Clinical trial NCT06422377
Conditions: Dravet Syndrome (DS) Lennox-Gastaut Syndrome (LGS)
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2024-04-25; Completion date: 2024-08-14
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to check how soticlestat impacts symptoms of Dravet syndrome \[DS\] and Lennox-Gastaut syndrome \[LGS\] in participants who have been exposed to fenfluramine.

Detailed description:
The drug being tested in this study is called soticlestat. Soticlestat is being tested to treat people who have DS or LGS and have been exposed to fenfluramine. This study will assess the efficacy and safety of soticlestat in addition to standard care in the treatment of DS or LGS.

The study will enroll approximately 45 patients. This study comprises a screening period of up to 6 weeks, a 4-week titration period, a 48-week maintenance period, a taper period of up to 1 week and a follow-up safety visit. Participants will be enrolled to receive soticlestat along with the standard of care:

• Soticlestat 100-300 milligrams (mg)

Participants will receive oral administration of soticlestat Dose 1 (days 1 to 7), Dose 2 (days 8 to 14), and Dose 3 (Days 15 to 28) with a minimum dose of 100 mg to a maximum dose of 300 mg depending on participant's body weight in the titration period followed by maintenance period up to end of treatment (up to approximately 52 weeks). Percent change from baseline in convulsive in participants with DS and major motor drop (MMD) in participants with LGS seizure frequency per 28 days during the initial 12 weeks of the maintenance period will be assessed.

This multi-center trial will be conducted in the United Kingdom and Europe. The overall time to participate in this study is approximately 60 weeks. Participants will make multiple visits to the clinic and will be followed up for safety by visiting the clinic or by telephone approximately 2 weeks after the last dose of the study drug.

Arms: arm 1: Participant received soticlestat at a starting dose of 100 mg to 200 mg in the 4-week titration. As a part of maintenance (initially planned for 48 weeks per protocol), participant remained on the 200 mg BID dose for 9 days followed by a 1-week taper to receive soticlestat 100 mg BID.
Interventions: intervention 1: Soticlestat
Intervention descriptions: intervention 1: Soticlestat tablets or mini-tablets

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


 
 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
An Open-label, Nonrandomized, Phase 3 Study to Evaluate the Efficacy and Safety of 
Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have 
Been Exposed to Fenfluramine 
Brief Title 
A Study Evaluating Soticlestat in Participants Who Have Been Exposed to Fenfluramine 
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 USA 
Study Number: 
TAK-935-3004 
Study Phase: 
Phase 3 
IND Number: 
133627 
Abbreviated EU CT 
Number: 
2023-504104-29 
Investigational 
Product: 
Soticlestat 
Date: 
27 June 2023 
Version/Amendment 
Number: 
Amendment 1 
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. 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 
APPROVALS  
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants 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 Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use Good Clinical Practice.
•
All applicable laws and regulations, including, without limitation, data privacy laws,
clinical trial disclosure laws, and regulations.
SIGNATURES OF THE RESPONSIBLE TAKEDA MEDICAL OFFICER AND OTHER 
SIGNATORY(IES) 
Electronic signatures of the following individuals 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 understand this protocol, the investigator’s brochure, prescribing 
information, and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, life, 
dignity, integrity, confidentiality of personal information, safety, privacy, and well-being of 
study participants in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use Good Clinical Practice.
•
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.
•
Regulatory requirements for reporting serious adverse events as defined in this protocol.
•
Terms outlined in the clinical study site agreement.
•
Responsibilities of the investigator as described in this protocol.
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a potential participant to obtain their informed consent to 
participate. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the sponsor. 
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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CONFIDENTIAL 
SUMMARY OF CHANGES  
Protocol Amendment 1 
Amendment Date:  
27 June 2023 
Global/Region/Country/Site Specific:  
Global 
Overall Reason for the Amendment: 
Minor updates for protocol clarification/correction.  
 
Description of Each Change and Rationale  
Section(s) Affected by Change  
Change #  
Description of Change 
Rationale for Change 
Section 
1.  
Revised inclusion criterion 
#9 in the synopsis to align 
with the protocol body 
(Section 5.1). 
Inclusion criterion #9 in 
the synopsis was 
inadvertently written 
incorrectly.  
Section 1.1  
2.  
Revised text regarding home 
visits to be at the discretion 
of the investigator.  
Home visits should be 
conducted at the discretion 
of the investigator.  
Section 1.3 
Section 4.1 
Appendix 3 
3.  
Revised text regarding video 
calls.  
Revised for clarification 
on use of video calls, 
particularly during home 
visits.  
Section 4.1 
4.  
Removed reference to serum 
pregnancy test.  
Revised text for 
clarification as per 
Schedule of Activities, 
which specifies only that 
urine pregnancy tests are 
requested; additional 
pregnancy tests (serum or 
urine) may be performed 
throughout the study at the 
investigator’s discretion. 
Section 8.3.6 
5.  
Added “soticlestat program” 
to Data Monitoring 
Committee text.  
Added to clarify that 
although there is no data 
monitoring committee for 
this study, there is a data 
monitoring committee for 
the soticlestat program. 
Section 10.1.12.2 
6.  
Removed alpha-1 acidic 
glycoprotein from list of 
tests required for each 
laboratory specimen. 
Alpha-1 acidic 
glycoprotein will not be 
included as part of clinical 
chemistry.  
Section 10.2, Table 10.a  
7.  
Revised the description of 
calculations in the section on 
sample size determination  
The supporting calculation 
was updated. 
Section 9.8 
See Section 10.9 for protocol history, including all previous amendments.  
 
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CONFIDENTIAL 
ADMINISTRATIVE INFORMATION  
CONTACTS 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in this section and relevant guidelines 
provided to the site. 
Takeda sponsored investigators will be provided with emergency medical contact information 
cards to be carried by each participant, per individual country requirements. 
ADDITIONAL INFORMATION  
The study operations manual contains additional contact information for:  
• Medical monitor, for medical advice on the protocol and the study drug.  
• Sponsor’s responsible medical officer. 
• Monitor assigned to the study site, for general advice on protocol procedures.  
• Serious adverse event (SAE) reporting, adverse event of special interest (AESI).  
• Special Situation Reporting (SSR) reporting forms. 
• Pregnancy reporting.  
PRODUCT QUALITY COMPLAINTS 
A product quality complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, strength, purity, 
effectiveness, or performance of a product, device, or combination product after it is released for 
distribution.  
Report product complaints using the form called “Clinical Trial Material Complaint Form.”  
Send it to the following email address: 
ctmcomplaint@takeda.com 
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CONFIDENTIAL 
TABLE OF CONTENTS 
APPROVALS ..................................................................................................................................2 
SUMMARY OF CHANGES ...........................................................................................................4 
ADMINISTRATIVE INFORMATION ..........................................................................................5 
ADDITIONAL INFORMATION ....................................................................................................5 
PRODUCT QUALITY COMPLAINTS..........................................................................................5 
TABLE OF CONTENTS .................................................................................................................6 
1.0 
PROTOCOL SUMMARY .................................................................................................13 
1.1 
Synopsis .......................................................................................................................13 
1.2 
Schema .........................................................................................................................21 
1.3 
Schedule of Activities ..................................................................................................22 
2.0 
INTRODUCTION .............................................................................................................27 
2.1 
Study Rationale ............................................................................................................27 
2.2 
Background ..................................................................................................................27 
2.3 
Benefit-Risk Assessment .............................................................................................29 
3.0 
OBJECTIVES AND ENDPOINTS ...................................................................................30 
3.1 
Objectives ....................................................................................................................30 
3.1.1 
Primary Objectives ..............................................................................................30 
3.1.2 
Exploratory Objectives ........................................................................................30 
3.2 
Endpoints .....................................................................................................................30 
3.2.1 
Primary Endpoint .................................................................................................30 
3.2.2 
Exploratory Endpoints .........................................................................................31 
4.0 
STUDY DESIGN...............................................................................................................32 
4.1 
Overall Design .............................................................................................................32 
4.1.1 
Dose Titration Period (4 Weeks) .........................................................................34 
4.1.2 
Maintenance Period (Approximately 48 Weeks) ................................................34 
4.1.3 
Study Discontinuation/Completion .....................................................................35 
4.1.4 
Period of Evaluation ............................................................................................35 
4.2 
Scientific Rationale for Study Design..........................................................................35 
4.2.1 
Participant Input Into Design ...............................................................................36 
4.3 
Justification for Dose ...................................................................................................36 
4.4 
Overall End of Study ...................................................................................................38 
5.0 
STUDY POPULATION ....................................................................................................38 
5.1 
Inclusion Criteria .........................................................................................................38 
5.1.1 
Justification of Inclusion Criteria ........................................................................41 
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5.2 
Exclusion Criteria ........................................................................................................41 
5.3 
Lifestyle Considerations ..............................................................................................42 
5.3.1 
Meals and Dietary Restrictions ...........................................................................42 
5.3.2 
Contraception and Breastfeeding ........................................................................43 
5.3.2.1 
Contraception for Participants Capable of Producing Viable Ova and/or 
Becoming Pregnant .....................................................................................43 
5.3.2.2 
Contraception for Participants Capable of Producing Viable Sperm..........43 
5.4 
Screening......................................................................................................................43 
5.4.1 
Screen Failures ....................................................................................................43 
5.5 
Criteria for Temporarily Delaying Enrollment/Administration of Study Drug ...........44 
5.6 
Enrollment....................................................................................................................44 
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ...............................44 
6.1 
Study Intervention(s) Administered .............................................................................44 
6.2 
Preparation, Handling, Storage, and Accountability ...................................................45 
6.2.1 
Accountability Throughout the Study .................................................................46 
6.2.2 
Receiving Product at the Site ..............................................................................46 
6.2.3 
Handling and Storage at the Site .........................................................................47 
6.2.4 
Labeling ...............................................................................................................48 
6.2.5 
Preparation ...........................................................................................................48 
6.2.6 
Dispensing/Administration ..................................................................................48 
6.2.6.1 
Dispensing ...................................................................................................49 
6.2.6.2 
Administration ............................................................................................49 
6.2.7 
Destruction or Return ..........................................................................................51 
6.3 
Measures to Minimize Bias: Randomization and Blinding .........................................51 
6.3.1 
Randomization .....................................................................................................51 
6.3.2 
Blinding the Treatment Assignment ....................................................................51 
6.3.3 
Unblinding ...........................................................................................................52 
6.4 
Study Drug Compliance ...............................................................................................52 
6.5 
Dose Modification .......................................................................................................52 
6.6 
Continued Access to Study Drug After the End of the Study......................................53 
6.7 
Treatment of Overdose ................................................................................................53 
6.8 
Concomitant Therapy...................................................................................................54 
6.8.1 
Rescue Medicine .................................................................................................54 
6.8.2 
Excluded Medications .........................................................................................54 
6.8.2.1 
Justification of Excluded Medications ........................................................54 
6.8.3 
Permitted Concomitant Medications and Procedures ..........................................54 
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CONFIDENTIAL 
7.0 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................55 
7.1 
Discontinuation of Study Drug ....................................................................................55 
7.1.1 
Liver Chemistry Stopping Criteria ......................................................................57 
7.1.2 
Rechallenge .........................................................................................................57 
7.2 
Participant Discontinuation/Withdrawal From the Study ............................................57 
7.3 
Lost to Follow-up .........................................................................................................58 
8.0 
STUDY ASSESSMENTS AND PROCEDURES .............................................................58 
8.1 
Demographics, Medical History, and Medication History ..........................................58 
8.1.1 
Demographics ......................................................................................................58 
8.1.2 
Medical History ...................................................................................................58 
8.1.2.1 
Historical Seizure Data ...............................................................................59 
8.1.3 
Prior and Concomitant Treatments/Medications .................................................59 
8.1.4 
Diagnostic Criteria/Disease Classification ..........................................................60 
8.2 
Efficacy Assessments...................................................................................................60 
8.3 
Safety Assessments ......................................................................................................60 
8.3.1 
Physical Examinations .........................................................................................61 
8.3.2 
Vital Signs ...........................................................................................................61 
8.3.2.1 
Weight and Height ......................................................................................61 
8.3.3 
Neurological Examination Procedure ..................................................................62 
8.3.4 
Ophthalmological Evaluation Procedure .............................................................62 
8.3.5 
Clinical Safety Laboratory Tests .........................................................................63 
8.3.6 
Pregnancy Testing ...............................................................................................63 
8.3.7 
Suicidal Ideation and Behavior Risk Monitoring ................................................64 
8.3.8 
AEs, SAEs, and Other Safety Reporting .............................................................64 
8.3.8.1 
Time Period and Frequency for Collecting AE and SAE Information .......65 
8.3.8.2 
Method of Detecting AEs and SAEs ...........................................................65 
8.3.8.3 
Follow-up of AEs and SAEs .......................................................................65 
8.3.8.4 
Regulatory Reporting Requirements for SAEs ...........................................65 
8.3.8.5 
Pregnancy in a Participant or Participant’s Partner During the Study ........66 
8.3.8.6 
Deaths ..........................................................................................................67 
8.3.8.7 
AESIs ..........................................................................................................67 
8.3.8.8 
SSR ..............................................................................................................67 
8.4 
Clinical Outcome Assessments ....................................................................................68 
8.4.1 
CGI Baseline Questionnaires (Clinician) ............................................................68 
8.4.1.1 
CGI Baseline and Care GI Baseline ............................................................68 
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CONFIDENTIAL 
8.4.1.2 
CGI Baseline–Seizure Intensity and Duration ............................................69 
8.4.1.3 
CGI Baseline–Nonseizure Symptoms .........................................................69 
8.4.2 
CGI-I (Clinician) .................................................................................................69 
8.4.3 
CGI-I Seizure Intensity and Duration (Clinician) ...............................................69 
8.4.4 
CGI-I Nonseizure Symptoms (Clinician) ............................................................69 
8.4.5 
Care GI-I (Caregiver) ..........................................................................................70 
8.4.6 
QI-Disability (Parent/Caregiver Version) ...........................................................70 
8.4.7 
EQ-5D-5L Quality of Life Scale (Assessing Caregiver’s Health) ......................70 
8.5 
Diaries ..........................................................................................................................71 
8.6 
Health Economics/Medical Resource Utilization and Health Economics ...................71 
8.7 
Genetics........................................................................................................................71 
8.8 
Other ............................................................................................................................71 
8.8.1 
Caregiver Satisfaction Questionnaire ..................................................................71 
8.9 
PK ................................................................................................................................72 
8.10 
PD ................................................................................................................................72 
8.11 
Biomarkers ...................................................................................................................72 
8.11.1 
Bioanalytical Methods .........................................................................................72 
9.0 
STATISTICAL CONSIDERATIONS...............................................................................72 
9.1 
Statistical Hypotheses ..................................................................................................72 
9.2 
Analysis Sets ................................................................................................................72 
9.3 
Efficacy Analyses ........................................................................................................72 
9.3.1 
Primary Efficacy Endpoint ..................................................................................72 
9.3.2 
Exploratory Efficacy Endpoints ..........................................................................73 
9.4 
Safety Analyses ............................................................................................................73 
9.5 
Multiplicity Adjustment ...............................................................................................73 
9.6 
Other Analyses .............................................................................................................73 
9.7 
Interim Analysis ...........................................................................................................74 
9.8 
Determination of Sample Size .....................................................................................74 
10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....74 
10.1 
Regulatory, Ethical, and Study Oversight Considerations...........................................74 
10.1.1 
Regulatory and Ethical Considerations ...............................................................74 
10.1.2 
Financial Disclosure ............................................................................................75 
10.1.3 
Informed Consent Process ...................................................................................75 
10.1.3.1 Informed Consent Requirements in This Study ..........................................75 
10.1.3.2 Standards the Informed Consent Follows ...................................................75 
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10.1.3.3 Who Creates the Informed Consent Materials ............................................78 
10.1.3.4 Who Conducts the Informed Consent Process ............................................79 
10.1.3.5 Re-Consent ..................................................................................................80 
10.1.4 
Data Protection ....................................................................................................80 
10.1.4.1 Notice Regarding the Use and Transfer of the Investigator’s Personal 
Information ..................................................................................................81 
10.1.5 
Committees Structure ..........................................................................................83 
10.1.5.1 IRB and/or IEC Approval ...........................................................................83 
10.1.6 
Dissemination of Clinical Study Data .................................................................84 
10.1.6.1 Study Results Disclosure ............................................................................84 
10.1.7 
Data Quality Assurance .......................................................................................84 
10.1.7.1 Protocol Deviations .....................................................................................84 
10.1.7.2 Study-Site Monitoring Visits ......................................................................85 
10.1.7.3 Audits ..........................................................................................................85 
10.1.8 
Source Documents ...............................................................................................85 
10.1.8.1 eCRFs ..........................................................................................................86 
10.1.8.2 Documentation and Retention of Records ..................................................87 
10.1.8.3 Data Handling .............................................................................................88 
10.1.8.4 Record Retention .........................................................................................88 
10.1.9 
Study and Site Start and Closure .........................................................................88 
10.1.9.1 First Act of Recruitment..............................................................................88 
10.1.9.2 Study/Site Termination ...............................................................................89 
10.1.10 Publication Policy ................................................................................................89 
10.1.11 Responsibilities of the Sponsor and the Investigator ..........................................91 
10.1.11.1 Sponsor Responsibilities .............................................................................91 
10.1.11.2 Investigator Responsibilities .......................................................................91 
10.1.12 Site Termination or Suspension ...........................................................................94 
10.1.12.1 Criteria for Premature Termination or Suspension of Study Sites ..............94 
10.1.12.2 Criteria for Premature Termination or Suspension of the Study ................94 
10.1.12.3 Procedures for Premature Termination or Suspension of the Study or 
the Participation of Study Site(s) ................................................................94 
10.2 
Clinical Laboratory Tests .............................................................................................94 
10.2.1 
Clinical Laboratory Assessments and Other Safety Assessments .......................95 
10.2.2 
Biological Sample Retention and Destruction ....................................................96 
10.3 
AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting ...............................................................................................................97 
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CONFIDENTIAL 
10.3.1 
Definition of AE ..................................................................................................98 
10.3.2 
Definition of SAE ................................................................................................99 
10.3.3 
Additional Considerations in Identifying and Defining AEs ............................101 
10.3.3.1 Defining Discrete AEs ..............................................................................101 
10.3.3.2 AESIs ........................................................................................................102 
10.3.4 
Recording and Follow-up of AE and/or SAE ....................................................103 
10.3.4.1 Frequency ..................................................................................................103 
10.3.4.2 Intensity .....................................................................................................104 
10.3.4.3 Causality/Relatedness ...............................................................................104 
10.3.4.4 Action Taken .............................................................................................105 
10.3.4.5 Outcome ....................................................................................................106 
10.3.4.6 Follow-up ..................................................................................................106 
10.3.4.7 Reference Safety Information ...................................................................107 
10.3.4.8 Unexpected AEs ........................................................................................107 
10.3.4.9 TEAEs .......................................................................................................107 
10.3.5 
Expedited Reporting of SAEs and Selected AEs ..............................................107 
10.3.5.1 Reporting of Abnormal Liver-Associated Test Results ............................108 
10.3.5.2 Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities .................................................................................................109 
10.3.6 
Reporting of Non-SAEs Related to Auxiliary Medicinal Products ...................109 
10.4 
Contraceptive and Barrier Guidance ..........................................................................109 
10.4.1 
Definitions .........................................................................................................109 
10.4.2 
Contraception Guidance ....................................................................................110 
10.4.3 
Pregnancy ..........................................................................................................113 
10.5 
Genetics......................................................................................................................113 
10.6 
Abnormal Liver-Associated Test Result Monitoring and Follow-up Assessments 
and Study Drug Restart/Rechallenge Guidelines .......................................................113 
10.7 
Country-Specific Requirements .................................................................................117 
10.8 
Abbreviations and Definitions ...................................................................................118 
10.8.1 
Abbreviations ....................................................................................................118 
10.9 
Protocol Amendment History ....................................................................................121 
REFERENCES ............................................................................................................................122 
 
