. Refer to Section 9.2.3 for rules to select a record from analysis visit windows. 
Shift tables for qualitative parameters of Hematology and Chemistry will be created. For shift 
tables, both central and local lab data will be used. For details, refer to Section 9.2.3. The same 
window approach (Table 6.d) will be used.  
Table 6.d 
Analysis Windows for Laboratory Evaluations Summary 
Analysis Visit  
Analysis Visit Window 
V9  
The next day after the day of the initial dose – the midpoint 
between V9 and V11 per the protocol schedule (inclusive) 
V11  
> the midpoint between V9 and V11 as per the protocol 
schedule. 
For subjects who rolled over to the OLE study, the upper 
bound of the window is the date of V1 of the OLE 
(inclusive) if available, and if V1 of OLE date is not 
available it is min(V11, last scheduled visit including ET if 
available) (inclusive). 
For urinalysis, qualitative parameters will be summarized by treatment group and overall, in shift 
tables (as applicable) comparing the results at each scheduled post-baseline visit with those at the 
baseline visit. The aforementioned window approach specified in Table 6.d will be used.  
For laboratory parameters with normal reference ranges, the number and percentage of subjects 
with at least one postbaseline measurement outside of the normal reference range will be 
summarized by treatment group and overall. 
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Listings of all clinical safety laboratory data will be provided in SI units. Laboratory data outside 
of the normal reference range will be indicated in the listings. For laboratory data ≤LLOQ or 
≥ULOQ, original data will be presented in the listing and will be flagged. The listing will include 
site number, subject identifier, age, gender, treatment group, study visit, and sample collection 
date. 
Refer to Section 9.2.3 for rules to select a record from analysis visit windows. 
6.6.3.2 
Vital Signs 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters (including height, weight, systolic and diastolic blood pressure, 
heart rate, respiratory rate and temperature) at baseline, each post-baseline visit, and change from 
baseline to each post-baseline visit. A window approach (Table 6.d) as described in 
Section 6.6.3.1 will be used. Refer to Section 9.2.3 for rules to select a record from analysis visit 
windows. 
Listings of all vital signs data will be provided. The listing will include site number, subject 
identifier, age, gender, treatment group, study visit, and sample collection date. 
6.6.3.3 
12-Lead ECG 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters will 
be presented for baseline, each post-baseline visit, and change from baseline to each post-
baseline visit. A window approach (Table 6.d) as described in Section 6.6.3.1 will be used. Refer 
to Section 9.2.3 for rules to select a record from analysis visit windows. No inferential statistics 
will be presented. 
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant) is collected at V1, V2, V9 and V11. Shifts in ECG interpretation will be 
presented as cross-tabulations (baseline versus each post-baseline visit) of numbers of subjects 
with normal limits, abnormal not clinically significant, abnormal clinically significant, and not 
evaluable interpretations with missing, if applicable, and total categories by treatment group. The 
worst interpretation within the window will be used for the shift table. 
For each treatment group, the number and percentage of subjects with worst post-baseline QTcF 
in each of these categories will be presented: <450 msec, 450 msec – <480 msec, 480 msec – 
500 msec, >500 msec, and Missing. In addition, the number and percentage of subjects with 
worst QTcF change from baseline in each of these categories will be presented: <30 msec, 30 
msec – 60 msec, > 60 msec, and Missing. A higher QTcF value implies a worse outcome.  
Listings of all 12-lead ECG data will be provided. The listing will include site number, subject 
identifier, age, gender, treatment group, study visit, and sample collection date. 
6.6.3.4 
C-SSRS 
Suicidal ideation and behavior will be assessed in children aged ≥6 years by use of the C-SSRS. 
The C-SSRS is a 3-part scale that measures suicidal ideation (eg, subject endorses thoughts 
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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). 
Two versions of the C-SSRS will be used in this study for all participants ages 6 through 21 
years: the C-SSRS Children’s Screening/Baseline (recall period lifetime/12 months) and the C-
SSRS Children’s Since-Last-Visit. 
C-SSRS analysis will be based on subjects in the safety analysis set who have at least 1 post-
baseline C-SSRS measurement, regardless of whether they had a baseline C-SSRS measurement.  
For each C-SSRS question, the baseline will be the worst measurement (including life-time 
measurement) prior to initial dose of study drug. For details, refer to Section 9.2.2. For post-
baseline assessments, the same window approach described in Section 6.6.3.1 will be used as per 
Table 6.d. 