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LIST OF TABLES 
Table 1.a 
Schedule of Activities ............................................................................................22 
Table 4.a 
Dosing Schedules by Weight .................................................................................33 
Table 6.a 
Study Interventions Administered .........................................................................45 
Table 6.b 
Study Intervention(s): Storage Conditions.............................................................48 
Table 10.a 
Protocol-Required Laboratory Tests ......................................................................95 
Table 10.b 
AE Subtypes Defined in This Section ...................................................................97 
Table 10.c 
Acceptable Contraception Methods and Lactation Guidance for This Study ......111 
Table 10.d 
Unacceptable Contraception Methods .................................................................112 
Table 10.e 
Hepatic Investigation ...........................................................................................116 
 
LIST OF FIGURES 
Figure 1.a 
Study Schema.........................................................................................................21 
Figure 10.a 
Abnormal Liver-Associated Test Results: Monitoring and Follow-up ...............115 
Figure 10.b 
Abnormal Liver-Associated Test Results: Considerations for Study Drug 
Discontinuation ....................................................................................................117 
 
LIST OF APPENDICES 
Appendix 1 
Strong CYP3A Inducers ......................................................................................123 
Appendix 2 
Blood Volumes ....................................................................................................124 
Appendix 3  
Minimizing Stress and Pain for Study Participants .............................................125 
 
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CONFIDENTIAL 
1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc. 
Compound: 
TAK-935 
Study Number: 
TAK-935-3004 
Phase: 
3 
IND No.: 
133627 
Abbreviated EU CT No.: 
2023-504104-29 
Title of Protocol: 
An Open-label, Nonrandomized, Phase 3 Study to Evaluate the Efficacy and Safety of Soticlestat in Participants 
With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have Been Exposed to Fenfluramine. 
Short Title: 
A Study Evaluating Soticlestat in Participants Who Have Been Exposed to Fenfluramine 
Number of Participants: 
This study plans to enroll approximately 45 participants; 15 participants with Dravet syndrome [DS] and 30 
participants with Lennox-Gastaut syndrome [LGS], approximately. 
Investigator(s): Multicenter study 
Site(s) and Region(s): United States, Europe 
Study Period (Planned): 
Q4 2023 to approximately Q1 2026 
Objectives and Endpoints: 
Objectives  
Primary Objective 
To assess the efficacy of soticlestat in participants with DS or LGS who have been exposed to fenfluramine. 
Exploratory Objectives 
•
To explore effects of soticlestat on seizure frequency, quality of life and non-seizure symptoms in
participants with DS or LGS who have been exposed to fenfluramine.
•
To explore safety and tolerability of soticlestat in participants with DS or LGS who have been exposed to
fenfluramine.
Endpoints  
Primary Endpoint: 
Percent change from baseline in convulsive (DS) and major motor drop (MMD) (LGS) seizure frequency per 28 
days during the initial 12 weeks of the maintenance period. 
Exploratory Endpoints: 
•
Percent change from baseline in convulsive (DS) /and MMD (LGS) seizure frequency per 28 days during
every 12 weeks after the initial 12 weeks of the maintenance period.
•
Percent change from baseline in convulsive (DS) and /MMD (LGS) seizure frequency per 28 days during the
initial 16 weeks of the treatment period (4 weeks of titration + initial 12 weeks of maintenance).
•
Percent change from baseline in total seizure frequency per 28 days of all seizure types during the initial 12
weeks of the maintenance period.
•
Percent change from baseline in total seizure frequency per 28 days of all seizure types during every 12
weeks after the initial 12 weeks of the maintenance period.
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• 
Percent change from baseline in total seizure frequency per 28 days of all seizure types during the initial 16 
weeks of the treatment period (4 weeks of titration + initial 12 weeks of maintenance). 
• 
Percent change from baseline in seizure frequency per 28 days of each seizure type identified at the time of 
screening or baseline during the maintenance period and full treatment period (52 weeks). 
• 
Treatment response as defined by ≥50% reduction in convulsive (DS) and MMD (LGS) seizure frequency 
per 28 days from baseline every 12 weeks after the initial 12 weeks of the maintenance period. 
• 
Treatment response as defined by ≥50% reduction in convulsive (DS) and MMD (LGS) seizure frequency 
per 28 days from baseline during the initial 16 weeks of the full treatment period (4 weeks of titration period 
+ initial 12 weeks of maintenance period). 
• 
Clinical Global Impression of Improvement (CGI-I) (clinician).  
• 
Caregiver Global Impression of Improvement (Care GI-I). 
• 
CGI-I Seizure Intensity and Duration. 
• 
CGI-I Non-seizure Symptoms completed by clinician with input from the caregivers. 
• 
Quality of Life Inventory-Disability (QI-Disability). 
• 
Change in EQ-5D 5-level version (EQ-5D-5L) and EQ-5D visual analogue scale (EQ VAS) scores.  
• 
Caregiver satisfaction questionnaire. 
• 
Days when rescue anti-seizure medication (ASM) is used. 
• 
The safety endpoints include 
– 
Incidence of treatment- emergent adverse events (TEAEs). 
– 
Columbia-Suicide Severity Rating Scale (C-SSRS).  
– 
Ophthalmological evaluations.  
Rationale: 
Currently, soticlestat is being studied in 2 global phase 3, multicenter, double-blind, randomized, placebo-
controlled, parallel-group studies in approximately 234 participants with LGS and 142 participants with DS. 
These studies will evaluate efficacy, safety, and tolerability of soticlestat as an adjunctive therapy in participants 
with DS and LGS and are expected to be completed during the TAK-935-3004 study. 
A multisite, phase 3, open-label extension (OLE) study TAK-935-3003 (ENDYMION 2) is ongoing to obtain 
additional safety and tolerability data related to soticlestat administered long-term in participants who participated 
in either of the antecedent phase 3 clinical studies, TAK-935-3001 (participants with DS) or TAK-935-3002 
(participants with LGS). 
The TAK-935-3004 study is specifically designed to obtain additional clinical efficacy, safety and tolerability 
data in participants who have been exposed to fenfluramine. In clinical practice ASMs are generally added on as 
standard of care. Because fenfluramine is expected to be part of standard of care ASM regimens but is not widely 
used in current clinical practice due to its recent approval in the European Union, we propose this study to 
evaluate soticlestat in participants with DS and LGS, who are previously or currently exposed to fenfluramine.  
There are no pharmacokinetic or pharmacodynamic interactions expected by combining soticlestat with 
fenfluramine. 
Study Drug, Dose, and Mode of Administration: 
In this study, the study drug is soticlestat. 
The total daily dose of soticlestat will be calculated based on body weight at Visit 1 (screening visit) and given 
twice a day (BID). The minimum dose allowed during the study is 100 mg BID (or 100 mg BID equivalent 
weight-based dosing for weight <45 kg). Participants weighing <45 kg will be dispensed 20 mg mini-tablets, if 
appropriate. Participants weighing ≥45 kg may be dispensed 20 mg mini-tablets or 100 mg tablets. The maximum 
allowed dose is 300 mg BID. Intermediate doses between dose levels may be allowed after discussion with 
medical monitor.  
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Overall Design and Methodology: 
This is a phase 3, open-label, nonrandomized, single-arm study in participants with DS or LGS who have been 
exposed to fenfluramine.  
“Exposure” is defined as participants who are current or prior users of fenfluramine 
Note: Participants who have discontinued fenfluramine for reasons of lack of efficacy or intolerability are eligible 
as prior users. 
Approximately 15 participants with DS and 30 participants with LGS will be enrolled in the study. 
The study will consist of the following periods: 
• 
A 4- to 6-week screening/baseline period. 
• 
Approximately 52-week full treatment period including:  
– 
A 4-week titration period.  
– 
Approximately 48-week maintenance period.  
• 
A 1-week taper period for those discontinuing study drug (participants not entering the phase 3 OLE study 
ENDYMION 2). 
• 
A safety follow-up visit or a phone call (participants not entering ENDYMION 2) to occur approximately 1 
week after the taper period concludes. 
 
The total daily dose of soticlestat will be calculated based on body weight at Visit 1 (screening visit) and given 
twice daily (BID). Participants will receive the initial dose of the study drug, ie. Dose 1 (100 mg BID adult 
reference dose, weight-based dosing for weight <45 kg) for the first 7 days of the dose titration period.  
Approximately 7 days after starting Dose 1, study drug dose will be increased to Dose 2 (200 mg BID adult 
reference dose, weight-based dosing for weight <45 kg) and continued for approximately 7 days. Seven days after 
receiving Dose 2, drug dose can be increased to Dose 3 (300 mg BID adult reference dose, weight-based dosing 
for weight <45 kg). If the participants do not experience any tolerability issues, they will remain on the Dose 3 for 
the remainder of the titration period, followed by a safety follow-up phone call. 
The minimum dose allowed during the study is 100 mg BID (weight-based dosing for weight <45 kg). 
Participants who cannot tolerate the minimum dose will be discontinued from the study. The dose may be 
decreased during the initial 12 weeks of maintenance period for safety or tolerability issues based on investigator 
clinical judgment. After the initial 12 weeks of maintenance period, intermediate doses between dose levels may 
be allowed after discussion with medical monitor.  
The final dose tolerated by the end of the 4-week titration period should be maintained during the first 12 weeks 
of the maintenance period unless tolerability issues arise.  
ASMs taken as standard of care, should remain stable for initial 12 weeks of the maintenance period, after which, 
doses can be adjusted based on standard of care and investigator judgement. 
Rescue medication dose can be adjusted throughout the study per standard of care (SOC).  
After the initial 12 weeks of maintenance period, dose of soticlestat can be adjusted according to participant 
weight changes and investigator judgement. At the end of the overall maintenance period, participants will have 
the option to enroll in the OLE study ENDYMION 2 at the same dose they were on in TAK-935-3004, as deemed 
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appropriate by the investigator.  
For participants not entering ENDYMION 2, the dose will be tapered for approximately 1 week (unless already at 
the lowest dose), followed by a safety follow-up visit or phone call approximately 2 weeks after the final 
visit/early termination. 
Benefit-Risk Profile:  
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 cholesterol-24-hydroxylase and clinical safety data). 
• 
Suicidal ideation or behaviors (class effect of ASMs). 
• 
Cataracts (based on nonclinical data). 
In prior studies, soticlestat was generally well tolerated in participants with developmental epileptic 
encephalopathies at doses up to 300 mg BID (with titration) of adult equivalent dose. 
Given the severe, profound, and chronic nature of DS and LGS, associated signs and symptoms, and impact on 
quality of life, and considering the potential benefits that soticlestat treatment can confer to patients affected by 
DS or LGS, the benefit-risk profile of soticlestat administration is acceptable in these populations.  
The phase 2 study, ELEKTRA showed that soticlestat treatment resulted in a significant median percent reduction 
from baseline in convulsive (DS) and MMD (LGS) seizure frequency compared with placebo in the combined 
population of DS and LGS during the maintenance period. It also showed statistically significant median percent 
reduction from baseline convulsive seizure frequency in participants with DS compared with placebo as well as a 
directional median percent reduction from baseline in drop seizure frequency in participants with LGS. Soticlestat 
was generally well tolerated, with findings consistent with those from previous studies. We will further evaluate 
these findings in participants who were exposed to fenfluramine in this study.  
Inclusion and Exclusion Criteria:  
Inclusion Criteria: 
1. In the opinion of the investigator, the participant or the participant’s parent or legal guardian or caregiver is 
capable of understanding and complying with protocol requirements, complete appropriate assessments, 
maintain an accurate and complete daily seizure diary and take study drug for the duration of the study. 
If the participant is living in a residential facility, a minimally possible number of staff member(s) at the 
facility who are the participant’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 participant/participant’s legally acceptable representative has provided informed consent (that is, in 
writing, documented via a signed and dated informed consent form) and any required privacy authorization 
before the initiation of any study procedures. 
3. The participant, of any sex, aged ≥2 years, at the time of informed consent. 
4. The participant has a documented clinical diagnosis of DS supported by variable combinations of typical 
clinical features such as those noted as follows and as determined by the investigator. 
– 
Onset of seizures usually in the first year of life.  
– 
History of fever-induced prolonged seizure as determined by the investigator 
– 
May include prolonged (approximately 15 minutes or longer) hemi-clonic seizures. 
– 
Multiple seizure types, which may include: 
• 
Generalized tonic-clonic.  
• 
Focal to bilateral tonic-clonic. 
• 
Clonic. 
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• 
Myoclonic 
– 
History of developmental delay/intellectual disability presenting after onset of seizures and usually 
presenting after 12 months of age. 
– 
Documented genetic mutation consistent with DS is not required, but results of genetic testing will be 
collected if available. If genetic testing was not performed previously or if the SCN1A result is negative 
(without any other positive gene reported that is consistent clinically with DS), testing for SCN1A will 
be offered at the time of screening, per local restrictions.  
OR 
The participant has a documented clinical diagnosis of LGS supported by variable combinations of typical 
clinical features such as those noted as follows and as determined by the investigator. 
– 
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) results (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. The participant has experienced failure of treatment 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. 
6. The participant has been exposed to fenfluramine (currently on or used previously).  
Note: Participants, who have discontinued fenfluramine for reasons of lack of efficacy or intolerability are 
eligible as prior users. 
7. The participant has a clinical diagnosis of LGS and a history of, on average, ≥12 MMD seizures in the last 90 
days immediately before screening based on historical information, and the participant has ≥4 MMD seizures 
during a minimum of 4 weeks of seizure data collection during the prospective baseline period. 
The total number of seizures includes only primary outcome seizure types with documentation as determined 
by the investigator: 
– 
Hemi-clonic or focal clonic. 
– 
Focal to bilateral tonic-clonic. 
– 
Generalized tonic-clonic. 
– 
Bilateral clonic. 
– 
Convulsive status. 
– 
Focal 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. 
OR 
The participant has a clinical diagnosis of DS and a history of, on average, ≥9 convulsive seizures in the last 
90 days before screening visit based on the historical information, and the participant has ≥3 convulsive 
seizures during a minimum of 4 weeks of seizure data collection during the prospective baseline period. 
The total number of seizures includes only primary outcome seizure types with documentation as determined 
by the investigator: 
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– 
Hemi-clonic or focal clonic. 
– 
Focal to bilateral tonic-clonic. 
– 
Generalized tonic-clonic. 
– 
Bilateral clonic. 
– 
Convulsive status. 
8. The participant weighs ≥10 kg at the screening visit (Visit 1). 
9. Artisanal cannabidiols/nonpharmaceutical grade cannabidiols are allowed. Participants should be on a stable 
dose for at least 4 weeks before the screening visit (Visit 1); the dosing regimen and manufacturer should 
remain constant during the initial 16 weeks of treatment period (including 4 weeks of titration period and 12 
weeks of maintenance period) of the study. (Artisanal cannabidiols will not be counted as ASMs.) 
10. The participant is currently taking 0 to 5 antiseizure treatments (eg. VNS, ketogenic diet) at stable doses, of 
which:  
a) Four can be ASMs, before the screening visit (Visit 1); benzodiazepines used chronically (daily) to treat 
seizures are considered ASMs. Cannabidiol (Epidiolex) is allowed where available and should be 
counted as an ASM. ASM dosing regimen must remain constant during the initial 16 weeks of treatment 
period (4 weeks of titration + initial 12 weeks of maintenance).  
b) If using a VNS, the participant must have had VNS placed at least 3 months before the screening visit 
(Visit 1) with stable settings for at least 4 weeks before the screening visit (Visit 1); VNS parameters 
must remain constant during the initial 16 weeks of treatment period (4 weeks of titration + initial 12 
weeks of maintenance) of the study.  
c) If on a ketogenic diet (or any other diet used for treatment of epilepsy, such as modified Atkins diet), the 
participant must have started the diet at least 3 months before the screening visit (Visit 1), and the 
participant’s diet should be stable for 4 weeks before the screening visit (Visit 1); the participant should 
continue this diet during the initial 16 weeks of treatment period (4 weeks of titration + initial 12 weeks 
of maintenance) of the study. 
11. The use of felbamate is allowed provided that the participant does not meet the liver function test exclusion 
criteria, the dose has been stable for at least 6 months before the screening (Visit 1), and the participant has 
had stable liver function (as determined by serum aspartate aminotransferase and alanine aminotransferase 
levels) and hematology laboratory tests during the course of treatment. 
12. Participants of childbearing potential (defined as first menarche) must have a negative pregnancy test and 
agree to use an effective (not applicable for Germany) or highly effective method of birth control (as defined 
in this protocol) during the study and for 30 days following the last dose of study drug. 
Exclusion Criteria: 
1. The participant is not an 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. The participant is not Takeda employee or immediate family member. 
3. The participant is currently enrolled in a clinical study involving an investigational product or treatment 
device (ie, not approved in that country, other than soticlestat), or concurrently enrolled in any other type of 
medical research judged not to be scientifically or medically compatible with this study.  
Note: Compatibility will be determined on the basis of consultation with the sponsor/designee. 
4. The participant has 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. The participant has a known hypersensitivity to any component of the soticlestat formulation. 
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6. The participant has an 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 sponsor/designee may be warranted. 
7. The participant has any history of alcohol, opioid, or other drug use disorder, per the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition, within 2 years of the screening visit (Visit 1). 
8. The participant is considered by the investigator to be at imminent risk of suicide or injury to self, others, or 
property, or the participant has attempted suicide within 12 months before the screening visit (Visit 1). 
Participants aged ≥6 years 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 participants aged ≥6 years at the time of 
enrollment or participants who turn 6 after enrollment. 
9. The participant is unable to withhold the use of strong inducers of cytochrome P450(CYP 3A4) during the 
entire clinical study, (except for ASMs [eg, carbamazepine, phenobarbital, phenytoin] and topical 
preparations). 
10. The participant is currently pregnant or breastfeeding or is planning to become pregnant within 30 days of 
the last dose of study drug. 
Drug Groups and Duration, Including Maximum Duration of Participant Involvement in the Study: 
The total duration of study participation for each participant includes:  
Planned duration of screening period: 4 to 6 weeks 
Planned duration of enrollment/treatment period: Approximately 4 weeks of titration period and 48 weeks of 
maintenance period. 
Planned duration of follow-up: 2 weeks (if not enrolled into ENDYMION 2) 
Statistical Analysis:  
Safety analysis set: All participants who take at least 1 dose of study drug. 
Intent-to-treat (ITT) analysis set: All participants who enroll in the study. 
Modified intent-to-treat (mITT) analysis set: All enrolled participants who take at least 1 dose of study drug 
and are assessed for seizures for at least 1 day in the treatment period. 
Efficacy analyses will be performed using the mITT analysis set. Results will be presented separately for the DS 
and LGS cohorts using descriptive statistics.  
For all efficacy analyses on seizure frequency, baseline refers to the prospective 4- to 6-week screening/baseline 
period.  
Percent change from baseline in primary seizure frequency (convulsive for DS and MMD for LGS) per 28 days 
during the initial 12 weeks of the maintenance period will be summarized using descriptive statistics including 
mean, median, SD, first quartile, third quartile, minimum, and maximum. A distribution-free 95% CI for the 
median will be presented.  
Other percent change from baseline in seizure frequency endpoints will be summarized similarly to the primary 
endpoint. Percent change from baseline in seizure frequency (convulsive for DS and MMD for LGS) per 28 days 
and total seizure frequency per 28 days will be summarized for the initial 16 weeks of the treatment period (4 
weeks of titration + initial 12 weeks of maintenance), and every 12-week period thereafter. 
Descriptive summaries of CGI-I, Care GI-I, CGI-I Seizure Intensity and Duration, CGI-I Nonseizure Symptoms, 
QI-disability, caregiver satisfaction, and EQ-5D-5L will be presented for each scheduled collection time point 
and at end of study. Global impression of improvement scales (CGI-I, Care GI-I, CGI-I Seizure Intensity and 
Duration, and CGI-I Nonseizure Symptoms) will also be summarized dichotomously in terms of the number and 
proportion of participants who gave responses of minimally improved or better. Two-sided 95% CIs will be 
presented for proportions for dichotomous categories. Other binary endpoints will be summarized in a similar 
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fashion, as appropriate. 
The EQ VAS score and the total score for QI-Disability will also be summarized in terms of change from 
baseline at each collection time point. EQ-5D-5L will be summarized descriptively by visit including baseline by 
presenting the number and percentage of responses in each level within each dimension.  
The proportion of days when rescue ASM is used during the study period will be summarized descriptively.  
Details will be provided in the statistical analysis plan for appropriate summaries based on data type for these 
assessments. 
Analyses will be based on as-observed data. No imputation will be implemented. Baseline assessment for 
efficacy analyses other than seizure is the assessment prior and closest to the first administration of the study drug 
unless otherwise specified. 
Interim data cuts from this ongoing study will be analyzed to support any regulatory submissions. Since there is 
no hypothesis testing involved, no interim analysis will require spending any type-I error. 
Safety analyses will be performed using the safety analysis set. Results will be presented descriptively. Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities. TEAEs will be summarized using 
Preferred Terms and primary System Organ Classes. 
Data summaries will be displayed for incidence of TEAEs, clinical laboratory variables, and vital sign 
parameters. Ophthalmological evaluations and C-SSRS will be listed by participant. 
Data Monitoring/Other Committee: No 
 
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1.2 
Schema 
Figure 1.a 
Study Schema 
 
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c The investigator is expected not to adjust concomitant ASM(s) as well as calories of ketogenic diet and VNS setting through during the baseline period. The minimum duration 
for screening is 28 days and maximum is 42 days. 
d The investigator is expected not to adjust concomitant ASM(s) as well as calories of ketogenic diet and VNS setting during the titration period through the initial 16 weeks of 
treatment period (4 weeks of titration period + initial 12 weeks of maintenance period).  
e Dose reductions during the first 12 weeks of the maintenance period are allowed for safety or tolerability reasons only as assessed by the investigator; dose changes will need to 
be discussed with the sponsor/designee. 
f Taper period (up to 1 week) and follow-up period (1 week after the taper period concludes) will not be required for participants enrolling in extension study (ENDYMION 2). 
Follow-up visit to occur approximately 1 week after taper period concludes. Same course to be followed for ET participants. 
g If the date of a participant visit does not conform to the study plan, the timing of subsequent visits should be planned so that the visit schedule relative to Day 1 is maintained. 
Note: this does not apply to dose titration days. 
h Visit is encouraged to be in-person but can be virtual based on investigator judgement. If virtual, investigator should conduct CGI scales via video at minimum. The remaining 
scales may be conducted via phone. 
i Virtual visits are allowed if aligned with institutional or local guidelines, via phone or via any platforms approved by local regulations. Participants may be seen at times other 
than indicated in the schedule of assessments if clinically required.  
j It is recommended to stabilize participants at the participant’s optimal dose level before proceeding to the maintenance period (eg, do not start participants on 300 mg 1 day before 
the maintenance period). There is no specific requirement to stay at a dose level if not tolerated. Investigator’s judgment will be used to determine the optimal dose based on 
participant’s tolerability and response. Taper down procedures including participant monitoring should be followed. 
k Participants will take the initial dose of study drug (Dose 1) the morning after the enrollment day (Day -1). For participants receiving the study drug at home through courier 
should take it the morning after they receive it, therefore for these participants Day 1 may not immediately follow Day -1. Dose 2 and Dose 3 are started the evening of dose 
titration (Day 8 [Visit 4] and Day 15 [Visit 5], respectively).  
l Approximately 2 days after starting Dose 1 and after each dose change or taper, sites should contact participants 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 adverse events. These safety checks are calculated as approximately 2 
days after starting Dose 1, Dose 2, and Dose 3, respectively. Additional monitoring during optimization period is permissible based on investigator’s clinical judgement. 
m This is NOT a study visit, hence, no study procedures will be performed. The study participants are not required to visit. At approximately Day 56, caregivers will return to the 
site for the purposes of drug dispensing, return of paper diaries and unused study drug. 
n At Day 364/ET, participants who do not enroll in the extension study (ENDYMION 2) that day will be dispensed study drug to taper down, and they will begin taking the taper 
down study drug. in the evening of the Day 364/ET visit. 
o Participants who do not continue into the extension study (ENDYMION 2) will undergo the dose taper procedures and safety follow-up visit/call. 
p Participants who enroll in the extension study (ENDYMION 2) that day (Day 364/ET) should take their final dose of TAK-935-3004 open-label study drug in the evening of the 
day of Day 364/ET. 
q Investigator to sign-off via target eligibility form.  
r Weight only to be collected at these visits (height is not required). 
s For participants of childbearing potential, pregnancy test at Visit 2 (Day -1/enrollment) is not required for eligibility if Visit 1 (screening) test is negative and if the investigator 
does not deem it necessary to repeat pregnancy test at Visit 2 (Day -1/enrollment). Urine hCG pregnancy tests will also be performed at Visit 7, 8, 9, and 10 (Day 364)/ET. 
Additional pregnancy tests (serum or urine) may be performed throughout the study at the investigator’s discretion. The investigator can do a serum hCG test at a local laboratory 
to confirm any positive urine hCG test.  
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t Clinical laboratory tests can be performed anytime during 4 to 6 weeks of screening period. Unscheduled/retests are allowed at investigator discretion. Volume will not exceed 2.4 
mL/kg of body weight during any 4-week period. 
u These evaluations are to be conducted at baseline (between the screening and enrollment visits), at Day 112 (±2 weeks) and at Day 364 (±1 week) or at the ET visit (±1 week) for 
those participants who do not complete the study. 
v Two versions of the C-SSRS will be used for all participants aged ≥6 years. The C-SSRS Children’s Screening/Baseline (recall period lifetime/12 months) will be completed at 
the screening (Visit 1) and the C-SSRS Children’s Since-Last-Visit at subsequent visits. Children who are younger than 6 years at the start of the study will have an unscheduled 
visit after turning age 6 years, 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. 
w For assessing baseline Care GI and overall CGI (clinician), the clinician will interview the caregiver and complete the CGI Baseline–Care GI Baseline questionnaire provided by 
the sponsor. The clinician will use this same questionnaire to record their own CGI baseline assessment. This is for the clinician and caregiver’s reference for completing the CGI-I 
(clinician only) and Care GI-I after baseline and hence responses may not be required to be recorded in eCRF. 
x For assessing baseline CGI-I Nonseizure Symptoms, site rater will complete the CGI Baseline–Nonseizure Symptoms questionnaire provided by sponsor instead of the CGI-I 
Nonseizure Symptoms scale. This is to be completed by the clinician and for the clinician’s reference for completing the CGI-I Nonseizure Symptoms after baseline and hence 
responses may not be required to be recorded in eCRF. 
y For assessing baseline CGI-I Seizure Intensity and Duration, site rater will complete the CGI Baseline–Seizure Intensity and Duration questionnaire provided by the sponsor 
instead of the CGI-I Seizure Intensity and Duration scale. This is to be completed by the clinician and for the clinician’s reference for completing the CGI-I Seizure Intensity and 
Duration after baseline and hence responses may not be required to be recorded in eCRF. 
z A questionnaire to be provided to caregiver for completion to assess overall satisfaction with soticlestat. 
aa The dispensing of study drug (soticlestat) will be performed at the enrollment visit (Visit 2), approximately Day 56 (Week 8), Day 112 (Week 16) and then every 3 months. If 
additional study drug needs to be dispensed, enter as an unscheduled visit. Note: Site may not courier study drug to participants in locations where it is not permitted. 
bb The investigator will determine the frequency and timing of study drug (soticlestat) return, compliance, and accountability. 
cc For participants with DS only: If genetic testing was not performed previously or if the SCN1A result is negative (without any other positive gene reported that is consistent 
clinically with DS), testing for SCN1A will be offered at the time of screening, per local restrictions.  
 
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2.0 
INTRODUCTION  
2.1 
Study Rationale  
Currently, soticlestat is being studied in 2 global phase 3, multicenter, double-blind, randomized, 
placebo-controlled, parallel-group studies in approximately 234 participants with 
Lennox-Gastaut syndrome (LGS) and 142 participants with Dravet syndrome (DS). These 
studies will evaluate efficacy, safety, and tolerability of soticlestat as an adjunctive therapy in 
participants with DS and LGS and are expected to be completed during the TAK-935-3004 
study.  
A multisite, phase 3, open-label extension (OLE) study TAK-935-3003 (ENDYMION 2) is 
ongoing to obtain additional safety and tolerability data related to soticlestat administered long-
term in participants who participated in either of the antecedent phase 3 clinical studies, 
TAK-935-3001 (participants with DS) or TAK-935-3002 (participants with LGS). 
The TAK-935-3004 study is specifically designed to obtain additional clinical efficacy, safety 
and tolerability data in participants who have been exposed to fenfluramine. In clinical practice 
antiseizure medications (ASMs) are generally added on as standard of care (SOC). 
There are no pharmacokinetic (PK) or pharmacodynamic (PD) interactions expected by 
combining soticlestat with fenfluramine. 
Due to its recent approval in the European Union (EU), fenfluramine is not widely used in 
current clinical practice, although it is expected to be part of the SOC ASM regimens. This study 
evaluates soticlestat in participants with DS and LGS, who are currently or previously exposed to 
fenfluramine. 
2.2 
Background  
DS or severe myoclonic epilepsy in infancy is one of the best described disorders of epileptic 
encephalopathies. Clinically, DS is characterized at onset by frequent convulsive febrile seizures, 
followed later by frequent status epilepticus and nonfebrile seizures that are mainly clonic, 
unilateral, and of long duration (Dravet 2011). 
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 in adulthood. LGS includes the presence of multiple seizure types: 
including 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 convulsive seizure control in participants with DS 
and major motor drop (MMD) seizure control in participants with LGS. 
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Nonclinical studies have demonstrated that soticlestat modulates glutamatergic signaling and 
significantly reduces spontaneous seizures in murine models of DS. Additional details on the 
nonclinical program are provided in Section 3 of the current investigator’s brochure (IB). 
Clinical Study TAK-935-2002 (ELEKTRA) showed efficacy of soticlestat in participants with 
DS or LGS. ELEKTRA was a phase 2, multicenter, randomized, double-blind, 
placebo-controlled study that evaluated the efficacy, safety, tolerability, PK, and PD of 
soticlestat as adjunctive therapy in pediatric participants aged ≥2 and ≤17 years with LGS or DS. 
A total of 141 participants were enrolled (51 with DS and 90 with LGS), and 126 completed the 
study. Participants 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 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). Participants who met the entry 
criteria were stratified by syndrome and randomized in a 1:1 ratio to soticlestat or matching 
placebo within each cohort. Participants 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. Participants 
weighing <60 kg received weight-based equivalent doses.  
In the DS cohort (N = 51), participants treated with soticlestat demonstrated a 33.8% median 
reduction in convulsive seizure frequency compared with a 7.0% median increase seen in 
participants 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 participants 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% 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 participants with DS and LGS showed 
improvement than those receiving placebo (26.9% vs 8% and 27.9% vs 11.1%, respectively) as 
deemed by the investigator. 
Caregivers also rated greater improvement in 57.7% and 51.2% of soticlestat-treated participants 
with DS and LGS 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 participants (80.3%) who received 
soticlestat experiencing at least 1 TEAE compared with 52 participants (74.3%) who received 
placebo. The most common TEAEs in the soticlestat group were upper respiratory tract 
infection, pyrexia, seizure, nasopharyngitis, decreased appetite, and vomiting. The most frequent 
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TEAEs reported in soticlestat-treated participants with ≥5% difference from placebo were 
lethargy and constipation. The incidence of serious TEAEs was similar in both soticlestat and 
placebo groups, with 11 participants (15.5%) in the soticlestat group experiencing at least 
1 serious TEAE compared with 13 participants (18.6%) in the placebo group. Four participants 
(5.6%) in the soticlestat group discontinued the study due to TEAEs compared with 
3 participants (4.3%) in the placebo group. 
An open-label study (TAK-935-18-001, ENDYMION 1) of participants with developmental 
epileptic encephalopathies (DEEs) is currently in progress. In addition to ELEKTRA, 
participants from other soticlestat phase 1b/2a or 2 studies were eligible to roll over into 
ENDYMION 1. These include TAK-935-2001, a phase 1b/2a study of soticlestat in a 
multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study 
with an open-label part designed to examine the safety, tolerability, PK, and PD of soticlestat as 
adjunctive therapy (to antiepileptic drugs) in 18 adult participants diagnosed with a DEE, and 
TAK-935-18-002 (ARCADE), an open-label, parallel-group study in participants with 
chromosome 15q duplication syndrome or cyclin-dependent kinase-like 5 deficiency disorder 
demonstrating ≥4 bilateral motor seizures per month 
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 IB. 
2.3 
Benefit-Risk Assessment  
In the phase 1b/2a TAK-935-2001, phase 2 ELEKTRA, and open-label pilot ARCADE studies, 
the safety and tolerability data indicate that soticlestat was generally well tolerated in participants 
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 (based on 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 participants with DS and LGS. 
DS is characterized by treatment-resistant seizures, presenting at a very young age. In addition, 
mortality is especially high in DS (up to 21%) (Shmuely et al. 2016), even compared with other 
epilepsy syndromes, with a 30-fold higher rate of sudden unexpected death in epilepsy that 
accounts for up to 60% of deaths in these patients (Richards et al. 2018). Given the severe, 
profound, and chronic nature of DS and its associated signs and symptoms and their impact on 
quality of life, and considering the potential benefits that soticlestat treatment can confer to 
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patients affected by DS, the benefit-risk profile of soticlestat administration is acceptable for this 
population. 
LGS is characterized by multiple treatment-resistant seizure types, electroencephalogram (EEG) 
findings, and intellectual impairment. 
In prior studies, soticlestat was generally well tolerated in participants with DEEs at doses up to 
300 mg BID of adult equivalent dose. 
Given the severe, profound, and chronic nature of DS and LGS, their associated signs and 
symptoms, and impact on quality of life, and considering the potential benefits that soticlestat 
treatment can confer to patients affected by DS or LGS, the benefit-risk profile of soticlestat 
administration is acceptable in these populations.  
The phase 2 study, ELEKTRA showed that soticlestat treatment resulted in a significant median 
reduction from baseline in convulsive (DS) and MMD (LGS) seizure frequency compared with 
placebo in the combined population of DS and LGS during the maintenance period. It also 
showed statistically significant median percent reduction from baseline convulsive seizure 
frequency in participants with DS compared with placebo as well as a directional median percent 
reduction from baseline in drop seizure frequency in participants with LGS. Soticlestat was 
generally well tolerated, with findings consistent with those from previous studies. We will 
further evaluate these findings in participants who were exposed to fenfluramine in this study. 
3.0 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objectives 
To assess the efficacy of soticlestat in participants with DS or LGS who have been exposed to 
fenfluramine. 
3.1.2 
Exploratory Objectives 
• To explore effects of soticlestat on seizure frequency, quality of life and nonseizure 
symptoms in participants with DS or LGS who have been exposed to fenfluramine. 
• To explore safety and tolerability of soticlestat in participants with DS or LGS who have 
been exposed to fenfluramine 
3.2 
Endpoints  
3.2.1 
Primary Endpoint 
Percent change from baseline in convulsive (DS) and MMD (LGS) seizure frequency per 
28 days during the initial 12 weeks of the maintenance period. 
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3.2.2 
Exploratory Endpoints 
• Percent change from baseline in convulsive (DS) and MMD (LGS) seizure frequency per 
28 days during every 12 weeks after the initial 12 weeks of the maintenance period. 
• Percent change from baseline in convulsive (DS) and MMD (LGS) seizure frequency per 
28 days during the initial 16 weeks of the treatment period (4 weeks of titration period + 
initial 12 weeks of maintenance period). 
• Percent change from baseline in total seizure frequency per 28 days of all seizure types 
during the initial 12 weeks of the maintenance period. 
• Percent change from baseline in total seizure frequency per 28 days of all seizure types every 
12 weeks after the initial 12 weeks of the maintenance period. 
• Percent change from baseline in total seizure frequency per 28 days of all seizure types 
during the initial 16 weeks of the treatment period (4 weeks of titration period + initial 
12 weeks of maintenance period). 
• Percent change from baseline in seizure frequency per 28 days of each seizure type identified 
at the time of screening or baseline during the maintenance period and full treatment period 
(52 weeks). 
• Treatment response as defined by ≥50% reduction in convulsive (DS) and MMD (LGS) 
seizure frequency per 28 days from baseline every12 weeks after the initial 12 weeks of the 
maintenance period. 
• Treatment response as defined by ≥50% reduction in convulsive (DS) and MMD (LGS) 
seizure frequency per 28 days from baseline during the initial 16 weeks of the full treatment 
period (4 weeks of titration period + initial 12 weeks of maintenance period). 
• Clinical Global Impression of Improvement (CGI-I) (clinician).  
• Caregiver Global Impression of Improvement (Care GI-I). 
• CGI-I Seizure Intensity and Duration. 
• CGI-I Nonseizure Symptoms completed by clinician with input from the caregivers. 
• Quality of Life Inventory-Disability (QI-Disability). 
• Change in EQ-5D 5-level version (EQ-5D-5L) and EQ-5D visual analogue scale (EQ VAS) 
scores.  
• Caregiver satisfaction questionnaire. 
• Days when rescue ASM is used. 
• The safety endpoints include 
– Incidence of TEAEs. 
– Columbia-Suicide Severity Rating Scale (C-SSRS).  
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– Ophthalmological evaluations. 
4.0 
STUDY DESIGN  
4.1 
Overall Design  
This is a phase 3, open-label, nonrandomized, single-arm study in participants with DS or LGS 
who have been exposed to fenfluramine.  
“Exposure” is defined as participants who are current or prior users of fenfluramine. 
Note: Participants who have discontinued fenfluramine for reasons of lack of efficacy or 
intolerability are eligible as prior users. 
Approximately 15 participants with DS and 30 participants with LGS will be enrolled in the 
study. 
The study will consist of the following periods: 
• A 4- to 6-week screening/baseline period.  
• Approximately 52-week full treatment period including:  
– A 4-week titration period.  
– Approximately 48-week maintenance period. 
• A taper period (up to 1 week) and follow-up period (1 week after the taper period concludes); 
this will not be required for participants enrolling in the extension study (ENDYMION 2).  
• Follow-up visit/call occurs approximately 1 week after the taper period concludes.  
This is an open-label study to receive standard-of-care plus soticlestat in participants who have 
been exposed to fenfluramine. Soticlestat added to current antiseizure therapy will be 
administered orally BID with or without food (oral or enteral feeds including but not limited to 
nasogastric tube [NG-tube] or via gastrostomy tube [G-tube] or low-profile gastric tube 
(Mic-Key Button), or a jejunostomy tube [J-tube]). See Section 6.2.6.2 for more details about 
study drug administration. 
The total daily dose of study drug (soticlestat) will be calculated on the basis of body weight at 
Visit 1 (screening visit) and given BID. The dosing schedules by weight are shown in Table 4.a. 
The minimum dose allowed during the study is 100 mg BID (or 100 mg BID equivalent 
weight-based dosing for weight <45 kg). Participants who cannot tolerate the minimal dose will 
be discontinued from the study. Participants weighing <45 kg will be dispensed 20 mg 
mini-tablets. Participants weighing ≥45 kg may be dispensed 20 mg mini-tablets or 100 mg 
tablets.  
Intermediate doses between dose levels may be allowed after discussing with the medical 
monitor.  
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Table 4.a 
Dosing Schedules by Weight 
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 
10 to <15 kg Weight Reference Dose 
Soticlestat 
40 mg 
BID 
2 mini-tablets 
soticlestat BID 
60 mg 
BID 
3 mini-tablets 
soticlestat BID 
100 mg 
BID 
5 mini-tablets 
soticlestat BID 
15 to <30 kg Weight Reference Dose 
Soticlestat 
60 mg 
BID 
3 mini-tablets 
soticlestat BID 
120 mg 
BID 
6 mini-tablets 
soticlestat BID 
200 mg 
BID 
10 mini-tablets 
soticlestat BID 
30 to <45 kg Weight Reference Dose 
Soticlestat 
80 mg 
BID 
4 mini-tablets 
soticlestat BID 
140 mg 
BID 
7 mini-tablets 
soticlestat BID 
200 mg 
BID 
10 mini-tablets 
soticlestat BID 
≥45 kg Weight Reference Dose 
Soticlestat 
100 mg 
BID 
1 tablet soticlestat 
BID  
OR 
5 mini-tablets 
soticlestat BID 
200 mg 
BID 
2 tablets 
soticlestat BID 
OR 
10 mini-tablets 
soticlestat BID 
300 mg 
BID 
3 tablets 
soticlestat BID 
OR 
15 mini-tablets 
soticlestat BID 
BID: twice daily. 
Participants <45 kg may request adult size tabs for Dose 3 only. 
 