C-SSRS incidences will be categorized as follows: no suicidal ideation or suicidal behavior or 
non-suicidal self-injurious behavior, non-suicidal self-injurious behavior, suicidal ideation, and 
suicidal behavior. For each visit, the “Yes” answer to the question with the highest severity rank 
in Table 6.e will be used to determine the C-SSRS category of a subject.  
Table 6.e 
Severity Rank for C-SSRS Questions 
C-SSRS Categories 
Severity Rank of CSSRS questions (from low to high) 
Non-suicidal self-
injurious behavior 
1. Engaged in non-suicidal self-Injurious behavior 
Suicidal ideation 
2. Wish to be dead 
3. Non-specific active suicidal thoughts 
4. Active suicidal ideation with any methods (not plan) without intent 
to act 
5. Active suicidal ideation with some intent to act, without specific 
plan 
6. Active suicidal ideation with specific plan and intent 
Suicidal behavior 
7. Preparatory acts or behavior 
8. Aborted attempt 
9. Interrupted attempt 
10. Actual attempt 
11. Completed suicide (only applicable for the postbaseline 
assessments) 
The number and percentage of subjects with suicidal ideation, suicidal behavior, and the number 
and percentage of subjects who have “Yes” answers of the suicidal ideation and behavior 
questions will be summarized by treatment group for each post-baseline visit, using the same 
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windows as described in Table 6.d. The baseline values (per Section 9.2.2) will also be included 
in the summary. 
Shifts in C-SSRS will be presented as cross-tabulation (baseline versus worst post-baseline 
categories as in Table 6.e) of numbers and percentages of subjects of no suicidal ideation or 
suicidal behavior or non-suicidal self-injurious behavior, non-suicidal self-injurious behavior, 
suicidal ideation, suicidal behavior, and missing by treatment group. 
C-SSRS data will also be listed. 
6.6.3.5 
Ophthalmological Evaluations 
Ophthalmological evaluations will be done at V1 and V11/ET, while the examination at V11 is 
applicable only for subjects who complete the 16 weeks of double-blind treatment (not 
applicable for ET subjects) and may be conducted within a 14-day window before V11. 
The data of the following items will be summarized in terms of number and percentage of 
subjects in each of ophthalmological evaluations category by left eye, right eye, both eyes and 
either eye: 
• Visual Acuity:  
o V11: Has the visual acuity of the right/left eye significantly declined since the last 
visit? 
• Cataract Screening:  
o Baseline and V11: Are there any anterior or posterior lens opacities in the 
right/left eye? 
o V11: Has the opacity in the right/left eye worsened since the last visit? 
• Fundoscopic Examination:  
o Baseline and V11: Right/left Eye Optic Nerve Exam Interpretation 
o Baseline and V11: Right/left Eye Retinal Exam Interpretation 
The analysis visit window of V11 is defined below. 
• For subjects who did not roll over to OLE study window will be ≥ Day after first 
dose 
• For subjects who rolled over to the OLE study, the window is:  
o Day after first dose day – V1 date of OLE study if that date is available 
(inclusive)  
o If OLE V1 date is not available, Day after first dose day – min(V11, last 
scheduled visit including ET if available) (inclusive) 
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For the above summaries, if multiple post-baseline measurements are available, the latest post-
baseline measurement will be mapped to V11. If multiple measurements are recorded at the same 
time, then the worst measurement will be used.  
6.6.3.6 
Physical Examination 
Physical examination data will be listed. 
6.6.3.7 
New Seizure Types 
The number and percentage of patients who develop new seizure types post-study treatment 
initiation will be summarized for each new seizure type and all new seizure types by treatment 
group and overall. The data will also be listed. 
6.6.4 
Extent of Exposure and Compliance 
Subject compliance with study drug will be assessed at each visit.  
Subjects who are significantly noncompliant will be discontinued from the study. A subject will 
be considered significantly noncompliant if he or she missed more than 20% of study medication 
during the study duration unless there is a valid reason for interruption in the study medication 
such as hospitalization. 
Duration of exposure to double-blind study medication is defined as (date of last dose – date of 
first dose +1). Total dose is defined as the sum of actual doses (all non-missed doses are 
considered full dose). 
Total dose taken, average daily dose, and duration of exposure (days) will be summarized for all 
patients by stratum, treatment and overall based on the safety analysis set. In addition, the 
number and percentage of subjects in each maintenance dose categories (< dose 1, dose 1, dose 1 
- dose 2, dose 2, dose 2 – dose 3, dose 3 and > dose 3 as per Table 2.a – Table 2.d) will be 
summarized. Maintenance dose is defined as the longest duration dose within the maintenance 
period. If there are multiple doses with the longest duration, the highest dose will be used as the 
maintenance dose. 