The dose can be adjusted according to the participant’s weight change after completing the initial 
12 weeks of the maintenance period, per investigator judgement. 
ASMs taken as SOC, should remain stable for initial 12 weeks of the maintenance period, after 
which, doses can be adjusted based on SOC and investigator judgement.  
Rescue medication dose can be adjusted throughout the study as per SOC. 
Soticlestat doses should also remain stable for initial 12 weeks of maintenance period, after 
which it can be adjusted according to participant weight changes and investigator judgement. 
The study design allows virtual visits to be conducted via phone or an appropriate platform(s) as 
long as approved and aligned with institutional or local guidelines. The decision to perform a 
visit virtually is at the discretion of the investigator. 
Screening (Visit 1), Visit 7 and final visit/early termination (ET) must be conducted in clinic or 
in person (home visits). Safety calls may be conducted virtually.  
All other visits can be virtual (visits including assessment of Clinical Global Impression [CGI] 
scale[s] should be conducted via video call, not phone call), at investigator discretion and if 
permitted by local regulations. Additionally, home health visits may be conducted by site staff at 
the discretion of the investigator and if permitted by local regulations. During home visits, 
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assessment of CGI scale(s) should be conducted via video call and not phone call (if qualified 
rater is not present in person during home visit). 
In addition, any visit identified as virtual in this protocol may be conducted in clinic and in 
person if requested by the participant/parent or guardian and/or at the investigator’s discretion.  
4.1.1 
Dose Titration Period (4 Weeks)  
Participants will take the initial dose of study drug, that is, Dose 1 (100 mg BID adult reference 
dose, weight-based dosing for weight <45 kg) the morning after the enrollment day (Day -1). 
Participants receiving the study drug at home through a courier should take it the morning after 
they receive it.  
Approximately 7 days after starting Dose 1, study drug dose will be increased to Dose 2 (200 mg 
BID adult reference dose, weight-based dosing for weight <45 kg) and continued for 
approximately 7 days. Seven days after receiving Dose 2, the drug dose can be increased to, 
Dose 3 (300 mg BID adult reference dose, weight-based dosing for weight <45 kg). If the 
participants do not experience any tolerability issues, they will continue Dose 3 for the remainder 
of the titration period. 
Participants will only be allowed to increase their dose within the 4-week titration period. A 
decrease in dose level (to Dose 2 or Dose 1) is allowed during the titration period if required for 
safety and tolerability. Intermediate doses between scheduled dose levels may be allowed after 
discussing with the medical monitor. 
Participants who cannot tolerate the minimum dose of 100 mg BID (or weight-based equivalent 
dosing for participants weighing <45 kg) will be discontinued from the study. The maximum 
allowed dose is 300 mg BID (or weight-based equivalent dosing for participants weighing 
<45 kg). 
The participants/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 and again at the 
end of the titration period for that dose. The final dose tolerated by the end of the 4-week 
titration period should be maintained during the initial 12 weeks of the maintenance period 
unless tolerability issues arise.  
Any changes to the dose levels provided in Table 4.a may be allowed after further discussion 
with medical monitor. 
4.1.2 
Maintenance Period (Approximately 48 Weeks)  
In the absence of safety or tolerability considerations, the final dose level at the end of the 
titration period should be maintained for first 12 weeks of the maintenance period. The dose can 
be adjusted according to the participant’s weight change after completing the initial 12 weeks of 
the maintenance period. 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 (300 mg 
BID adult reference dose, weight-based dosing for weight <45 kg) may be reduced to Dose 2 
(200 mg BID adult reference dose, weight-based dosing for weight <45 kg), and Dose 2 may be 
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reduced to Dose 1 (100 mg BID adult reference dose, weight-based dosing for weight <45 kg). 
The minimum dose is Dose 1; participants who cannot tolerate the minimum dose will be 
discontinued from the study. The dose may be decreased during the initial 12 weeks maintenance 
period for safety or tolerability reasons as assessed by the investigator; however, if possible, dose 
changes should be discussed with the sponsor/designee. After the initial 12 weeks of 
maintenance period, intermediate doses between dose levels may be allowed after discussion 
with the medical monitor. 
4.1.3 
Study Discontinuation/Completion 
At the end of overall maintenance period, at Visit 10, participants will have the option to enroll 
into the OLE study ENDYMION 2 on the dose they are receiving in the maintenance period in 
TAK-935-3004, as deemed appropriate by the investigator.  
Participants not entering ENDYMION 2, will begin a 1-week taper period (unless already at the 
lowest dose). During the 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) no more frequently than every 3 days until the 
study drug is discontinued. On completion of the taper period a safety phone call or visit will be 
completed approximately 2 weeks after the participant’s final visit/ET.  
Participants who terminate the study early for reasons other than safety/tolerability may also 
have the opportunity to join ENDYMION 2 study at sponsor discretion. 
4.1.4 
Period of Evaluation  
Approximately 60 weeks (including up to 6-week screening/baseline period, 52-week treatment 
period [4-week titration and 48-week maintenance periods], 1-week taper period for those 
discontinuing study drug, followed by a safety follow-up visit/call 1 week after the taper period 
ends. 
For a schematic of the study design, see Section 1.2. For the Schedule of Activities (SoA), see 
Section 1.3. 
4.2 
Scientific Rationale for Study Design  
DS and LGS are rare and severe forms of epilepsies that begin in early childhood. These are 
lifelong conditions that lead to significant neurological and developmental problems including 
severe cognitive disabilities and can also increase the risk of sudden unexpected death in 
epilepsy. Although there are over 30 ASMs used to treat seizures in this patient population in the 
clinical settings, approximately 40% of these patients continue to have treatment refractory 
seizures and will comprise the target patient population for this study. 
This study is designed to obtain additional clinical efficacy and safety data of soticlestat in 
participants who have been exposed to fenfluramine.  
Fenfluramine is approved for the treatment of DS and LGS by the Food and Drug Administration 
(FDA) and has recently received a marketing authorization in the EU for DS and LGS. The 
real-world data regarding its efficacy is limited due to the recent approval and few participants 
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with prior or concomitant use of fenfluramine are expected to be enrolled in the ongoing phase 3 
studies of soticlestat. 
This study will provide additional safety and effectiveness data of soticlestat as an add-on 
therapy in participants previously or currently exposed to fenfluramine. This study will be 
enrolling participants in countries where fenfluramine is recently approved for the treatment of 
seizures in DS and LGS.  
Additional aims are to explore efficacy as assessed by the investigator (characterized by CGI-I) 
as well as by the caregivers, CGI-I in nonseizure-related symptoms, impact on quality of life, and 
the safety, tolerability, of soticlestat administration in pediatric and adult participants with DS 
and LGS. 
4.2.1 
Participant Input Into Design  
Not applicable as participants/caregiver input was not required in this study design.  
4.3 
Justification for 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 participants; the safety, 
tolerability, and PK data from the phase 1b/2a study of soticlestat as adjunctive therapy in adult 
participants with DEEs; and the efficacy, safety, PK, and PD data in the ELEKTRA study in 
pediatric participants 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 participants with DS while maintaining a favorable safety and tolerability profile. A 
numerical reduction in seizure frequency was also noted in participants 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 a 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 cholesterol 24-hydroxylase [CH24H] inhibitor, soticlestat, with liquid 
chromatography/tandem mass spectrometry. Report number: 16354). In summary, these 
nonclinical pharmacology studies suggest that a 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. On the basis of a population 
PK/PD/EO model using data from 4 phase 1 studies in healthy participants, the phase 1b/2a 
study in adult participants with DEEs, and the ELEKTRA study in pediatric participants with DS 
or LGS, the 300 mg BID dose (weight-based equivalent in pediatrics) is estimated to achieve 
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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 a seizure reduction 
in participants with LGS while maintaining a favorable safety and tolerability profile. 
Approximately 79% of participants 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 participants 
with LGS reported a 20.6% median reduction in drop seizures, while those participants 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 
participants 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 participants (80.3%) 
experiencing at least 1 TEAE compared with 52 placebo participants (74.3%). The most frequent 
TEAEs reported in soticlestat-treated participants with ≥5% difference from placebo were 
lethargy and constipation. The incidence of SAEs was similar in both soticlestat and placebo 
groups, with 11 participants (15.5%) in the soticlestat group experiencing at least 
1 treatment-emergent SAE compared with 13 participants (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, participants 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 [AUC]) were performed. A threshold for the fraction of participants at or above the 
reference value was set to 35%. Setting the percentage threshold at “35%” ensures the safety of 
pediatric participants because 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 4.a. 
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4.4 
Overall End of Study 
The global end-of-the-study is defined as the last scheduled procedure for the last participant in 
the study. 
5.0 
STUDY POPULATION 
Informed consent must be obtained before any screening procedures other than activities the 
institutional review board (IRB)/independent ethics committee (IEC) has specifically approved 
for use as prescreening procedures. Specifically, informed consent must be obtained before 
beginning test procedures outlined in the SoA (Section 1.3). Informed consent requirements are 
described in Section 10.1.3. 
All entry criteria, including test results, must be confirmed by the investigator before enrollment. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
Investigators must account for all individuals who sign informed consent forms (ICFs), 
regardless of the outcome of the screening, by completing the required electronic case report 
forms (eCRFs).  
Rescreening may be allowed after discussion with the medical monitor. 
5.1 
Inclusion Criteria  
Participants must meet all of the following criteria to be eligible for inclusion in the study: 
1. In the opinion of the investigator, the participant or the participant’s parent or legal guardian 
or caregiver is capable of understanding and complying with protocol requirements, complete 
appropriate assessments, maintain an accurate and complete daily seizure diary and take 
study drug for the duration of the study. 
If the participant is living in a residential facility, a minimally possible number of staff 
member(s) at the facility who are the participant’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 participant/participant’s legally acceptable representative has provided informed consent 
(that is, in writing, documented via a signed and dated ICF) and any required privacy 
authorization before the initiation of any study procedures. 
3. The participant, of any sex, and aged ≥2 years, at the time of informed consent. 
4. The participant has a documented clinical diagnosis of DS supported by variable 
combinations of typical clinical features such as those noted as follows and as determined by 
the investigator. 
– Onset of seizures usually in the first year of life.  
– History of fever-induced prolonged seizure as determined by the investigator 
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– May include prolonged (approximately 15 minutes or longer) hemi-clonic seizures. 
– Multiple seizure types, which may include: 
• Generalized tonic-clonic.  
• Focal to bilateral tonic-clonic. 
• Clonic. 
• Myoclonic 
– History of developmental delay/intellectual disability presenting after onset of seizures 
and usually presenting after 12 months of age. 
– Documented genetic mutation consistent with DS is not required, but results of genetic 
testing will be collected if available. If genetic testing was not performed previously or if 
the SCN1A result is negative (without any other positive gene reported that is consistent 
clinically with DS), testing for SCN1A will be offered at the time of screening, per local 
restrictions.  
OR 
The participant has a documented clinical diagnosis of LGS supported by variable 
combinations of typical clinical features such as those noted as follows and as determined by 
the investigator. 
– 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 results (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. The participant has experienced failure of treatment 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. 
6. The participant has been exposed to fenfluramine (currently on or used previously).  
Note: Participants, who have discontinued fenfluramine for reasons of lack of efficacy or 
intolerability are eligible as prior users. 
7. The participant has a clinical diagnosis of LGS and a history of, on average, ≥12 MMD 
seizures in the last 90 days immediately before screening based on historical information, and 
the participant has ≥4 MMD seizures during a minimum of 4 weeks of seizure data collection 
during the prospective baseline period. 
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The total number of seizures includes only primary outcome seizure types with 
documentation as determined by the investigator: 
– Hemi-clonic or focal clonic. 
– Focal to bilateral tonic-clonic. 
– Generalized tonic-clonic. 
– Bilateral clonic. 
– Convulsive status. 
– Focal 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. 
OR 
The participant has a clinical diagnosis of DS and a history of, on average, ≥9 convulsive 
seizures in the last 90 days before screening visit based on the historical information, and the 
participant has ≥3 convulsive seizures during a minimum of 4 weeks of seizure data 
collection during the prospective baseline period. 
The total number of seizures includes only primary outcome seizure types with 
documentation as determined by the investigator: 
– Hemi-clonic or focal clonic. 
– Focal to bilateral tonic-clonic. 
– Generalized tonic-clonic. 
– Bilateral clonic. 
– Convulsive status. 
8. The participant weighs ≥10 kg at the screening visit (Visit 1). 
9. Artisanal cannabidiols/nonpharmaceutical grade cannabidiols are allowed. Participants 
should be on a stable dose for at least 4 weeks before the screening visit (Visit 1); the dosing 
regimen and manufacturer should remain constant during the initial 16 weeks of treatment 
period (including 4 weeks of titration period and 12 weeks of maintenance period) of the 
study. (Artisanal cannabidiols will not be counted as ASMs.) 
10. The participant is currently taking 0 to 5 antiseizure treatments (eg. VNS, ketogenic diet) at 
stable doses, of which; 
a) Four can be ASMs, before the screening visit (Visit 1); benzodiazepines used chronically 
(daily) to treat seizures are considered ASMs. Cannabidiol (Epidiolex) is allowed where 
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available and should be counted as an ASM. ASM dosing regimen must remain constant 
during the initial 16 weeks of treatment period (4 weeks of titration + initial 12 weeks of 
maintenance).  
b) If using a VNS, the participant must have had VNS placed at least 3 months before the 
screening visit (Visit 1) with stable settings for at least 4 weeks before the screening visit 
(Visit 1); VNS parameters must remain constant during the initial 16 weeks of treatment 
period (4 weeks of titration + initial 12 weeks of maintenance) of the study.  
c) If on a ketogenic diet (or any other diet used for treatment of epilepsy, such as modified 
Atkins diet), the participant must have started the diet at least 3 months before the 
screening visit (Visit 1), and the participant’s diet should be stable for 4 weeks before the 
screening visit (Visit 1); the participant should continue this diet during the initial 16 
weeks of treatment period (4 weeks of titration + initial 12 weeks of maintenance) period 
of the study. 
11. The use of felbamate is allowed provided that the participant does not meet the liver function 
test (LFT) exclusion criteria, the dose has been stable for at least 6 months before the 
screening (Visit 1), and the participant 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. 
12. Participants of childbearing potential (defined as first menarche) must have a negative 
pregnancy test and agree to use an effective* (not applicable for Germany) or highly 
effective method* of birth control during the study and for 30 days following the last dose of 
study drug. 
*Definitions, effective and highly effective methods of contraception are described in 
Section 10.4. 
5.1.1 
Justification of Inclusion Criteria 
All clinical studies in soticlestat are conducted or being conducted for participants aged at least 
2 years. We do not have data in children younger than 2 years; furthermore, there is no 
appropriate formulation for participants younger than 2 years (ie, dose <20 mg) because it is 
currently under development. The appropriate dose for this age group is still under evaluation. 
5.2 
Exclusion Criteria  
The participant will be excluded from the study if any of the following exclusion criteria are met:  
1. The participant is an 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. The participant is a Takeda employee or immediate family member. 
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3. The participant is currently enrolled in a clinical study involving an investigational product 
or treatment device (ie, not approved in that country, other than soticlestat), or concurrently 
enrolled in any other type of medical research judged not to be scientifically or medically 
compatible with this study.  
Note: Compatibility will be determined on the basis of consultation with the 
sponsor/designee. 
4. The participant has 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. The participant has a known hypersensitivity to any component of the soticlestat formulation. 
6. The participant has an 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 
sponsor/designee may be warranted. 
7. The participant has any history of alcohol, opioid, or other drug use disorder, per the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, within 2 years of the 
screening visit (Visit 1). 
8. The participant is considered by the investigator to be at imminent risk of suicide or injury to 
self, others, or property, or the participant has attempted suicide within 12 months before the 
screening visit (Visit 1). Participants aged ≥6 years 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 participants aged ≥6 years at the time of enrollment or participants who turn 
6 after enrollment. 
9. The participant is unable to withhold the use of strong inducers of cytochrome 
P450 (CYP 3A4) during the entire clinical study, (except for ASMs [eg, carbamazepine, 
phenobarbital, phenytoin] and topical preparations). 
10. The participant is currently pregnant or breastfeeding or is planning to become pregnant 
within 30 days of the last dose of study drug. 
5.3 
Lifestyle Considerations  
5.3.1 
Meals and Dietary Restrictions  
There are no dietary restrictions for this study. 
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5.3.2 
Contraception and Breastfeeding  
5.3.2.1 
Contraception for Participants Capable of Producing Viable Ova and/or Becoming 
Pregnant 
Participants who are of childbearing potential (that is, capable of producing viable ova and/or 
becoming pregnant) must use effective (not applicable for Germany) or highly effective 
contraception as agreed to in Inclusion Criterion 12. Section 10.4 defines childbearing potential 
and lists acceptable methods of contraception. 
5.3.2.2 
Contraception for Participants Capable of Producing Viable Sperm 
Male participants 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. 
5.4 
Screening 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. Diagnosis will be reviewed (medical history, seizure history, and 
other diagnostic procedures) by the investigator.  
The investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
5.4.1 
Screen Failures  
An individual who has provided informed consent to participate in the study may be categorized 
as a screen failure for any of the following reasons:  
• Did not meet entrance criteria. 
• AE. 
• Lost to follow-up. 
• Pregnancy. 
• Withdrawal by participant/parent or legal guardian. 
• Study terminated by sponsor. 
• Other (specify). 
Participants are not considered screen failures if they were enrolled but not treated. See 
Section 7.2.  
Information about screen failures should be collected via the eCRFs, including participant 
identification, screening disposition (including the reason for screen failure), demography, 
inclusion/exclusion criteria, and AEs (if applicable). If a potential participant experiences an 
SAE during screening, all of the participant’s screening eCRFs must be available for collection. 
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Participant identification numbers assigned to participants who do not meet eligibility criteria 
should not be reused. 
An individual who has been designated a screen failure may be rescreened with a new participant 
ID, after discussion with the medical monitor.  
5.5 
Criteria for Temporarily Delaying Enrollment/Administration of Study Drug  
Not applicable. 
5.6 
Enrollment  
A participant is defined as enrolled when all of the following have occurred:  
• The participant and/or the participant’s legally acceptable representative has provided 
informed consent (that is, in writing, documented via a signed and dated ICF). 
• The participant has provided assent to participate in the study, if applicable. 
• The participant has completed screening, having satisfied all entry criteria.  
6.0 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
6.1 
Study Intervention(s) Administered  
In this study, the interventions include: 
• Investigational product: soticlestat 
• Other products required for the study: not applicable  
The table following describes the drug administered in this study. 
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Storage 
Study drug must be kept in an appropriate, temperature-controlled, limited-access, secure place 
until it is dispensed, destroyed by the site (if approved by sponsor or designee), or returned to the 
sponsor or designee for destruction. Study drug must be stored under the conditions specified on 
the label and remain in the original container until dispensed. A daily temperature log of the drug 
storage area must be maintained every day. 
Please refer to the pharmacy manual for additional information related to the study drug. In 
instances where the protocol and pharmacy manual text conflict, the pharmacy manual text shall 
supersede the text in the protocol. 
6.2.1 
Accountability Throughout the Study 
The investigator or designee must ensure that the sponsor-supplied study product is used in 
accordance with the protocol and is only used for participants enrolled in the study.  
To document appropriate use of sponsor-supplied study product (Section 6.1), the investigator or 
designee must maintain 100% accountability for all sponsor-supplied study drugs that the site 
receives and dispenses during his or her entire participation in the study.  
Proper drug accountability includes, but is not limited to: 
• The investigator or designee must maintain records of all sponsor-supplied study drugs 
delivery to the site, current site inventory, dispensing for use by each participant, and return 
to the sponsor or designee.  
• The investigator or designee must record this inventory on a sponsor-approved drug 
accountability log.  
• Based on entries in the log, it must be possible to reconcile study products delivered with 
those used and returned.  
• All study products must be accounted for and all discrepancies investigated and documented 
to the sponsor’s satisfaction.  
• All study drugs not returned to the site by a participant must be investigated by the site and 
appropriately documented on the log.  
• If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
• The IRT will include all required information as a separate entry for each participant to 
whom sponsor-supplied drug is dispensed. 
6.2.2 
Receiving Product at the Site 
Investigators will be provided with sufficient amounts of the study drug to carry out this protocol 
for the agreed number of participants.  
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On receipt of sponsor-supplied study drug, the investigator or designee must verify the contents 
of the shipments against the packing list. The verifier should ensure that the quantity is correct, 
and the medication is in good condition.  
This may include an examination of temperature-monitoring devices. 
If quantity and conditions are acceptable, the investigator or designee should acknowledge the 
receipt of the shipment in the IRT. If there are any discrepancies between the packing list and the 
actual product received, the sponsor must be contacted to resolve the issue. The packing list 
should be filed in the investigator’s essential document file. 
6.2.3 
Handling and Storage at the Site 
The investigator bears the overall responsibility for ensuring that the study drugs are stored in an 
appropriate location. Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  
An appropriate storage location is one that is secure, with access that is limited to the 
investigator and authorized site staff; and that is environmentally controlled (manually or 
automated) in accordance with labeled storage requirements. 
The investigator is responsible for ensuring that soticlestat is maintained according to the 
requirements described in Table 6.b.  
The investigator is responsible for ensuring that the investigational drug is maintained within an 
established temperature range, that the temperature is monitored throughout the duration of the 
study, and that records are maintained. 
A daily temperature log of the drug storage area must be maintained every working day.  
The temperature should be monitored continuously by using either an in-house system, a 
mechanical recording device such as a calibrated chart recorder, or by manual means, such that 
both minimum and maximum thermometric values over a specific time period can be recorded 
and retrieved as required. Such a device (ie, certified minimum/maximum thermometer) would 
require manual resetting on each recording.  
The sponsor must be notified immediately on discovery of any excursion from the established 
range. Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the impact of reported excursions in relation to the suitability of the 
product for future use and will inform the site of the decision accordingly. Under no 
circumstances should the product be dispensed to participants until the impact has been 
determined and the product is deemed appropriate for use by the sponsor. 
Study drugs must be kept in these conditions until they are used or returned to the sponsor for 
destruction. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
study drug that could affect the integrity of the product(s), eg, fumigation of a storage room. 
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The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, the 
sponsor or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites. 
Table 6.b 
Study Intervention(s): Storage Conditions 
Intervention Label 
Soticlestat 
Intervention Name 
Soticlestat 
Required Environmental Storage Conditions 
This product should be stored according to the labeled 
storage conditions and pharmacy manual 
 