Study medication data will be collected by the case report form. The number of tablets returned 
will be collected also. 
The percentage of study drug compliance will be defined in two ways: 
1. Using the exposure data captured by case report form, as [(dose recorded as taken) / (total 
planned dose)]x 100%, 
2. Using number of returned tablets, [(dose dispensed – dose returned) / (total planned 
dose)] x 100%. 
Total planned dose will be derived as the sum of the dose the subject is supposed to take. 
For each treatment group and overall, study medication compliance will be summarized by 
compliance category (0 to <20%, 20% to <40%, 40% to <60%, 40% to <60%, 60% to <80%, 
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80% to <90%, 90% to < 100%, 100% to < 120% and ≥ 120%) and the number of subjects in 
each compliance category. Study medication compliance will also be summarized as a 
continuous variable using descriptive statistics (n, mean, SD, median, minimum, and maximum) 
for each treatment group and overall.  
The number and percentage of patients who are significantly non-compliant (compliance < 80%) 
or not will be summarized. 
All study drug administration and compliance data will be listed. 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.7.1 
Pharmacokinetic Analysis 
Pharmacokinetic analyses are based on the PK analysis set. 
6.7.1.1 
Plasma Concentrations of Soticlestat and the Soticlestat Metabolite(s) at Multiple 
Time Points 
Individual plasma concentration-time data for soticlestat and the soticlestat metabolite(s) will be 
presented in listings and summarized descriptively per nominal visit, geometric mean and 
geometric coefficient of variation will be reported. Mean plasma concentrations over time will be 
presented graphically. Concentrations that are reported as below the lower limit of quantitation 
(LLOQ) will be assigned a value of 0 for calculation of summary statistics. 
6.7.1.2 
Population Soticlestat PK Modeling Based on Sparse PK 
The population PK/PD model developed for soticlestat based on the data from phase 1 studies in 
healthy subjects and phase 2 studies in patients will be updated using data from this study and 
used to estimate PK and PD parameters. The detailed population analysis approach will be 
described in a separate data analysis plan before database lock. The results of the population 
PK/PD modeling will be reported separately. Available ASM information will be included in the 
population PK/PD analysis, if appropriate. 
6.7.2 
Pharmacodynamic Analysis 
Pharmacodynamic Analyses are based on the PD analysis set. 
6.7.2.1 
Percent Change from Baseline in Plasma 24HC  
Individual plasma 24HC levels will be presented in listings and summarized descriptively per 
nominal time points. Percent change from baseline will be summarized descriptively by nominal 
time point. 24HC values below lower limit of quantification (LLOQ) are set to 0 for computing 
descriptive statistics. Mean percent change from baseline in 24HC over time may be presented 
graphically. 
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6.7.2.2 
 Soticlestat Exposure-PD (Plasma 24HC Level) and Efficacy Response Analysis. 
Correlation between change in PD (24HC) and efficacy (change in MMD seizure frequency over 
the full treatment period) will be investigated. A scatter plot of 24HC percent change from 
baseline at visit V11/ET vs percent change from baseline in MMD seizure frequency per 28 days 
will be presented, and Spearman correlation will be calculated. 
Exposure-PD analysis will be conducted based on a population PK/PD model and reported 
separately. The exposure-efficacy analysis will be conducted and reported separately. 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
6.8.1 
Health Care Utilization Analysis 
Health care resource utilization including but not limited to emergency room visits and 
hospitalizations will be summarized and presented in listings.  
6.9 
Interim Analysis 
The protocol states that a blinded interim analysis may be performed. However, per sponsor’s 
decision, no interim analysis was or is planned to be conducted.  
6.10 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will meet regularly to review unblinded 
clinical safety data. Details are provided in the DMC Charter.  
7.0 
REFERENCES 
1. Li, K.-H., Meng, X.-L., Raghunathan, T. E., & Rubin, D. B. Significance levels from 
repeated p-values with multiply-imputed data. Statistica Sinica, 1991;1(1): 65–92. 
2. Frangakis CE, Rubin DB. Principal Stratification in Causal Inference. Biometrics. 2002 
Mar;58(1):21–9. 
3. Lou Y, Jones MP, Sun W. Estimation of causal effects in clinical endpoint 
bioequivalence studies in the presence of intercurrent events: noncompliance and missing 
data. Journal of Biopharmaceutical Statistics. 2019 Jan 2;29(1):151–73. 