6.2.4 
Labeling 
Changes to sponsor-supplied packaging, including the addition of labels before dosing, may not 
be made without full agreement in advance by the sponsor. Such additional labels (eg, those used 
when dispensing marketed product) may, on a case-by-case basis, be applied to the study drug to 
satisfy local or institutional requirements, but must not: 
• Contradict the clinical study label. 
• Obscure the clinical study label. 
• Identify the study participant by name. 
6.2.5 
Preparation 
Refer to the pharmacy manual for any additional study drug preparation instructions, as required. 
6.2.6 
Dispensing/Administration 
The investigator has overall responsibility for dispensing/administering the study drug.  
Where permissible, tasks may be delegated to a qualified designee (for example, a pharmacist or 
a home healthcare representative) who is adequately trained in the protocol and who works under 
the direct supervision of the investigator. This delegation must be documented in the applicable 
study delegation of authority form. 
The investigator or their designee will dispense the study drug only to participants enrolled in 
this study, following the procedures set out in the study protocol. Each participant will be given 
only the study drug carrying their treatment assignment. 
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All study drug provided to pediatric participants should be supervised by the study site/principal 
investigator and parent/legally authorized representative/caregiver, depending on the setting. 
6.2.6.1 
Dispensing 
The sponsor will supply the study sites with soticlestat 20 mg mini-tablets and soticlestat 100 mg 
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. 
Changes to sponsor-supplied packaging, including the addition of labels before dosing, may not 
be made without full agreement in advance by the sponsor. Such additional labels (eg, those used 
when dispensing marketed product) may, on a case-by-case basis, be applied to the study 
intervention to satisfy local or institutional requirements, but must not: 
• Contradict the clinical study label. 
• Obscure the clinical study label. 
• Identify the study participant by name. 
The label shall also include a batch identifier and medication identification number to allow for 
traceability of the study drug via IRT. 
All participants will continue on SOC antiseizure therapies throughout the study (not provided 
by the sponsor). 
6.2.6.2 
Administration 
This study involves open-label administration of soticlestat (weight-based dosing) BID. Weight-
based doses and the regimens for titration, increase, and decrease of dose at each weight are 
specified in Table 4.a. 
The investigator or his/her designee is responsible for the following: 
• Explaining the correct use of the study drug to the participant/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. 
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The participant/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. 
Soticlestat added to current antiseizure therapy will be administered BID orally with or without 
food or via enteral feeding tubes including, but not limited to, NG-tube, G-tube, or a low-profile 
gastric tube (MIC-KEY Button). A J-tube may be considered following approval by the medical 
monitor or sponsor.  
Note: Study drug will be administered only orally for participants 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. See Section 4.1.1 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 on the number of tablets/mini-tablets the participant is taking; a 
half teaspoon or 2.5 mL of applesauce or yogurt or other liquid of similar consistency is needed 
for each mini-tablet taken, and 2 teaspoons or 10 mL is needed for each tablet taken. 
For participants receiving study drug via enteral feeding tubes, study drug will be crushed and 
suspended in water, and the suspension will be administered via the feeding tubes. Complete 
instructions for enteral feeding tubes will be provided to the participant/parent or caregiver. 
Other medications or enteral feeds should not be given concurrently with the study drug. 
The scheduled dose can be administered or taken up to 4 hours after the scheduled time of 
dosing. If the participant/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 daily seizure and 
medication diary and on the next clinic visit. If a participant misses a dose, the missed dose 
should be skipped, and the participant should continue with his/her normal dosing schedule. 
The planned daily dose and tablet count to be administered to participants during the titration 
period is shown in Section 4.1.1. During the titration period, 2 days after each dose escalation or 
taper, the participant/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 participant/parent or caregiver should return unused study drug at each study visit to allow 
the investigator or designee to evaluate participant’s compliance with the dosing instructions. 
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6.2.7 
Destruction or Return  
Before site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied product accountability and reconciliation before sponsor-supplied 
products are returned to the sponsor or its designee for destruction. The investigator or designee 
will retain a copy of the documentation regarding sponsor-supplied study drugs’ accountability, 
return and/or destruction. Originals will be sent to the sponsor or designee. 
Drug supplies, including the number of returned tablets to sites, will be counted and reconciled at 
the site before being destroyed locally by the site (if approved by sponsor or designee) or 
returned to the sponsor or designee. 
The investigator or designee must ensure that the study drug is used in accordance with the 
protocol and is dispensed only to participants enrolled in the study. The investigator or designee 
is responsible for ensuring that the study drug provided to the participant and returned from the 
participant 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 participant, destruction by the site (if approved 
by sponsor or designee), and return to the sponsor or designee. If any dispensing errors or 
discrepancies are discovered, the sponsor must be notified immediately. 
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 
destroyed by the site (if approved by sponsor or designee) or returned to the sponsor or its 
designee for destruction. All study drug not returned to the site by a participant must be 
investigated by the site and appropriately documented. 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. 
Destruction at the site, where applicable, must be in accordance with local standard practice with 
prior approval from the sponsor/contract research organization (CRO).  
The site must have destruction procedures in place and be able to supply a Certificate of 
Destruction or similar document once destruction is completed. Sites shall also document the 
event in the IRT. 
Further instructions regarding the final disposition of unused study drugs are provided in the 
pharmacy manual. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1 
Randomization  
This is not a randomized study; therefore, no randomization schedule will be generated. 
6.3.2 
Blinding the Treatment Assignment  
This is an open-label study. There will be no blinding. 
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6.3.3 
Unblinding  
Not applicable. 
6.4 
Study Drug Compliance  
Confirmation of study drug intake and dosing will be recorded in the daily seizure and 
medication diary on a daily basis. Any missed doses will be recorded in the daily seizure and 
medication diary by the participant or parent or caregiver and reviewed by the site personnel. 
The participant or parent or caregiver will be required to bring used/unused study drug and the 
daily seizure and medication diary to each site visit. All participants or parents or caregivers 
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 participant’s source 
records. 
Compliance with study drug and seizure diary will be assessed at each visit (or unscheduled 
visits per principal investigator discretion). 
Compliance will be tracked through the participant daily seizure and medication diary and all 
entries will be reviewed by site personnel and reconciled against returned study medication with 
queries, as necessary. 
Participants who are significantly noncompliant will be discontinued from the study. A 
participant 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 medical 
monitor. Similarly, a participant 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. 
6.5 
Dose Modification  
During the titration period, a decrease in dose level (to Dose 2 or Dose 1) is allowed if required 
for safety and tolerability. Doses between the scheduled dose levels may be allowed after 
discussing with the medical monitor.  
Participants 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 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. 
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); participants who cannot tolerate the minimum dose 
(Dose 1) will be discontinued from treatment. Dose decrease during the initial 12 weeks of the 
maintenance period are allowed as assessed by the investigator. Intermediate doses may be 
allowed after discussing with the medical monitor.  
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6.6 
Continued Access to Study Drug After the End of the Study  
Following completion of the study, participants will have the option to enroll in an OLE study, 
ENDYMION 2. 
ENDYMION 2 is a multisite, phase 3, OLE study designed to obtain additional safety and 
tolerability data related to soticlestat administered long-term in participants who participated in 
either of the antecedent phase 3 clinical studies, TAK-935-3001 (participants with DS) or 
TAK-935-3002 (participants with LGS). Additional aims are to assess efficacy in terms of 
seizure frequency, non–seizure-related symptoms, impact on quality of life, and the PK and PD 
(concentration of 24HC) of soticlestat administration in pediatric and adult participants with DS 
or LGS. 
Participants who will not enroll in ENDYMION 2, should be returned to the care of a physician 
and standard therapies initiated or resumed as required.  
6.7 
Treatment of Overdose  
In this study, an overdose is defined as a known deliberate or accidental administration of the 
study drug, either to or by a study participant, at a dose above that assigned to that individual 
participant. 
In the event of a drug overdose, the participant should be treated symptomatically, as determined 
by the investigator. 
In addition, the investigator should:  
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study drug should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
drug can no longer be detected systemically (at least 1 day). 
All cases of overdose, must be documented, including the quantity of the excess dose and the 
duration of the overdose. Because these events are not, in and of themselves, AEs, they should be 
reported regardless of whether any manifested signs or symptoms are considered AEs. If there 
are signs and symptoms meeting the criteria for reporting as AEs or SAEs, they should also be 
reported, as described in Section 10.3. 
Overdose must be reported to the sponsor according to the SAE reporting procedure whether or 
not it resulted in an AE/SAE. However, the 24-hour reporting requirement for SAEs will not 
apply unless the event being reported also resulted in an SAE. 
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6.8 
Concomitant Therapy  
6.8.1 
Rescue Medicine  
The use of rescue medications is allowed throughout the study. The date of rescue medication 
administration, as well as the name and dosage regimen of the rescue medication, must be 
recorded in the daily seizure and medication diary.  
Rescue medication will not be supplied by the sponsor. 
6.8.2 
Excluded Medications 
1. Strong CYP3A4 inducers are excluded from screening (Visit 1) until the end of the follow-up 
period, (except for ASMs [eg, carbamazepine, phenobarbital, phenytoin] and topical 
preparations) Appendix 1.  
2. The use of herbal preparations (when used as an ASM) are not permitted. 
3. Participants are instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
6.8.2.1 
Justification of Excluded Medications 
The above criteria were selected to avoid participant risk and potential interference with 
evaluation of endpoints. 
Drug-drug interaction studies in healthy participants (ClinicalTrials.gov identifiers: 
NCT05064449 and NCT05098041) have shown that while soticlestat can be administered with 
CYP3A4 or UGT1A9 inhibitors without clinically meaningful drug-drug interactions, strong 
CYP3A inducers significantly reduce the concentration of soticlestat in plasma and are excluded 
in the currently ongoing clinical studies except for the ASMs (eg, carbamazepine, phenobarbital, 
phenytoin). 
6.8.3 
Permitted Concomitant Medications and Procedures 
1. ASMs are allowed; benzodiazepines used chronically (daily) only to treat seizures are 
considered ASMs. Cannabidiol (Epidiolex) is allowed where available and should be counted 
as an ASM. SOC ASMs should be stable for at least 4 weeks before screening. 
2. Vaccinations are allowed (including vaccination for COVID19); however, the 
sponsor/designee should be informed about changes in the participant’s vaccination status 
and document it under the concomitant medication section of the eCRF. 
3. The use of felbamate is allowed provided that the participant meets the relevant inclusion and 
exclusion criteria. 
4. If the participant is using VNS, the device must have been placed at least 3 months before the 
screening visit with stable settings for >4 weeks; VNS parameters must remain constant 
during the initial 12 weeks of the maintenance period of the study (VNS will not be counted 
as an ASM). 
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All medications, including vitamin supplements and over-the-counter medications, will be 
documented throughout the study.  
7.0 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
This section describes the circumstances under which individual participants would withdraw or 
be discontinued from the study drug or from the study itself.  
Section 10.1 describes circumstances in which specific sites or the study itself would be 
discontinued. 
7.1 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a participant to permanently discontinue study drug. If 
study drug is permanently discontinued, the participant may remain in the study to be evaluated 
for safety follow-up. See the SoA for data to be collected at the time of discontinuation of study 
drug (listed for ET), and follow-up and for any further evaluations that need to be completed 
(Section 1.3). 
Potential circumstances for which a participant may permanently discontinue study drug or 
withdraw from study include: 
1. Failure to meet continuation criteria: Enrollment in any other clinical study involving an 
investigational product or enrollment in any other type of clinical study judged not to be 
scientifically or medically compatible with this study. 
2. Withdrawal by investigator: The investigator decides that the participant should be 
discontinued from the study. Note: The specific reason for discontinuation must be recorded 
in the eCRF, therefore “withdrawal by investigator” may only to be used if no other pertinent 
reason for discontinuation is applicable. 
3. Withdrawal by participant/parent or legal guardian. Note: The specific reason for 
discontinuation should be recorded in the eCRF, therefore “withdrawal by participant/parent 
or legal guardian” may 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 participant’s participation in the study for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and Good Clinical Practice (GCP). 
c) The sponsor or its designee stops the clinical study at a particular site. 
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5. Discontinuation due to AE: The participant has experienced an AE that requires ET because 
continued participation imposes an unacceptable risk to the participant’s health, or the 
participant is unwilling to continue because of the AE. 
If the investigator decides that the participant 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 
participant from the study should be discussed with the sponsor/medical monitor) with 
appropriate clinical follow-up, including repeat laboratory tests, until a participant’s 
laboratory profile has returned to normal/baseline status (see Section 10.6) if the 
following circumstances occur at any time during study drug treatment: 
i. Serum ALT or AST >8 times the upper limit of normal (ULN), or 
ii. Serum ALT or AST persistently >5 × ULN that persists for more than 2 weeks, or 
iii. Serum ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × 
ULN or international normalized ratio (INR) >1.5, or 
iv. Serum ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
b) Not tolerating the lowest dose of the study drug. 
c) Suicidal ideation: Participants who experience suicidal ideation or who attempt suicide 
will be immediately withdrawn from the study. 
6. Lost to follow-up: The participant did not attend visits, and multiple attempts to contact the 
participants were unsuccessful. Attempts to contact the participant must be documented in 
the participant’s source documents. 
7. Pregnancy: Participant of childbearing potential is found to be pregnant. 
Note: If the participant is found to be pregnant, the participant must be withdrawn 
immediately. The procedure is described in Section 10.4.3. 
8. Coronavirus disease 2019 (COVID-19)/pandemic: If, in the opinion of the investigator, the 
safety of a study participant is at risk because the participant cannot complete key evaluations 
or adhere to critical mitigation steps, then the investigator should consider discontinuing that 
participant. In addition, for any such participant with COVID-19 diagnosis or in a pandemic 
circumstance, GCP for AE reporting processes will apply. 
9. Death 
10. Noncompliance with study drug. 
11. Significant protocol deviation: The discovery after soticlestat dosing that the participant 
failed to meet protocol entry criteria or did not adhere to protocol requirements (after 
discussion with sponsor), and/or continued participation poses an unacceptable risk to the 
participant’s health based on investigator judgement. 
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12. Lack of efficacy as determined by the investigator (withdrawal by participant/parent/legal-
guardian should not be captured as lack of efficacy). 
13. Other: The specific reason should be recorded in the eCRF. 
Note: Participants who do not qualify for the study (screen failures) are not considered to have 
discontinued; instead see Section 5.4.1.  
If the study drug is discontinued, regardless of the reason, the evaluations listed for ET visit will 
be performed as completely as possible. 
The investigator must determine the reason(s) for discontinuation of study drug and/or the 
participant withdrawal from the study; date of discontinuation of the study drug and/or the 
participant withdrawal from the study; and the total amount of study drug administered and 
record this information in the eCRF. 
7.1.1 
Liver Chemistry Stopping Criteria  
Participants with abnormal liver-associated test results should be evaluated to determine whether 
study drug should be continued, interrupted, or discontinued. See Section 10.6. 
Discontinuation of study drug for abnormal liver test results is required by the investigator when 
a participant meets one of the conditions outlined in Section 10.3.5.1 or in the presence of 
abnormal liver chemistry results not meeting protocol-specified stopping rules if the investigator 
believes that it is in best interest of the participant. 
7.1.2 
Rechallenge  
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study is not allowed. 
7.2 
Participant Discontinuation/Withdrawal From the Study  
A participant may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the physician or at the institution, or may be withdrawn at any time 
at the discretion of the investigator or sponsor (eg, in the interest of participant safety). The 
investigator is encouraged to discuss withdrawal of a participant with the medical monitor when 
possible.  
The investigator may discontinue a participant’s study participation at any time during the study 
when the participant meets the study termination criteria described in Section 7.1. 
At the time of discontinuing from the study, if possible, an ET visit should be conducted, as 
shown in the SoA (Section 1.3). The primary criterion for termination must be recorded by the 
investigator. See SoA for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
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If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. For any case of early 
discontinuation, the investigator should ask the participant to participate in the follow-up visit 
procedures, provided that the participant has not withdrawn consent for those procedures. If a 
participant refuses to complete ET and/or the follow-up procedures, this information will be 
recorded. 
Participants who discontinue or withdraw will not be replaced. 
7.3 
Lost to Follow-up  
A minimum of 3 documented attempts must be made to contact any participant (or their legally 
authorized representative) who is lost to follow-up at any time point before the last scheduled 
contact (in person or by phone or video). At least 1 of these documented attempts must include a 
written communication sent to the participant’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that the participant be assessed for final safety 
evaluations and return any unused study drug.  
8.0 
STUDY ASSESSMENTS AND PROCEDURES  
Written informed consent must be obtained (signed and dated) before study assessments and 
procedures can be performed, as described in Section 10.1.3. 
The following sections describe the study procedures and data to be collected at planned time 
points per the SoA (Section 1.3). Protocol waivers or exemptions are not allowed.  
Repeat or unscheduled samples may be taken for safety reasons or due to technical issues with 
the samples. Whenever possible, the same person should perform each assessment. 
8.1 
Demographics, Medical History, and Medication History 
8.1.1 
Demographics 
Participant demographic information will be collected prior to the participant receiving the first 
dose of study drug. 
Demographic information to be obtained will include: 
• Age/date of birth (where permitted) at the time of informed consent. 
• Sex.  
• Race, ethnicity.  
• Height and weight, of the participant at screening.  
8.1.2 
Medical History 
Medical history, including concurrent medical conditions, will be collected. 
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Medical history to be obtained will include determining whether the participant has any 
significant conditions or diseases relevant to the disease under study that resolved before the 
participant signed the ICF. Ongoing conditions are considered concurrent medical conditions. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present when informed consent is provided. This includes clinically significant laboratory, 
physical examination, and/or vital signs abnormalities noted at screening examination, according 
the judgment of the investigator. The condition (ie, diagnosis) should be described. 
8.1.2.1 
Historical Seizure Data  
Per inclusion criteria, historical seizure information will be used to support study entry. It is very 
common for caregivers of participants with DS and 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 (90 days before screening) 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 participants/caregiver the number of seizures over the last 3 months for each seizure 
type and attest eligibility to the study at screening (Visit 1). 
8.1.3 
Prior and Concomitant Treatments/Medications 
Prior and concomitant treatments and medications will be collected and recorded in the 
participant’s source document. 
Such treatments/medications include but are not limited to: 
• Medications or vaccines.  
• Over-the-counter or prescription medicines. 
• Recreational drugs. 
• Vitamins.  
• Herbal supplements. 
• Medications relevant to the eligibility criteria. 
• Other specific categories of interest. 
Prior medications/treatments are defined as those that were: 
• Stopped at or within 90 days before signing the ICF (note: all prior ASMs including 
fenfluramine use or its reason for discontinuation [if applicable] will be documented 
regardless of when it was stopped).  
Concomitant medications/treatments are defined as those given in addition to the study drug:  
• Between the signing of the ICF and participant completion. 
• Between the first dose of study drug and the end of the follow-up period, inclusive. 
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• Starting before the signing of the ICF and continuing during the study. 
Concomitant medications may be prescribed by a physician or obtained by the participant over 
the counter. Concomitant medication is not provided by the sponsor.  
At each study visit, participants/parent or caregiver will be asked whether they have taken any 
medication or received any treatment 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. 
Information to be recorded (including prior ASMs) will include: 
• Identification of the medication or treatment. 
• Reason for use. 
• Dates of treatment/medication administration: start and end dates. 
• Dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
8.1.4 
Diagnostic Criteria/Disease Classification  
Refer to Inclusion Criterion 4 for diagnostic criteria of DS and LGS. 
8.2 
Efficacy Assessments  
Efficacy measurements include: 
• Seizure frequency captured via diaries. 
• Clinician administered assessments.  
• Observer-reported outcomes (as completed by the caregiver as applicable). These 
assessments are described in Section 8.4.  
8.3 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
Investigators are responsible for monitoring the safety of participants 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 participant. 
The investigator is responsible for the appropriate medical care of participants 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 procedures, or that 
caused the participant to discontinue before completing the study. The participant should be 
followed until the event is resolved or explained. Frequency of follow-up evaluation is left to the 
discretion of the investigator. 
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8.3.1 
Physical Examinations  
A baseline physical examination (defined as the assessment before first dose of study drug) will 
consist of the following body systems: eyes; ears; nose; throat; cardiovascular system; 
respiratory system; gastrointestinal system; dermatologic system; musculoskeletal system; 
extremities; nervous system; lymph nodes; and other (if required per principal investigator 
discretion). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
All subsequent physical examinations should assess clinically significant changes from the 
baseline physical examination. Physical examination information should be entered on the 
eCRFs as part of the medical history or in the context of AEs. 
If clinically significant changes from baseline are noted, the changes will be documented as 
TEAEs in the AE eCRF. 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 
participant until the parameter returns to baseline or until the investigator determines that follow-
up is no longer medically necessary. 
8.3.2 
Vital Signs  
Vital signs will include:  
• Temperature.  
• Respiratory rate.  
• Sitting blood pressure (systolic and diastolic, resting more than 5 minutes).  
• Pulse (beats per minute). 
Blood pressure should be determined by cuff (using the same method, the same arm, and the 
same position throughout the study). Manual techniques will be used only if an automated device 
is not available. 
The investigator will assess whether a change in vital signs from baseline may be deemed 
clinically significant on the Vital Signs eCRF and whether the change should be considered and 
recorded as an AE on the AE eCRF. 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 
participant until the parameter returns to baseline or until the investigator determines that follow-
up is no longer medically necessary. 
8.3.2.1 
Weight and Height 
Weight and height will be measured and recorded. 
A participant should have weight and height measured while wearing indoor clothing and with 
shoes off. Weight is collected in kilograms (kg). Height is recorded in centimeters (cm).  
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If unable to obtain height or weight, data may be collected from other sources (eg, medical 
records or the participant’s caregiver). The investigator must record in the source document the 
reason for not obtaining height or weight (eg, the participant is in a wheelchair). 
8.3.3 
Neurological Examination Procedure 
A separate neurological examination will be performed, and results collected in the eCRF. The 
following assessments will be completed as much as possible during each examination: mental 
status, gait, cerebellar function, cranial nerves, motor function (including strength and reflexes), 
and sensation. If certain assessments could not be completed due to the participant’s inability to 
cooperate, the reason should be documented. Partially completed neurological examinations may 
not be considered protocol deviations, as, in this patient population, complete neurological 
examination may be difficult to conduct. 
8.3.4 
Ophthalmological Evaluation Procedure 
An ophthalmologic evaluation will be conducted by a pediatric ophthalmologist or 
neuroophthalmologist preferably, although an adult ophthalmologist or an optometrist 
experienced with examining children may be allowed after discussion with the medical monitor. 
The ophthalmologic evaluation may include: 
1. Age and developmentally appropriate quantitative visual acuity. 
a) If the participant 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 participants unable to 
cooperate with slit lamp examination due to age or developmental ability, a 20-D double 
aspheric binocular indirect ophthalmoscopy lens should be attempted. The use of penlight is 
acceptable only if the slit lamp and a 20-D double aspheric binocular indirect 
ophthalmoscope lens evaluations were unsuccessful. 
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 conducted at baseline (between the screening and enrollment visits), 
at Day 112 (±2 weeks) and at Day 364 (±1 weeks) or at the ET visit for those participants who 
do not complete the study. 
Additional unscheduled ophthalmological assessments may be conducted during the course of 
this study, if recommended by the ophthalmologist. 
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8.3.5 
Clinical Safety Laboratory Tests  
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the local laboratory requirements and regulations, laboratory manual, and the 
SoA (Section 1.3). Details about these procedures and required safety monitoring will be given 
in the laboratory manual if required. 
The local laboratories will perform laboratory tests for hematology, serum chemistries, and 
urinalysis.  
The clinical laboratory will return these results, along with their reference ranges, to the 
investigator. The investigator is responsible for reviewing the laboratory report, documenting 
this review, and filing the laboratory report with the source documents. 
Abnormal laboratory findings associated with the underlying disease should not be considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant’s condition.  
Clinically significant abnormal laboratory values obtained during participation in the study or 
within 4 weeks after the last dose of study drug should be repeated until the values return to 
normal or the baseline value or are no longer considered clinically significant by the investigator 
or medical monitor. The investigator should evaluate whether the laboratory result meets the AE 
criteria in Section 10.3. 
For participants with treatment-emergent ALT elevations >3 × ULN, see Section 10.6 for 
additional monitoring, evaluation, and follow-up recommendations.  
Abnormal clinical laboratory values that are unexpected or not explained by the participant’s 
clinical condition, may, at the discretion of the investigator or sponsor, be repeated as soon as 
possible until confirmed, explained, or resolved. 
If clinically significant/any values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified, and the sponsor notified. 
Investigators must document their review of each laboratory safety report. 
The investigator must record the following types of laboratory test results on the laboratory 
eCRF and if applicable on the AE eCRF: 
• Any changes that are considered clinically significant by the investigator (eg, SAE or AE or 
dose modification). 
• Any laboratory test results (local laboratory, nonprotocol specific local laboratory) that are 
used to make a study drug decision, that require a change in participant management, or that 
are used to make a response evaluation. 
8.3.6 
Pregnancy Testing  
A urine pregnancy test will be performed on all participants of childbearing potential at times 
described in the SoA (Section 1.3). For participants of childbearing potential, pregnancy test at 
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Visit 2 (Day -1/enrollment) is not required for eligibility if Visit 1 (screening) test is negative and 
if the investigator does not deem it necessary to repeat pregnancy test at Visit 2 (Day -
1/enrollment). Additional pregnancy tests (serum or urine) may be performed throughout the 
study at the investigator’s discretion. 
If a participant becomes pregnant during the study, the participant will be immediately 
discontinued from study intervention, withdrawn from the study, and the pregnancy must be 
followed as described in Section 10.4.3. 
8.3.7 
Suicidal Ideation and Behavior Risk Monitoring  
Suicidal ideation and behavior will be assessed in participants aged ≥6 years by use of the 
C-SSRS. The C-SSRS is a 3-part scale that measures suicidal ideation (eg, participant 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). 
Two versions of the C-SSRS will be used in this study for all participants ages >6 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 younger than 6 years at the start of the study will 
have an unscheduled visit after turning age 6 years, 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 participant suicidality using 
the C-SSRS, eliciting answers from the participant/parent or caregiver. Participants aged 
≥6 years who have positive answers on item numbers 4 or 5 on the C-SSRS before dosing (Visit 
2) are excluded, see Exclusion Criterion 8. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the clinical judgment of the investigator. If a participant 
exhibits signs of suicidal ideation or behavior, the participant will be withdrawn as described in 
Section 7.1. 
8.3.8 
AEs, SAEs, and Other Safety Reporting  
The definitions of AEs and SAEs are provided in Section 10.3.  
The investigator and any qualified designees are responsible for collecting, detecting, 
documenting, and recording events that meet the definition of an AE or SAE. They remain 
responsible for follow-up of these events (see Section 10.3.4).  
Any findings from investigator- or designee-administered assessments or patient reported 
outcomes assessments 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 these 
instruments, then proper follow-up with the participant for medical evaluation should be 
undertaken. If it is determined through this follow-up that an AE not previously reported has 
been identified, normal reporting requirements should be applied. 
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8.3.8.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until either the final visit (for participants 
enrolling into ENDYMION 2) or the final safety follow-up visit (for participants not enrolling 
into ENDYMION 2) at the time points specified in the SoA (Section 1.3).  
All SAEs will be recorded and reported to the sponsor or designee immediately. Under no 
circumstance should this exceed 24 hours. The investigator will also submit any updated SAE 
data within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly notify 
the sponsor via the reporting method described in Section 10.3.4.6. 
8.3.8.2 
Method of Detecting AEs and SAEs 
At each study visit specified in the SoA, participant/participant’s caregiver, or legally authorized 
representative will be questioned in a general way to ascertain if AEs have occurred since the 
previous visit. Open-ended and nonleading verbal questioning of the participant is the preferred 
method to inquire about AE occurrences without introducing bias. Participants may report AEs 
occurring at any time during the study. 
8.3.8.3 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All participants experiencing AEs, whether considered associated 
with the use of the study drug or not, will be documented in the AE page of the eCRF.  
All AEs must be monitored until the end of the study or until the event resolves, stabilizes, is 
otherwise explained, or the participant is lost to follow-up as defined in Section 7.3.  
SAEs must be monitored until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up.  
Information to be documented for each event is defined in Section 10.3.4. 
Further information on follow-up procedures is provided in Section 10.3.  
8.3.8.4 
Regulatory Reporting Requirements for SAEs  
All SAEs must be recorded and reported to the sponsor or designee immediately, via the 
procedure described in Section 10.3.5. Under no circumstance should this exceed 24 hours. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
drug under clinical investigation are met. The sponsor has a legal responsibility to notify both the 
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local regulatory authority and other regulatory agencies about the safety of a study drug under 
clinical investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB or state other documents and will notify the IRBs/IECs, if appropriate 
according to local requirements. 
The sponsor or designee must prepare safety reports for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and forward 
them to investigators as necessary. 
8.3.8.4.1 
Reporting of Abnormal Liver-Associated Test Results 
If participants experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total and direct bilirubin, gamma-glutamyl transferase, 
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 10.6 and Figure 10.a for the appropriate 
guidance on reporting abnormal LFTs.) 
If a participant is noted to have elevated ALT or AST >3 × 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 participant details. and possible alternative 
etiologies. The abnormality should be recorded as a TEAE (please refer to Section 10.2.1). 
If a participant is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which 
an alternative etiology has not been identified, a case report form (CRF) must be completed and 
transmitted with the SAE Report form (per Section 10.2.2). The investigator must contact the 
medical monitor for discussion of the relevant participant 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 10.a must also be performed. 
A consultation with a hepatologist may be considered as per investigator judgement or 
consultation with the medical monitor/sponsor. 
8.3.8.5 
Pregnancy in a Participant or Participant’s Partner During the Study 
Details about all pregnancies in participants or their partners will be collected after the start of 
study drug and until 30 days after end of the study. Collection of pregnancy data from a 
participant’s partner requires the partner’s informed consent.  
To the extent possible, the investigator will collect follow-up information on the outcome of the 
pregnancy and the neonate, and the information will be forwarded to the sponsor. 
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Once a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours. 
Pregnancy itself is not considered to be an AE or SAE; however, AEs or SAEs associated with 
pregnancy must be reported as such, including:  
• Any pregnancy complication or elective termination of a pregnancy for medical reasons (to 
be reported as an AE or SAE).  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) (to be reported as SAEs). 
• Any poststudy pregnancy-related SAE considered reasonably related to the study drug by the 
investigator will be reported to the sponsor as described in Section 10.3.4.7. Although the 
investigator is not obligated to actively seek poststudy pregnancy-related SAE information 
from former study participants or their partners, he or she may learn of an SAE through 
spontaneous reporting. 
Any participant who becomes pregnant while participating in the study will discontinue study 
drug and withdrawn from the study immediately. 
8.3.8.6 
Deaths  
Any death that occurs during the study will be reported per SAE reporting procedure, and 
should be carefully followed up to assess and identify the cause for death. 
8.3.8.7 
AESIs  
An AESI (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 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. 
Refer to Section 10.3.3.2 for list of events that will be reported as AESIs for this study. 
AESIs must be recorded as AEs in the eCRF within 24 hours. An evaluation form along with 
all documentation must be submitted to the sponsor. 
8.3.8.8 
SSR 
For EU countries only: abuse, misuse, overdose, medication error and other uses not foreseen 
in the protocol must be reported to sponsor within 7 days on a paper SSR form.  
Definitions: 
• Abuse: Persistent or sporadic, intentional excessive use of medicinal products that is 
accompanied by harmful physical or psychological effects.  
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• Misuse: Situations where the medicinal product is intentionally and inappropriately used not 
in accordance with the prescribed or authorized dose, route of administration, and/or the 
indications(s) or within the legal status of its supply. 
• Medication error: An unintentional error in the drug treatment process (prescribing, 
dispensing or administration, including incorrect dose or poor-quality administration) of a 
medicinal product while in the control of a health care provider, patient, or consumer, which 
leads to harm or has the potential to lead to harm. 
8.4 
Clinical Outcome Assessments 
Clinical Outcome Assessment 
Version Number 
Reporter 
CGI Baseline and Care GI 
Baseline 
Adapted for patient population by sponsor 
for soticlestat development program 
Clinician and caregiver (via 
Clinician) 
CGI Baseline–Seizure Intensity 
and Duration  
Adapted for patient population by sponsor 
for soticlestat development program 
Clinician 
CGI Baseline–Nonseizure 
Symptoms 
Adapted for patient population by sponsor 
for soticlestat development program 
Clinician 
CGI-I 
Adapted for patient population 
Clinician 
CGI-I Seizure Intensity and 
Duration  
Adapted for patient population 
Clinician 
CGI-I Nonseizure Symptoms  
Adapted for patient population 
Clinician 
Care GI-I 
Created by sponsor for soticlestat 
development program 
Caregiver (via clinician)  
QI-Disability 
2017 
Caregiver 
EQ-5D-5L 
EQ-5D-5L 2009 EQ-5D 5-Level v1.1, self-
complete 
Caregiver (self-report about the 
caregiver’s own quality of life) 
Caregiver satisfaction 
questionnaire 
Created by sponsor for soticlestat 
development program 
Caregiver 
 