4. Chiba Y, VanderWeele TJ. A Simple Method for Principal Strata Effects When the 
Outcome Has Been Truncated Due to Death. American Journal of Epidemiology. 2011 
Apr 1;173(7):745–51. 
5. Ratitch B, Lipkovich I, O’Kelly M. Combining analysis results from multiply imputed 
categorical data. PharmaSUG 2013-Paper SP03. 2013;2013:1-9. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
NA 
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9.0 
APPENDIX 
9.1 
Changes From the Previous Version of the SAP 
Changes made from the previous version of the SAP that have a material impact to the 
planned statistical analysis methods are described below. In addition, there were textual 
changes purely to improve the flow, organization, and clarity. As these represent cosmetic 
changes with no impact to the planned statistical analyses, they are not included in the table 
below.  
Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
3.1  [Row 5 (Secondary 
#4) in  Table 3.a]  
NA 
 
Added content: 
Testing (sequential) 
order will be as follows: 
alertness, 
communication, and 
disruptive behaviors. 
Statistical significance 
of individual domains 
within the hierarchy can 
be asserted with global 
type 1 error control 
provided all preceding 
tests are significant, but 
statistical significance 
of the full endpoint 
consisting of all 3 
domains of CGI-I 
Nonseizure Symptoms, 
can only be asserted if 
all 3 domains are 
statistically significant. 
Added details for clarification 
on testing order (as described 
already in Table 1.b 
[Secondary #4]) and related 
inference. 
5.2 
All randomized 
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 ITT (mITT) 
analysis set. 
Updated content: 
All randomized subjects 
who have received at 
least 1 dose of study 
drug and have been 
assessed for seizures 
for at least 1 day in the 
treatment period will be 
included in the modified 
ITT (mITT) analysis set.  
Added “for seizures” to align 
with protocol amendment 2. 
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Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
6.1 
NA 
Added content: 
If a subject is assigned 
to the wrong age 
stratum during 
randomization, the 
actual age, collected as 
a part of demographic 
information, will be 
used to identify the 
correct age stratum (≤6 
or >6 years) for all 
summaries and analyses 
that reference age 
stratum. 
Added as a clarification. 
6.4.2 
Concomitant 
medications, ASMs, 
and concomitant 
rescue medications 
will be summarized. 
The total number of 
ASMs and 
concomitant rescue 
medications will be 
presented as well as 
the number and 
percentage of patients 
with at least 1 ASM 
and rescue medication. 
ASM listing will 
also be presented. 
 
A separate summary 
will be created for the 
number and 
percentage of 
subjects receiving 
each of 
the ASMs at baseline. 
Updated content:  
Concomitant 
medications, 
concomitant ASMs, and 
concomitant rescue 
medications will be 
summarized. The 
number and percentage 
of patients receiving 
each ASM 
concomitantly, and each 
rescue medication 
concomitantly will be 
presented as well as the 
number and percentage 
of patients with at least 
1 concomitant ASM and 
concomitant rescue 
medication. ASM listing 
will also be presented. 
Analyses will be based 
on the data available in 
electronic data capture 
(EDC). 
 
Added clarifications. 
Removed number and 
percentage of subjects 
receiving each of the ASMs at 
baseline as it is deemed 
unnecessary. ASM at baseline 
will be continued as 
concomitant ASM and 
summary of concomitant ASM 
will be provided. 
6.5.1.3.1 
NA 
Updated content: 
A seed value of 14823 
will be used for multiple 
imputation analysis. 
Specified seed for 
reproducibility.  
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Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
6.5.1.5 
NA 
New analysis added. 
Explore seizure frequency 
change over time. 
6.5.1.3.7 
NA 
A sensitivity analysis 
excluding subjects from 
Ukraine was added. 
Explore potential impact of the 
Russia-Ukraine conflict. 
6.5.2.2.2, 6.5.2.5.2, 
6.5.4.2, 6.6.3.1 
NA 
Updated Analysis 
Windows Table 6.a, 
Table 6.b, Table 6.c, 
Table 6.d 
Added details to the rules 
defining analysis windows. In 
particular, defined an upper 
bound for analysis V11 
window for subjects who rolled 
over to the OLE study, to 
ensure data collected after start 
of OLE is not included in 
analysis of this study. 
6.5.2.2.3 6.5.2.2.3  
NA 
Added a sensitivity 
analysis based on 
multiple imputation 
under the assumption of 
MNAR 
Provide an alternative to the 
last-observation-carried-
forward (LOCF) method for 
imputing missing visit V11 
scores for Care GI-I and CGI-I 
scores. 