8.4.1 
CGI Baseline Questionnaires (Clinician) 
For assessing baseline CGI of overall illness severity at baseline, the investigator or designee 
will complete 3 CGI Baseline questionnaires, 1 for overall baseline clinical impression, 1 for 
seizure intensity and duration, and another for nonseizure symptoms. The baseline questionnaires 
must be referenced during postbaseline CGI-I assessments to rate the change scores for CGI-I, 
CGI-I Seizure Intensity and Duration, and CGI-I Nonseizure Symptoms. The CGIs have been 
adapted from (Guy 1976) for this study population by the sponsor and will be provided by 
sponsor. These CGI Baseline questionnaires have been created as a reference document for the 
clinician’s (and participant/parent/caregiver’s) use and these data are not required to be entered 
into the electronic data capture or eCRF. 
8.4.1.1 
CGI Baseline and Care GI Baseline 
For assessing baseline disease severity to inform subsequent CGI-I and Care GI-I ratings, the 
investigator or designee will complete the CGI Baseline/Care GI Baseline questionnaire. The 
investigator or designee will record their overall clinical impression of disease severity at 
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baseline. They will interview parent/caregiver and use input from parent/caregiver to inform 
their overall clinical impression assessment (Guy 1976). 
For assessing Care GI Baseline of overall illness severity, investigator or designee will record on 
behalf of the parent/caregiver’s assessment of the participant’s overall condition using the same 
questionnaire. This questionnaire will be completed at the time point specified in Section 1.3. 
8.4.1.2 
CGI Baseline–Seizure Intensity and Duration 
For assessing baseline CGI Seizure Intensity and Duration, the investigator or designee will 
complete the CGI Baseline–Seizure Intensity and Duration questionnaire. The investigator or 
designee will record an objective and comprehensive description of seizure frequency, intensity, 
and duration, based on input from the caregiver’s report on the participant’s functioning (Guy 
1976). 
8.4.1.3 
CGI Baseline–Nonseizure Symptoms 
For assessing baseline CGI Nonseizure Symptoms, the investigator or designee will complete the 
CGI Baseline–Non-Seizure Symptoms questionnaire. The investigator or designee will record 
how the participant is functioning in the past month for each of the following domains: 
communication, alertness, and disruptive behaviors (Guy 1976). 
8.4.2 
CGI-I (Clinician)  
The CGI-I (clinician) is a 7-point Likert scale that the investigator uses to rate a participant’s 
change (improvement) in overall seizure control, nonseizure symptoms, and behavior, as well as 
how well the participant is tolerating study drug and side effects, compared with baseline (before 
treatment with the study drug). The participant 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 
time points specified in Section 1.3. 
8.4.3 
CGI-I Seizure Intensity and Duration (Clinician) 
The CGI-I Seizure Intensity and Duration instrument is used by the investigator (with input 
from the parent/caregiver as needed) to rate changes in intensity and/or duration of the most 
impactful seizures compared with the baseline assessment. The participant’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 investigator or 
designee will complete the CGI-I Seizure Intensity and Duration in consultation with the 
primary caregiver at the time points specified in Section 1.3. 
8.4.4 
CGI-I Nonseizure Symptoms (Clinician) 
The CGI-I Nonseizure Symptoms instrument is a series of single-item assessments that the 
investigator (with input from the parent/caregiver as needed) uses to rate improvement in the 
symptoms and impacts in select nonseizure domains (including communication, alertness, and 
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disruptive behaviors) since initiating the study drug at baseline. The participant 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).  
The investigator or designee will complete the CGI-I Nonseizure Symptoms instrument 
in consultation with the primary caregiver at the time points specified in Section 1.3. 
8.4.5 
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 participant 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 time points specified in Section 1.3. 
8.4.6 
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 (4 items), positive emotions (4 items), negative 
emotions (7 items), social interaction (7 items), leisure and the outdoors (5 items), and 
independence (5 items). Items are rated on a Likert scale of: Never, Rarely, Sometimes, Often 
and Very Often; the Negative Emotions domain items are reverse coded. Items are linearly 
transformed to a scale of 0 to 100, with higher scores representing better quality of life. 
Parents/caregivers report on their child’s life over the past month.  
The parent/caregiver-reported questionnaires will be administered according to the SoA 
(Section 1.3). 
8.4.7 
EQ-5D-5L Quality of Life Scale (Assessing Caregiver’s Health) 
The EQ-5D-5L is the 5–response level version of the EQ-5D instrument. The EQ-5D-5L is a 
preference-based measure of health status suitable for calculating quality-adjusted life years to 
inform economic evaluations. It consists of 2 sections, a descriptive system questionnaire and 
the 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 selecting the most appropriate statement in 
each of the dimensions. In addition, the EQ VAS is used to indicate the general health status by 
rating their health “today” from 0 (worst) to 100 (best health you can imagine). These 
questionnaires will be administered according to the SoA (Section 1.3). 
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8.5 
Diaries 
Seizure frequency will be collected daily via a seizure and medication paper diary. For 
participants meeting eligibility criteria the study site will provide paper diaries to 
caregivers/parents (or participants, if appropriate) to be completed daily between screening 
period and the last study visit.  
Caregivers or participants (if applicable) will be instructed to record seizures or document 
seizure-free days in the diary daily (record within 7 days, if missed). Seizures should continue to 
be recorded even if treatment is discontinued. 
All entries will be reviewed by the investigator with the participant/parent or caregiver at the 
time of each visit to ensure proper recording. Any new seizure types that may have occurred 
since the last visit must be reviewed by the investigator and discussed with medical monitor, if 
needed.  
These diaries may also capture additional information such as the following: 
– Rescue medication/background ASM. 
– Soticlestat dosing (during study). 
At each visit and any other time point deemed to be appropriate by the investigator, the paper 
diary will be reviewed and collected. 
The paper diary will be translated into the regional languages as required. Additional instructions 
on how to complete the paper diary will also be provided to the site and parent/caregiver.  
8.6 
Health Economics/Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics will not be evaluated in this study. 
8.8 
Other 
8.8.1 
Caregiver Satisfaction Questionnaire 
The caregiver satisfaction questionnaire is a 7-point Likert scale that the caregiver uses to rate 
overall satisfaction with soticlestat. The parent/caregiver is asked to consider the study 
participant’s symptoms over the past 4 weeks and rate overall satisfaction with soticlestat using 
the following rating options: extremely satisfied, very satisfied, satisfied, neither satisfied nor 
dissatisfied, dissatisfied, very dissatisfied, extremely dissatisfied. 
The parent/caregiver will complete the caregiver satisfaction questionnaire according to the SoA 
(Section 1.3).  
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8.9 
PK  
PK parameters are not evaluated in this study. 
8.10 
PD 
PD parameters are not evaluated in this study. 
8.11 
Biomarkers 
Biomarkers will not be evaluated in this study. 
8.11.1 
Bioanalytical Methods 
Not applicable. 
9.0 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP) will be prepared and finalized before database lock. The SAP 
will provide further details regarding the definition of analysis variables and the statistical 
analysis methodology to address all study objectives. 
9.1 
Statistical Hypotheses  
No tests of statistical hypotheses are planned for any endpoints. 
9.2 
Analysis Sets 
Safety analysis set: All participants who take at least 1 dose of study drug  
Intent-to-treat (ITT) analysis set: All participants who enroll in the study. 
Modified intent-to-treat (mITT) analysis set: All enrolled participants who take at least 1 dose 
of study drug and are assessed for seizures for at least 1 day in the treatment period. 
9.3 
Efficacy Analyses 
Efficacy analyses will be performed using the mITT analysis set. Results will be presented 
separately for the DS and LGS cohorts using descriptive statistics. Analyses will be based on 
as-observed data. No imputation will be implemented.  
For all efficacy analyses on seizure frequency, baseline refers to the prospective 4- to 6-week 
screening/baseline period. Baseline assessment for efficacy analyses other than seizure is the 
assessment before and closest to the first administration of the study drug unless otherwise 
specified. 
9.3.1 
Primary Efficacy Endpoint 
Percent change from baseline in primary seizure frequency (convulsive for DS and MMD for 
LGS) per 28 days during the initial 12 weeks of the maintenance period will be summarized 
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using descriptive statistics including mean, median, SD, first quartile, third quartile, minimum, 
and maximum. A distribution-free 95% CI for the median will be presented.  
9.3.2 
Exploratory Efficacy Endpoints 
Percent change from baseline in seizure frequency (convulsive for DS and MMD for LGS) per 
28 days and total seizure frequency per 28 days will be summarized for the initial 16 weeks of 
the treatment period (4 weeks of titration + initial 12 weeks of maintenance), and every 12-week 
period thereafter. 
Descriptive summaries of CGI-I, Care GI-I, CGI-I Seizure Intensity and Duration, CGI-I 
Nonseizure Symptoms, QI-Disability, caregiver satisfaction, and EQ-5D-5L will be presented for 
each scheduled collection time point and at end of study, as appropriate. Global impression of 
improvement scales (CGI-I, Care GI-I, CGI-I Seizure Intensity and Duration, and CGI-I 
Nonseizure Symptoms) will also be summarized dichotomously in terms of the number and 
proportion of participants who gave responses of minimally improved or better. Two-sided 95% 
CIs will be presented for proportions for dichotomous categories. Other binary endpoints will be 
summarized in a similar fashion, as appropriate.  
The EQ VAS score and the total score for QI-Disability will also be summarized in terms of 
change from baseline at each collection time point. EQ-5D-5L will be summarized descriptively 
by visit including baseline by presenting the number and percentage of responses in each level 
within each dimension.  
The proportion of days when rescue ASM is used during the study period will be summarized 
descriptively. 
Details will be provided in the SAP for appropriate summaries based on data type for the 
exploratory endpoints. 
9.4 
Safety Analyses 
Safety analyses will be performed using the safety analysis set. Results will be presented 
descriptively. AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs will be summarized using Preferred Terms and primary System Organ 
Classes. 
Data summaries will be displayed for incidence of TEAEs, clinical laboratory variables, and vital 
sign parameters. Ophthalmological evaluations and C-SSRS will be listed by participant. 
9.5 
Multiplicity Adjustment 
No adjustments for multiplicity are required. 
9.6 
Other Analyses 
Demographic and other baseline characteristics will be summarized descriptively using the 
safety analysis set by DS and LGS cohorts. Medical history and medication history will be listed. 
All participants who discontinue from the study will be identified. If known, a reason for their 
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discontinuation will be given. Disposition information will be presented using the ITT analysis 
set. 
9.7 
Interim Analysis 
Interim data cuts from this ongoing study will be analyzed to support any regulatory 
submissions. Since there is no hypothesis testing involved, no interim analysis will require 
spending any type-I error. 
9.8 
Determination of Sample Size 
This study plans to enroll approximately 15 participants with DS and 30 participants with LGS. 
The study is not powered for hypothesis testing. The sample size is based on an estimation 
approach to ensure adequate precision to estimate the median change from baseline in convulsive 
(DS) or MMD (LGS) seizure frequency per 28 days during the first 12 weeks of the maintenance 
period. With the planned sample sizes, the expected half width of the 95% CI for the median is 
commensurate with the expected magnitude of the median. 
With 15 participants in the DS cohort treated with soticlestat, the expected median percent 
change from baseline in convulsive seizure frequency during the first 12 weeks of the 
maintenance period is 35% and expected half width of the 95% CI is 30%.  
With 30 participants in the LGS cohort, the expected median percent change from baseline in 
MMD seizure frequency during the first 12 weeks of the maintenance period is 37% and the 
expected half width of the 95% CI is 29%.  
To determine the expected median and 95% CI half width, simulations were performed assuming 
the data follow a log normal distribution, and the distribution of underlying parameters (ie, mean 
and SD of the log transform of the data distribution) developed using results of the phase 2 
ELEKTRA study. 
10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS  
10.1 
Regulatory, Ethical, and Study Oversight Considerations  
10.1.1 
Regulatory and Ethical Considerations  
This study will be conducted with the highest respect for the individual participants 
(ie, participants) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline for 
GCP.  
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or designee) is responsible for the preparation, submission, and confirmation 
of receipt of any regulatory authority approvals required before release of study drug for 
shipment to the site. 
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10.1.2 
Financial Disclosure  
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s).  
All investigators and subinvestigators must declare potential conflicts of interests to the sponsor. 
The sponsor will provide a financial disclosure form that must be signed by each investigator and 
subinvestigator before the study starts at their study site; in addition, any potential conflicts of 
interests that are not covered by this financial disclosure form should be disclosed separately to 
the sponsor before the start of the study at their site. 
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to sponsor before the start of the study. 
10.1.3 
Informed Consent Process  
10.1.3.1 
Informed Consent Requirements in This Study 
The goal of the informed consent process is to provide a potential participant or their legally 
authorized representative with sufficient information about the research to allow for an informed 
decision about their voluntary participation in the research study.  
The informed consent process must facilitate the participant’s comprehension of the information 
and allow adequate opportunity for the participant to ask questions and consider whether or not 
to participate. This process may extend beyond a participant’s initial consent due to changing 
circumstances within the study, the therapeutic landscape, or the participant’s situation.  
When a participant and/or their authorized representative consents to participate in the study, 
their informed consent must be documented in writing via a signed and dated ICF. The date of 
the informed consent will also be collected in the eCRF along with the initial protocol version. 
Minors or adults with intellectual disability comprise most of the participants with LGS or DS; 
therefore, the study would not be representative of these participant populations if it excluded 
them. 
In this study, informed consent will be required from all participants and/or their legally 
authorized representatives. 
A legally authorized representative is defined as “an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant, to the 
participant’s participation in the procedure(s) involved in the study.” 
In this study, informed consent will be obtained using paper forms. 
10.1.3.2 
Standards the Informed Consent Follows 
Informed consent documents, regardless of whether they are presented on paper or electronically, 
must 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.  
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The ICF: 
• Explain the nature of the study, its objectives, potential risks and benefits. 
• Describe the participant’s rights and responsibilities, including what the study will require of 
the participant. 
• Describe the planned and permitted uses, transfers, and disclosures of the participant’s 
personal and personal health information for purposes of conducting the study, including the 
use of electronic devices and associated technologies, if applicable. 
• State the fact the participant is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
More specifically, in seeking informed consent, the following information shall be provided to 
each participant: 
• A statement that the study involves research. 
• An explanation of the purposes of the research. 
• The expected duration of the participant’s participation. 
• A description of the procedures to be followed, including invasive procedures. 
• The identification of any procedures that are experimental. 
• The estimated number of participants involved in the study. 
• A description of the participant’s responsibilities. 
• A description of the conduct of the study. 
• A statement describing the treatment(s) and the probability for random assignment to each 
treatment. 
• A description of the possible side effects of the treatment that the participant may receive. 
• A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant. 
• A description of any required restrictions related to contraception, pregnancy, and 
breastfeeding. 
• Contraception requirements for participants of childbearing potential and for participants 
capable of making a partner pregnant. 
• Definition of relevant terms, such as “childbearing potential.”  
• Statement that participants of childbearing potential will undergo regular pregnancy tests 
during the study.  
• Explanation of required actions (such as discontinuation or treatment or from the study) if a 
participant or their partner becomes pregnant during study.  
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• Statement that the investigator will offer the participant the choice to receive unblinded 
treatment information if a pregnancy occurs. 
• Statement that the participant must avoid breastfeeding during the study. 
• A description of any benefits to the participant or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the participant, the participant 
should be made aware of this. 
• Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the participant and their important potential risks and benefits. 
• A statement describing the extent to which confidentiality of records identifying the 
participant 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 an ICF, the 
participant or the participant’s legally acceptable representative is authorizing such access. 
• 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. 
• The anticipated prorated payment(s), if any, to the participant for participating in the study. 
• The anticipated expenses, if any, to the participant for participating in the study. 
• An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the participant. 
• A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the participant otherwise is entitled 
• A statement that the participant or the participant’s legally acceptable representative may 
discontinue participation at any time without penalty or loss of benefits to which the 
participant is otherwise entitled. 
• The consequences of a participant’s decision to withdraw from the research and procedures 
for orderly termination of participation by the participant. 
• A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study. 
• A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so. 
• The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated. 
• A participant authorization (either contained within the ICF or provided as a separate 
document) describing to the participant the contemplated and permissible uses and 
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disclosures of the participant’s personal information (including personal health information) 
for purposes of conducting the study. The participant authorization must contain the 
following statements regarding the uses and disclosures of the participant’s personal 
information: 
– That deidentified 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. 
– That is possible that de-identified personal information (including personal health 
information) may be processed and transferred to countries that do not have data 
protection laws that offer participants 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. 
– That de-identified 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 
participants, developing a better understanding of disease, and improving the efficiency 
of future clinical studies. 
– That participants 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 
– That the participant’s identity will remain confidential in the event that study results are 
published. 
• A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as clinicaltrials.gov. 
• A description of the electronic devices and associated technology and its usage in the study. 
10.1.3.3 
Who Creates the Informed Consent Materials 
The sponsor will provide sample ICFs to the investigator.  
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the participant authorization form. 
The principal investigator will provide the sponsor with a copy of the ICF that was reviewed by 
the IRB/IEC and received their favorable opinion/approval. A copy of the IRB/IEC’s written 
favorable opinion/approval of these documents must be provided to the sponsor before the start 
of the study unless it is agreed to and documented (abiding by regulatory guidelines and national 
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provisions) before study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/IEC requires modification of 
the sample documents that the sponsor provided, the documentation supporting this requirement 
must be provided to the sponsor. Both the IRB or IEC and the sponsor must approve the ICF 
participant authorization form (if applicable), and participant information sheet (if applicable) 
before use. 
10.1.3.4 
Who Conducts the Informed Consent Process 
It is the responsibility of the investigator and the study personnel to: 
• Explain the detailed elements of the ICF to the participant/participant’s legally authorized 
representative.  
• Answer all of the participant’s/participant’s legally authorized representative’s questions 
about the study. 
• Provide the participant/participant’s legally authorized representative ample time to decide 
whether or not to participate in the study. 
• Obtain written informed consent from all participants/participants’ legally authorized 
representatives before any study-related procedures including screening assessments. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. If the participant is not capable of rendering adequate 
written informed consent, then the participant’s legally acceptable representative may provide 
such consent for the participant in accordance with applicable laws and regulations. 
If the participant, or the participant’s legally acceptable representative, determines they will 
participate in the study, then they must sign and date the ICF and participant authorization form 
(if applicable) at the time of consent and before entering into the study.  
The participant or the participant’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. 
A copy of the informed consent documentation (ie, a complete set of participant information 
sheets and fully executed signature pages) must be provided to the participant or the participant’s 
legally authorized representative. 
The investigator must also sign and date the ICF and participant authorization (if applicable) at 
the time of consent or after the receipt of participant signature (in the case of consent) and before 
the participant enters the study 
Signed consent forms or certified copies of electronic signature must remain in each participant’s 
study file at the site and must be available for verification at any time. 
The investigator must document the date the participant signs the ICF in the participant’s source 
documents. 
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10.1.3.5 
Re-Consent 
Participants/participants’ legally authorized representatives are required to re-consent/re-assent if 
changes are made to the protocol or if new information is made available that may affect the 
willingness of current participants (those who are already enrolled and actively participating) to 
continue in the clinical investigation. Re-consent/assent should be obtained as described in 
Section 10.1.3.1.  
Updated ICFs, individual consents, individual assents, individual re-consents and re-assents will 
be placed in the study master file. Re-consent information including the protocol version and 
re-consent date will also be recorded in the eCRFs. 
10.1.4 
Data Protection 
The confidentiality of records that may be able to identify participants will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After participants have consented to take part in the study, the sponsor and/or its representatives 