NA 
To evaluate the impact 
of period length in 
multiple imputations 
described in 
Section 6.5.1.3.1, the 
same approach 
described in 
Section 6.5.1.3.1 will 
be used, with the 
modification that the 
full treatment period 
will be divided into 
consecutive 7-day 
periods, except for the 
last period, which will 
begin the day after the 
end of the previous 
period and end at the 
day before scheduled 
V11. 
NA  
(Removed the 
Section 6.5.1.3.2 in 
previous version of SAP 
which contained this 
sensitivity analysis) 
The planned sensitivity 
analysis described in 
Section 6.5.1.3.1 is considered 
adequate to evaluate impact of 
missingness assumptions on 
the primary analysis. 
6.5.2.2.5 
no improvement or 
worse (scores 4, 5 and 
6)) 
Updated content: 
no change or worse 
(scores 4, 5, 6, and 7) 
Corrected typographical error 
and “no improvement” 
changed to “no change” for 
better clarity. 
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Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
6.5.2.3.4, 6.5.2.4.4, 
6.5.2.6.4 
no improvement or 
worse (scores 4, 5, 6 
and 7). 
Updated content: 
no change or worse 
(scores 4, 5, 6 and 7). 
“no improvement” changed to 
“no change” for better clarity. 
6.5.3.4 
Heading: 
Longest convulsive 
Seizure-free Interval 
Content removed: 
If a subject has two or 
more consecutive days 
of missing seizure 
diary data, the end of 
the corresponding 
MMD seizure-free 
interval will be the 
first date of missing 
seizure diary data, and 
the next MMD seizure-
free interval will begin 
on the next date that 
the seizure diary data 
are available and no 
MMD seizure occurs. 
Updated heading: 
Longest MMD Seizure-
free Interval 
Updated content: If a 
subject has one or more 
consecutive days of 
missing seizure diary 
data, the first day of 
missing seizure diary 
data will be considered 
as seizure-free provided 
it is preceded by a 
seizure-free day, and all 
other subsequent days, 
starting from the second 
day with missing 
seizure data, will be 
assumed to have MMD 
seizure occurrence, until 
the next non-missing 
seizure data are 
available. Identification 
of seizure free days will 
be based on the rules 
described in 
Section 9.2.4. 
Typographical error corrected. 
Clarify how a single missing 
day is handled in the 
calculation of longest seizure-
free interval 
6.5.4.1 
NA 
Added note that seizure 
types O (Infantile 
Spasms [Under 3 Years 
of Age]) and P 
(Epileptic Spasms [3 
Years of Age and 
Older]) will be grouped 
into single type in the 
summary outputs. 
Types O and P have similar 
semiology and therefore are 
grouped into single item to 
facilitate clinical interpretation. 
6.5.6 
NA 
Added additional 
exploratory analyses on 
subpopulations and 
seizure types. 
These subpopulations and 
seizure types are clinically 
relevant to the LGS population 
and are of scientific interest. 
6.6.1 
A Treatment-emergent 
adverse event (TEAE) 
is defined as any AE 
Updated content: 
A TEAE is defined as 
Updated the end date of TEAE 
collection in relation to the 
start of the OLE study, to 
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Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
that starts or increases 
in severity during or 
after the first dose of 
study drug of this 
study and prior to the 
first dose of study drug 
of the OLE for 
subjects rolling over 
immediately to the 
OLE (ie, V11 of the 
study is combined 
with V1 of the OLE), 
or through the last 
study visit for subjects 
not rolling over 
immediately to the 
OLE. 
any AE that starts or 
increases in severity 
during or after the first 
dose of study drug of 
this study and prior to 
the first dose of study 
drug of the OLE for 
subjects rolling over to 
the OLE, or through the 
last study visit for 
subjects not rolling over 
to the OLE. 
ensure no duplication in TEAE 
reporting /collection between 
this study and the OLE study. 
6.6.1 
Frequently occurring 
(≥5% of all subjects) 
TEAEs by PT 
Updated content: 
Frequently occurring 
(≥5% of subjects in 
either one of the 
treatment groups) 
TEAEs by PT 
Broadened the definition to 
allow capturing potentially 
more TEAEs that may not have 
been captured under the 
previous definition of 
frequently TEAE. 
6.6.3.1 
For summary table, 
lab results below or 
equal to lower limit of 
quantification (LLOQ) 
will be set to LLOQ/2 
Updated content: 
Only central lab data 
will be included in the 
summary table, and 
lab results below or 
equal to lower limit of 
quantification (LLOQ) 
will be set to LLOQ/2 
To facilitate interpretation, 
clarified that numerical 
summaries only include values 
from central labs, rather than a 
mix of central and local labs.  
6.6.3.4 
Shift table categories 
and baseline have been 
redefined 
Modify C-SSRS shift 
table categories and 
define C-SSRS baseline 
as the worst of the 
available measurements 
prior to initial dose. 
Refer to Table 6.e. for 
categories. 
Updated categories for shift 
tables and baseline definition 
allow more appropriate clinical 
interpretation 
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Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
6.6.3.5 
NA 
Added: “each of 
ophthalmological 
evaluations category by 
left eye, right eye, both 
eyes and either eye:” 
V11 window defined 
with modifications.  
Added more details on the 
analysis. 
V11 window definition 
updated based on OLE dates. 
6.6.4 
Total dose taken, 
average daily dose, 
duration of exposure 
(days), and total 
missed doses will be 
summarized for all 
patients by stratum, 
treatment and overall 
for the safety analysis 
set 
Updated content: 
Total dose taken, 
average daily dose, and 
duration of exposure 
(days) will be 
summarized for all 
patients by stratum, 
treatment and overall 
based on the safety 
analysis set. 
Removed total missed doses 
removed from summary as it 
does not provide any 
interpretable information. 
Moreover, compliance will be 
assessed based on dosing diary.  
6.6.4 
NA 
Added content: 
Summary of 
maintenance dose 
categories will be 
provided. 
Added to help assess 
distribution of maintenance 
dose. 
6.7.2.2 
A scatter plot of 24HC 
percent change from 
baseline at visit 
V11/ET vs percent 
change from baseline 
in MMD seizure 
frequency per 28 days 
will be presented, and 
Pearson correlation 
will be calculated. 
Updated content: 
A scatter plot of 24HC 
percent change from 
baseline at visit V11/ET 
vs percent change from 
baseline in MMD 
seizure frequency per 28 
days will be presented, 
and Spearman 
correlation will be 
calculated. 
Exposure-PD analysis 
will be conducted based 
on a population PK/PD 
model and reported 
separately. The 
exposure-efficacy 
analysis will be 
conducted and reported 
separately 
Spearman correlation is more 
appropriate. Clarified that 
Exposure-PD analyses will be 
reported separately. 
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Table 9.a 
Summary of changes in SAP 
SAP Section  
 
Impacted Text 
(shown in bold) 
Change  
Rationale for Change 
6.9 
Methodology for the 
proposed potential 
blinded interim 
analysis was removed. 
Updated content: 
 
The protocol stated that 
a blinded interim 
analysis may be 
performed. However, 
per sponsor’s decision, 
no interim analysis was 
or is planned to be 
conducted. 
Per sponsor’s decision, no 
interim analysis was or is 
planned to be conducted. 
9.2.3 
NA 
Added a section to 
provide rules to select 
the right record among 
multiple records. 
Added for clarity and to 
facilitate programming. 
9.2.4 
NA 
Added a section for 
seizure diary data 
handling. 
Specify rules for analysis in 
case of unresolvable seizure 
diary data conflicts. 
9.2 
Data Handling Conventions 
9.2.1 
General Data Reporting Conventions 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. CIs 
intervals will be presented using the same number of decimal places as the parameter estimate. 
Minimum and maximum values will be presented to the same number of decimal places as the 
recorded data. A decimal digit of ≥5 is rounded up away from zero, whereas <5 is rounded down 
toward zero, to account for rounding of negative numbers. P-values are rounded to 3 decimal 
places. P-values that would round to 0.000 are presented as <0.001. Seizure frequencies will be 
rounded to 1 decimal place. BMI will be rounded to 1 decimal place for reporting. Derived 
questionnaire scores, and other similar efficacy parameters recorded as integers, will be rounded 
to 1 decimal place for reporting. Averaged lab results (e.g. Diastolic/Systolic Blood Pressure and 
Pulse [when taken in triplicate]) will be rounded to 1 decimal place for reporting. PK related 
results will be displayed to the defined level of significant digits. 
Percentages will be reported to 1 decimal place, except when the percentage equals exactly 100 
where it will be displayed as an integer (100). For zero, only count and no percentage will be 
displayed. 