reviews their source documents and data collected during the study. These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market soticlestat; national or local regulatory authorities; and the IRB/IEC which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of participants’ identities. Participants are assigned a 
unique identifying number; however, their initials and date of birth may also be collected, if 
permitted under local laws governing privacy.  
The results of studies containing participants’ unique identifying number, relevant source 
documents, and possibly initials and dates of birth, where allowed per local law, may be 
transferred to, and used in, other countries which may not afford the same level of protection that 
applies within the countries where this study is conducted. The purpose of any such transfer 
would include: to support regulatory submissions, to conduct new data analyses to publish or 
present the study results, or to answer questions asked by regulatory or health authorities. 
• Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
• The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the ICF.  
• The participant must be informed that their source documents may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities 
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All United States (US)-based sites and laboratories or entities providing support for this study, 
must, where applicable, comply with the HIPAA of 1996. A site that is not a covered entity as 
defined by HIPAA must provide documentation of this fact to the sponsor. 
In the event that a serious data breach is detected, the sponsor or its designee and the investigator 
(as applicable) will take appropriate corrective and preventative actions in response. These 
actions will be documented, and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of the study participants, this would be done through the investigator. 
10.1.4.1 
Notice Regarding the Use and Transfer of the Investigator’s Personal Information  
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and telephone number, and other personally identifiable information such as education 
and professional details, payment-related details (if applicable), identity information (eg, medical 
registration number) and information relating to his or her interactions and activities with or 
involving Takeda. 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 their licensing partners. 
• Business partners assisting Takeda, its affiliates, and their 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. 
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– Posting investigator site contact information, study details and results on publicly 
accessible clinical trial registries, databases, and websites. 
In addition, where required by law or industry codes of practice, Takeda and/or its affiliates may 
have to report or publicly disclose any payments or transfers of value made in connection with 
the study by or on behalf of Takeda and/or its affiliates or their service providers to the 
investigator or their institution. 
The legal basis on which Takeda and its affiliates will process the investigator’s personal 
information for the above purposes are to comply with a legal obligation; or to perform any 
contract in place with the investigator (if applicable); or to meet the legitimate research, 
scientific and business interests of Takeda and its affiliates, including ensuring the proper 
performance of this study to the applicable standards, appropriate reporting of study results and 
archiving of study-related records and information, and further development and registration of 
the study drug or other compounds. The investigator may not be able to opt-out of this 
processing, or the investigator’s choice to opt-out may impact his or her ability to continue to 
participate in this study and/or future studies involving Takeda and/or its affiliates.  
Takeda and its affiliates will maintain physical, administrative and technical safeguards to 
protect the investigator’s personal information from loss, misuse, unauthorized access, 
disclosure, alteration or destruction. 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. 
However, where investigator’s personal information is transferred to Takeda affiliates, licensing 
partners, business partners or service providers in such countries, Takeda will ensure that all 
adequate safeguards are in place and that all applicable laws and regulations are complied with in 
connection with such transfers. 
The investigator’s personal information will only be stored as long as necessary for the purposes 
for which it was collected participant to local laws and regulations and legitimate scientific, 
research and business needs. 
Individuals located in the European Economic Area and in certain other countries have certain 
data participant rights which may be participant to limitations and/or restrictions. These rights 
include the right to: (i) request access to and rectification or erasure of their personal data; 
(ii) obtain restriction of processing or to object to processing of their personal data; (iii) the right 
to data portability; and (iv) obtain additional information regarding the safeguards Takeda has in 
place for cross-border transfers of their personal data. If the investigator wishes to exercise one 
of these rights, the investigator may use the contact information below.  
Individuals located in the European Economic Area and in certain other countries may also have 
the right to lodge a complaint about the processing of their personal data with their local data 
protection authority. 
The investigator can contact Takeda to exercise his or her rights, make inquiries or submit 
complaints concerning Takeda’s processing of his or her personal information. Takeda will take 
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appropriate steps to address requests, inquiries and complaints. Takeda will respond to such 
requests within thirty (30) business days. 
Contact Details: 
Mailing Address: Attn: Data Protection Officer, Legal Department, Takeda Pharmaceuticals 
International AG, Thurgauerstrasse 130, CH-8152 Glattpark-Opfikon (Zurich), Switzerland. 
Email Address: dataprivacy@takeda.com 
Investigator acknowledges and authorizes the use of his or her personal information by Takeda 
and other parties for the purposes described above. 
10.1.5 
Committees Structure  
10.1.5.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those Americas sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the US Department of 
Health and Human Services. 
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 ICF, and, if applicable, 
participant 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 participant 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, ICF) reviewed; and state the approval date. If 
required by country or regional regulations or procedures, approval from the competent 
regulatory authority will be obtained before commencement of the study or implementation of a 
substantial amendment. The sponsor will notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation Until the site receives notification no protocol 
activities, including screening may occur. 
Study sites must adhere to all requirements stipulated by their respective IRB/IEC. This may 
include notification to the IRBs/IECs regarding protocol amendments, updates to the ICF, 
recruitment materials intended for viewing by participants, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRBs/IECs, and submission of the investigator’s final status report to IRBs/IECs. All 
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IRBs/IECs approvals and relevant documentation for these items must be provided to the 
sponsor or designee. 
Participant incentives should not exert undue influence for participation. Payments to 
participants must be approved by the IRBs/IECs and sponsor. 
10.1.6 
Dissemination of Clinical Study Data 
10.1.6.1 
Study Results Disclosure  
To ensure that information on clinical studies 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 studies before study start and disclose the results of those studies in a 
manner and timeframe compliant with Takeda policy and all applicable laws and regulations. 
Clinical trial registration and results disclosures will occur on clinicaltrials.gov, other clinical 
trial registries/databases as required by law, and on Takeda’s corporate website(s). 
10.1.7 
Data Quality Assurance  
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
Guidance on completion of CRFs will be provided in Case Report Form Completion Guidelines. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, CROs). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator per local regulations or institutional policies. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
10.1.7.1 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances arise that will 
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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 sponsor will assess any protocol deviation. If it is likely to affect to a significant degree the 
safety and rights of a participant or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol. 
The site should document all protocol deviations in the participant’s source documents. In the 
event of a significant deviation, the site should notify the sponsor or its designee (and IRB or 
IEC, as required). Significant deviations include, but are not limited to, those that involve fraud 
or misconduct, increase the health risk to the participant, or confound interpretation of primary 
study assessment. 
10.1.7.2 
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. 
The investigator and the study site head guarantee access to source documents by the sponsor or 
its designee (CRO) and by the IRB/IEC. 
Alternative approaches may be used to ensure data quality, data integrity, and participant safety 
(eg, remote source data review/source data verification via phone or video) as permitted by 
regional and local regulations. See the monitoring plan for additional details. 
10.1.7.3 
Audits 
The study site also may be participant 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 US FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan, Center for Drug Evaluation in China). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately.  
The investigator and study site guarantee access for quality assurance auditors to all study 
documents as described in Section 10.1.8. 
10.1.8 
Source Documents  
All key data must be recorded in the participant’s source documents unless otherwise noted in 
the protocol. Source documents may be paper or electronic, including data obtained using 
electronic devices and associated technologies. Original source data to be reviewed during this 
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study will include, but are not limited to: participant’s medical file, appointment books, diaries, 
clinical outcome assessments, original clinical laboratory reports, histology reports, pathology 
reports, and x-rays. The investigator (as listed on the US FDA Form 1572) is responsible for 
maintaining adequate and accurate source documents.  
The investigator must provide direct access to inspect facilities, including original source records 
relevant to this study (regardless of media), to: the sponsor or its authorized representatives; the 
respective national, local, or foreign regulatory authorities; the IRB/IEC; and auditors. These 
records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency, United Kingdom Medicines and Healthcare products Regulatory 
Agency) or an auditor. The consent form includes a statement granting this access to source data.  
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.1.8.1 
eCRFs 
Completed eCRFs are required for each participant who has completed the consent process. The 
eCRFs are designed to record all observations and other data pertinent to the clinical 
investigation unless otherwise noted in the protocol.  
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. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. eCRFs must be completed in English.  
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF. 
The investigator or the investigator’s designee (ie, authorized site personnel, as stated in the site 
delegation log) must enter data from the source documents (Section 10.1.8) into the eCRF with 
guidance from eCRF Completion Guidelines. 
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. 
A study monitor from the sponsor or its designee will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Auditors, IRB/IEC members, or regulatory inspectors may also check the eCRF entries 
against the source documents. 
Discrepancies between source data and data entered on the CRF will be addressed by qualified 
site personnel. When a data discrepancy warrants correction, the correction will be made by 
authorized site personnel.  
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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 use of change and modification records of the 
eCRFs.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should also be included. The 
principal investigator must review the data change for completeness and accuracy, and must 
sign, or sign and seal, and date.  
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 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.  
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data. Alternative approaches may be used to ensure data quality, data integrity, 
and participant safety (eg, remote source data review via phone or video) as permitted by 
regional and local regulations. Additional details are in the monitoring plan.  
The CRFs should be approved by the investigator per study specifications and the sponsor’s data 
delivery requirements.  
The investigator’s signature constitutes their attestation to the integrity of the data transmitted to 
the sponsor. 
10.1.8.2 
Documentation and Retention of Records 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Source documents provide evidence for the existence of the 
participant and substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. A definition of what constitutes source data and its origin can be found in for 
example, source data acknowledgment or monitoring guidelines. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous source documents or transfer records, depending on the study. Also, current source 
documents must be available. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
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10.1.8.3 
Data Handling 
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 MedDRA. 
Drugs will be coded using the World Health Organization Drug Dictionary.  
Data are to be entered into a clinical database as specified in the CRO’s data management plan or 
similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
10.1.8.4 
Record Retention 
The investigator agrees to keep the records stipulated in Section 10.1.8.2 and those documents 
that include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, source documents, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated ICFs (including consent to use digital tools and 
applications, if applicable), participant authorization forms regarding the use of personal health 
information (if separate from the ICFs), query responses/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 participant’s chart to ensure long term legibility. Furthermore, ICH E6(R2) Section 5.5.11 
requires the investigator to retain essential documents specified in ICH E6(R2) (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(R2) 
Section 5.5.11 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. 
10.1.9 
Study and Site Start and Closure 
10.1.9.1 
First Act of Recruitment  
The first act of recruitment is the first site open. For clinical study disclosure purposes, the study 
start date is the date when the first participant signed ICF. 
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10.1.9.2 
Study/Site Termination  
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
The sponsor reserves the right to close the study site at its sole discretion. Study sites will be 
closed on study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/IECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• For study termination: 
– Discontinuation of further study drug development. 
• For site termination: 
– Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines. 
– Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator. 
– Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should ensure appropriate participant 
therapy and/or follow-up.  
For sites in the EU, the sponsor will make an end of study declaration to the relevant competent 
authority as required by EU Clinical Trials Regulation (CTR) (Regulation No. 536/2014). 
10.1.10 
Publication Policy 
During this study, until the open access period, only Takeda may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. 
Both during and after this study, all public disclosures containing data/information from this 
study must undergo review and receive written approval by the appropriate Takeda 
representative(s) before any public disclosure (including but not limited to submission, 
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presentation, posting on online platforms for archiving, and distribution of unpublished 
preprints).  
This policy applies to all publication types, including: abstracts and presentations (oral and 
poster, including invited presentations) for scientific congresses; articles (original research 
manuscripts, review articles, invited articles), letters to the editor, and editorials, in scientific 
peer-reviewed journals; print, electronic and enhanced multimedia publications associated with 
traditional congress and journal publishing (such as, but not limited to, audio, visual/graphical or 
video abstracts or manuscript summaries; video or animated posters; augmented reality); books 
and book chapters.  
Authorship will be determined in line with the requirements of the International Committee of 
Medical Journal Editors Recommendation for the Conduct, Reporting, Editing and Publication of 
Scholarly Work in Medical journals, unless otherwise required by the journal or forum where the 
publication appears. 
All publications must be developed with a dataset (such as statistical tables and listings, a clinical 
study report, and/or final report) that has been verified by a qualified Takeda employee per 
Takeda’s internal standards. Data relevant to the development of Takeda publications must be 
shared with all authors via a secure site.  
Publications derived from this study may never contain participants’ direct identifiers (such as 
participant ID, initials) but may contain indirect/quasi identifiers (for example sex/gender, 
age/birth date, geographic indicators). Publications derived from this study may not include 
products’ direct identifiers (lot numbers or batch numbers) unless specifically required by the 
journal or conference guidelines and if approved by Takeda.  
Takeda requires the submission of all manuscripts resulting from this study, regardless of the 
intended audience or language, to journals that offer public availability via an Open Access 
platform.  
The following types of information are required by ICH to be in the protocol if not addressed in 
another document (such as the site contracts): 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.  
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.1.11 
Responsibilities of the Sponsor and the Investigator 
10.1.11.1 Sponsor Responsibilities 
10.1.11.1.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform these activities 
either in full or in partnership with the sponsor. 
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and subinvestigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that 
must be signed by each investigator and subinvestigator before the study starts at their study site; 
in addition, any potential conflicts of interests that are not covered by this financial disclosure 
form should be disclosed separately to the sponsor before the start of the study at their site. 
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to sponsor before the start of the study. 
10.1.11.1.2 Insurance 
Each participant in the study must be insured in accordance with the regulations applicable to the 
site where the participant 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 
participants. Refer to the study site agreement regarding the sponsor’s policy on participant 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. The sponsor ensures that suitable 
clinical study insurance coverage is in place before the start of the study. An insurance certificate 
is supplied to the CRO as necessary. 
10.1.11.2 Investigator Responsibilities  
The investigator must perform the study in accordance with ICH GCP Guideline E6, EU CTR 
(Regulation No. 536/2014), other applicable regulatory requirements and guidelines, and rules 
considering the rights, safety, and wellbeing of human participants. 
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: 
• Conduct the study in accordance with the protocol. 
• Personally conduct or supervise the staff who will assist in the protocol. 
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• If the investigator/institution retains the services of any individual or party to perform study-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and 
any data generated. 
• Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential participants, before the receipt of 
written approval from relevant governing bodies/authorities. 
• Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
• 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. 
• 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 participants. 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. 
• Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
• Obtain valid informed consent from each participant who participates in the study, and 
document the date of consent in the participant’s medical chart. A valid ICF is the most 
current version approved by the IRB/IEC. Each ICF should contain a participant 
authorization section that describes the uses and disclosures of a participant’s personal 
information (including personal health information) that will take place in connection with 
the study. If an ICF does not include such a participant authorization, then the investigator 
must obtain a separate participant authorization form from each participant or the 
participant’s legally acceptable representative. 
• Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, and laboratory results, 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. 
• Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
• Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.  
• Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
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It is the investigator’s responsibility to ensure that adequate time, appropriately trained 
personnel, and resources are available before commitment to participate in this study.  
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, on request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study. 
The investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable participants within the agreed recruitment period.  
If a potential research participant has a primary care physician, the investigator should, with the 
participant’s consent, inform them of the participant’s participation in the study. 
The investigator listed on the Form FDA 1572 will verify by signature the integrity of the data 
transmitted to the sponsor. 
The investigator will be responsible for reviewing data, reports, and interlaboratory/reader 
standardization methods (if applicable); facilitating monitoring and auditing activities. 
10.1.11.2.1 Protocol Adherence and Investigator Agreement  
The investigator and any subinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those participants who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRBs/IECs and provide them with a detailed written explanation. The 
investigator will also return all study drug, containers, and other study materials to the sponsor. 
On study completion, the investigator will provide the sponsor, IRB/IEC, and regulatory agency 
with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/IECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
10.1.11.2.2 Principal Investigator/Coordinating Investigator 
The principal investigator/coordinating principal investigator will be required to review and sign 
the final clinical study report and by doing so agrees that it accurately describes the results of the 
study, in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995). 
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10.1.12 
Site Termination or Suspension 
10.1.12.1 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 as otherwise permitted by the contractual agreement. 
10.1.12.2 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 ET 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 risk/benefit 
is no longer acceptable for participants participating in the study. 
• The soticlestat program Data Monitoring Committee recommends that the study should be 
suspended or terminated.  
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises participant safety. 
10.1.12.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)  
In the event that the sponsor, an IRB/IEC or regulatory authority elects to terminate or suspend 
the study or the participation of a study site, a study-specific procedure for ET 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. 
10.2 
Clinical Laboratory Tests  
Table 10.a lists the tests that will be obtained for each laboratory specimen. These tests will be 
performed by the local laboratory. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
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Table 10.a 
Protocol-Required Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
Platelet count 
Mean platelet 
volume 
Hemoglobin 
Hematocrit 
RBC indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistry a 
Albumin 
BUN 
Creatinine 
Potassium 
Sodium 
Calcium 
AST  
ALT  
Alkaline phosphatase 
 