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9.2.2 
Definition of Baseline  
Unless otherwise stated, baseline values are defined as the last non-missing measurement prior to 
the first dose of study drug. If multiple measurements are recorded at the same time or time is 
not available, then the average of these measurements (for continuous data) or the worst among 
these measurements (for categorical data) will be considered as the baseline value. Both date and 
time of the measurement and the dosing date and time should be used when determining the 
baseline if possible. In the case where the last non-missing measurement (except AE and 
concomitant medications) and the first dose date coincide at the same time, or the same date if 
time of the measurement is not available, that measurement will be considered as baseline value.  
For C-SSRS, the worst value prior to initial dose will be used as the baseline for each question. 
Life-time values should be included in the baseline derivation. If multiple assessments have the 
same answer, prioritize “lifetime”, and then “12 month”, and then “since last visit.”  
For all efficacy analyses on seizure frequency, baseline refers to the prospective 4- to 6- week 
baseline period and is defined in Section 6.5.1.1 
9.2.3 
Rules to Select a Post-Baseline Record for Summary  
Unless otherwise specified, the rules provided below will be followed to select a post-baseline 
record from an analysis visit window which contains multiple records to report in the summary 
tables.  
Endpoints: Care GI-I, CGI-I, CGI-I Nonseizure Symptoms, CGI-I Seizure Intensity and 
Duration, QI-Disability, EQ-5D-5L, EQ-VAS 
If multiple assessments occur in the same window, the assessment done at the scheduled visit 
will be mapped to the corresponding analysis visit; ET visits are considered unscheduled visits 
for this purpose. If only unscheduled visits besides ET are available, the assessment closest to the 
scheduled visit within the window will be used. An ET visit supersedes other unscheduled visits; 
i.e., if the corresponding scheduled visit assessment is unavailable but ET visit assessment is 
available, ET visit assessment will be used for summary regardless of the availability of the other 
unscheduled visits. If there are two unscheduled assessments within the window and they are 
equally close to the scheduled visit, the later assessment will be used. 
Endpoints: Labs, Vital Signs, ECG  
When more than one result for a parameter (e.g. lab test, ECG, etc.) is obtained in a visit 
window, the latest one will be used. If multiple measurements are recorded at the same time, 
then the average of these measurements (for continuous data) or the worst among these 
measurements (for categorical data) will be used. If multiple measurements are recorded on the 
same day, and the collection time of at least one assessment is missing, then the average of these 
measurements (for continuous data) or the worst among these measurements (for categorical 
data) will be used.  
For shift summary, both central and local lab data will be used. If central and local laboratory 
data are available on the same day, central laboratory data will be used. If, after prioritizing 
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central lab data, there are multiple lab measurements recorded on the same day, then the worst 
among these measurements will be used.  
For shift tables of ECG, if multiple interpretations are available within the same window, the 
worst (most severe) interpretation will be used for cross-tabulation of shift. The order for ECG 
interpretation in decreasing order of severity is: abnormal clinically significant, abnormal not 
clinically significant, within normal limit, not evaluable 
Endpoint: C-SSRS 
If there are multiple records in an analysis window, the latest value within the window will be 
selected for summary; if multiple assessments are available at the same time, the worst value (for 
each question) will be used for summary. 
9.2.4 
Handling of Seizure Diary Data 
Seizure data are collected via the seizure diary, including the date of seizure, and the 
Yes/No/Unknown response on whether a day was seizure free. 
• If no seizures are entered for a day and a “Yes” response is given on whether that same 
day was seizure free, the number of seizures for that day is 0. That day will be counted as 
seizure free day. 
• If no seizures are entered for a day and a “Yes” response is not given on whether that 
same day was seizure free, seizure data for that day will be considered missing. For 
example, if only a response of “Unknown” or “No” is given on whether a day was seizure 
free, but no seizures are entered for that day, seizure data for that day will be considered 
missing. That day will not be counted as seizure free day. 
• If no seizures are entered for a day and seizure diary has “Yes” or “No” (or “Unknown”) 
as response given on whether that day was seizure free, then the “Yes” response for that 
day supersedes any other responses on the same day, i.e., the number of seizures for that 
day is considered 0. That day will be counted as seizure free day. 
• If seizures are entered for a day, the seizures recorded for that day supersede any “Yes” 
or “Unknown” responses given on whether that same day was seizure free. That day will 
not be counted as seizure free day. 
• Only completed records (available records with seizure occurrence date, seizure free date, 
seizure type, number of seizures during event, etc.) will be included in the seizure data 
summaries and analyses. 
9.3 
Analysis Software  
SAS System® Version 9.4 or higher will be used in the statistical analysis. 
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9.4 
Seizure Classifications Collected in Daily Seizure Diary 
Primary Outcome Seizure Types: Major Motor Drop (MMD) 
A - Hemiclonic or Focal Clonic 
B - Focal to Bilateral Tonic-Clonic 
C - Generalized Tonic-Clonic 
D - Bilateral Clonic 
E - Convulsive Status Epilepticus 
F - Focal with Major Motor Signs (e.g., Hypermotor 
Seizures or Involving Major Body Areas such as Lower 
Extremities or Trunk) Leading to Fall or Likely Fall 
G - Tonic Seizures Involving Major 
Body Areas such as Lower 
Extremities or Trunk Leading to 
Fall or Likely Fall 
H - Atonic Seizures Involving 
Major Body Areas such as Lower 
Extremities or Trunk Leading to 
Fall or Likely Fall  
 
 
Non-Primary Outcome Seizure Types 
I - Focal Without Motor Signs 
J - Focal with Minor Motor Signs (e.g., Lip 
Smacking, Eyelid Fluttering, Automatisms 
Only) 
K - Absence 
L - Tonic Seizures Without Fall or Without 
Likely Fall (e.g., Head Drop or Upper 
Extremities Only) 
 
M - Atonic Seizures Without Fall or Without 
Likely Fall (e.g., Head Drop or Upper 
Extremities Only) 
N - Myoclonic 
O- Infantile Spasms (Under 3 Years of Age) 
P - Epileptic Spasms (3 Years of Age and Older) 
Q - Non-Convulsive Status Epilepticus 
R – Other 
9.5 
Health Outcome Scales 
9.5.1 
QI-Disability Domains 
Domain 
Item 
Social interaction Expressed happiness when they were understood 
Appeared relaxed when making eye contact 
Initiated greetings with people verbally or nonverbally (e.g. eye contact) 
Enjoyed being included 
Enjoyed the social experiences of meal times 
Responded positively when others paid attention to them (e.g. your child 
smiled, showed interest) 
For non-commercial use only


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Statistical Analysis Plan Amendment 1 
5 Mar 2024
 
CONFIDENTIAL 
Domain 
Item 
Showed pleasure or excitement when looking forward to activities (e.g. 
going to school, outings, events) 
Positive 
emotions 
Been in a good mood 
Smiled or brightened their facial expression 
Showed happiness through body language (e.g. making eye contact, body 
facing others) 
Showed cheeky or comical mannerisms (e.g. laughed, giggled) 
Physical health 
Had enough energy to participate in daily routines and activities 
Kept in good general health (e.g. avoided coughs, colds, fever) 
Slept well during the night 
Been alert and aware during the day 
Negative 
emotions 
Been unsettled without an apparent reason 
Showed aggression (e.g. hitting, kicking, using offensive language, being 
destructive) 
Appeared upset or angry (e.g. crying, screaming, moving or stiffening the 
body) 
Become withdrawn with a low mood 
Deliberately hurt themselves 
Expressed discomfort with changes in routine (e.g. carers, school, respite, 
out-of-home care) 
Showed signs of being anxious or agitated (e.g. teeth grinding, fast 
breathing, avoidance) 
Leisure and the 
outdoors 
Enjoyed moving their body (e.g. crawling, walking, swinging, swimming) 
Enjoyed feeling steady or stable during physical activities (e.g. sitting, 
standing, bike riding) 
Enjoyed physical activities (e.g. going out for a walk, swimming, 
swinging, dancing) 
Enjoyed going on outings in the community (e.g. shopping, party, sports, 
theatre) 
For non-commercial use only


TAK-935-3002 
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Statistical Analysis Plan Amendment 1 
5 Mar 2024
 
CONFIDENTIAL 
Domain 
Item 
Enjoyed spending time outdoors (e.g. contact with water, grass, wind, 
sunshine) 
Independence 
Expressed their needs (e.g. hunger, thirst, toileting) 
Made their own choices for activities or things they enjoy (e.g. DVDs, 
toys) 
Helped to complete routine activities (e.g. dressing, feeding) 
Enjoyed making things with their hands – can be with help (e.g. building 
blocks, painting, cooking) 
Enjoyed using technology (e.g. computer, tablet, applications on phones) 
 
For non-commercial use only


Signature Page for Statistical Analysis Plan Amendment 1
Title: TAK-935-3002 Statistical Analysis Plan Amendment 1
Document Number: TDN-000246001 v1.0
Approval
Statistics
08-Mar-2024 15:27:52 GMT+0000
For non-commercial use only