Total bilirubin  
Direct bilirubin 
Indirect bilirubin 
Total protein 
PT/INR a 
Complete blood count with 
differential a 
ALP a 
GGT a 
Routine urinalysis 
Specific gravity 
pH, glucose, protein, ketones, bilirubin, nitrite, leukocyte esterase by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
For participants of childbearing potential only: highly sensitive (serum or urine) hCG 
pregnancy test  
Additional testing 
Genetic testing for SCN1A d 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; hCG: human 
chorionic gonadotropin; INR: international normalized ratio; MCH: mean corpuscular hemoglobin; MCV: mean 
corpuscular volume; PT: prothrombin time; RBC: red blood cell; WBC: white blood cell.  
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.1, 
Section 10.6 and Figure 10a (follow guidance in Section 10.6 on when these additional test are required)  
b To be performed only at screening.  
d For participants with DS only: If genetic testing was not performed previously or if the SCN1A result is negative 
(without any other positive gene reported that is consistent clinically with DS), testing for SCN1A will be offered at 
the time of screening, per local restrictions 
 
10.2.1 
Clinical Laboratory Assessments and Other Safety Assessments 
A change in the value of a clinical laboratory parameter, physical examination finding, or a vital 
sign measure can represent an AE if the change is clinically relevant or if, during administration 
of study drug, a shift of a parameter is observed from a value in the normative range to a value 
that is outside the normal range and considered clinically significant, or a further waning of an 
already clinically significant value. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the study drug, and the range of variation 
of the respective parameter within its reference range, should also be considered. 
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If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), physical examination, or vital signs that were not present at 
the pretreatment evaluation observed closest to the start of study treatment, further investigations 
should be performed until the values return to within the reference range or until a plausible 
explanation (eg, concomitant disease or expected disease evolution) is found for the abnormal 
values. 
The investigator should assess, based on the above criteria and the clinical condition of the 
participant, whether a change in a clinical laboratory value, physical examination, or vital sign 
parameter is clinically significant and represents an AE. The assessment of clinical significance 
is recorded on the eCRF related to the assessment (for example, the clinical laboratory value 
eCRF), but an event that is also classified as an AE will be recorded on the AE page.  
10.2.2 
Biological Sample Retention and Destruction 
Not applicable. There will be no collection, storage and future use of biological samples from 
clinical study participants in this study. 
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Note: The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
• Results in persistent or significant disability/incapacity. 
Note: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect. 
• Is a suspected transmission of any infectious agent via an authorized medicinal product. 
• Other situations: 
– Is an important medical event. 
– May require drug to prevent one of the outcomes listed above. 
– May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
Medical or scientific judgment should be exercised by the investigator in deciding whether SAE 
reporting is appropriate in other situations such as significant medical events that may jeopardize 
the participant or may require medical or surgical drug to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. 
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10.3.3 
Additional Considerations in Identifying and Defining AEs  
10.3.3.1 
Defining Discrete AEs 
Each reported AE should represent a single diagnosis, if the diagnosis is known. Accompanying 
signs (including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs UNLESS the diagnosis is unknown. Specific examples are as 
follows: 
Laboratory values and ECG findings: 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis should be 
reported as the AE. 
Worsening of a condition: 
If the participant experiences a worsening or complication of a medical condition, the worsening 
or complication should be recorded as an AE. Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”). This includes: 
• Pre-existing conditions present at the time of signing of informed consent. 
• Pre-existing episodic concurrent medical conditions (eg, asthma, epilepsy): An episode 
should only be recorded as an AE if the condition becomes more frequent, serious, or severe 
in nature.  
• A degenerative concurrent medical condition (eg, cataracts, rheumatoid arthritis): Worsening 
of the condition should only be recorded as an AE if it occurs to a greater extent than 
expected.  
• Worsening or complication of an AE after any change in study drug: The worsening or 
complication should be recorded as a new AE. 
Complications associated with preplanned procedures: 
• Changes in plan and surgical complications associated with preplanned or elective surgeries, 
therapies, or procedures should be recorded as AEs.  
• 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 an elective surgery should be recorded as AEs. 
Changes in intensity of AEs: 
• If the participant experiences changes in intensity of an AE, the event should be recorded 
once with the maximum intensity recorded. 
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10.3.3.2 
AESIs 
An AESI (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 to 
characterize and understand them. 
The following events will be reported as AESI for this study: 
• 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 participants in the TAK-935-2001 study of adult participants with 
DEEs. To assess this potential interaction, clinical safety monitoring and expanded evaluation 
will be performed to closely monitor seizure frequency in these participants.  
• 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. (See Section 8.3.4.) 
• Psychosis: 
During the phase 1 multiple rising dose study in healthy participants, episodes of confusion, 
euphoria, and psychosis were seen at the highest dose of 600 mg/d. However, in this study 
participants 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 10.3.4. 
AESIs must be recorded as AEs in the eCRF within 24 hours. An evaluation form along with 
all documentation must be submitted to the sponsor. 
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10.3.4.7 
Reference Safety Information 
The reference safety information (RSI) for this study is the IB, which the sponsor has provided 
under separate cover to all investigators. 
10.3.4.8 
Unexpected AEs 
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not consistent with 
the term, representation, or description used in the RSI. “Unexpected” also refers to the AEs that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the product, but are not specifically mentioned as occurring with 
the particular product under investigation.  
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
will not be based on what might be anticipated based on the pharmacological properties of a 
product. 
10.3.4.9 
TEAEs  
As described in Section 1.3, all AEs will be collected from the time when the ICF is signed. For 
reporting purposes in the study, a TEAE is defined as any event emerging or manifesting at or 
after the initiation of treatment with a study drug or medicinal product or any existing event that 
worsens in either intensity or frequency following exposure to the study drug or medicinal 
product. 
10.3.5 
Expedited Reporting of SAEs and Selected AEs 
This section describes the expedited reporting required for certain types of events, in addition to 
eCRF completion: 
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10.3.5.2 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for identifying and reporting all SUSARs and any other 
applicable SAEs to regulatory authorities, investigators, and IRB or IEC in accordance with 
national regulations in the countries where the study is conducted. AEs that are already classified 
as expected (and therefore are not SUSARs) are listed in the RSI, See Section 10.3.4.7 for the 
location of the RSI.  
The following specialized types of events have their own reporting windows:  
• SUSARs will be submitted to the regulatory authorities as an expedited report within 7 days 
for fatal and life-threatening events and 15 days for other serious events, relative to the first 
awareness of an event by/or further provision to the sponsor or sponsor’s designee, unless 
otherwise required by national regulations.  
• The sponsor will prepare an expedited reports for other safety issues that 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 study.  
The study site will forward a copy of all expedited reports to its IRB or IEC in accordance with 
local regulations. 
10.3.6 
Reporting of Non-SAEs Related to Auxiliary Medicinal Products 
Not applicable. 
10.4 
Contraceptive and Barrier Guidance  
10.4.1 
Definitions  
For the purposes of this study, reproductive status is defined as follows:  
• Nonpregnant: Negative urine and/or serum beta human chorionic gonadotropin (hCG) 
pregnancy test result. 
• Person who is not of childbearing potential: 
– Premenarchal and 1 of the following:  
• Tanner stage 1.  
• <9 years of age. 
– Surgically sterile for at least 6 weeks at screening (defined as having undergone one of 
the following procedures: hysterectomy, bilateral tubal ligation, bilateral oophorectomy 
or bilateral salpingectomy). 
– Postmenopausal at screening (defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
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contraception or hormonal replacement therapy. However in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
• Person who is of childbearing potential: following menarche and until becoming 
postmenopausal unless permanently sterile by the definition above. 
• Male who is not fertile: Sterilized males should be at least 1 year after a bilateral vasectomy 
and have confirmed that they have obtained documentation of the absence of sperm in the 
ejaculate or have had bilateral orchidectomy. 
• Male who is fertile: postpuberty, unless permanently sterile by the definition above. 
10.4.2 
Contraception Guidance  
In this study, the use of effective (not applicable for Germany) or highly effective contraception 
is generally required unless otherwise noted. In addition, contraceptive use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical 
studies. 
The failure rates of contraceptives that are used consistently and correctly may differ in typical 
use. Therefore, when study participation requires any of these methods of contraception to be 
used, participants must commit to using them: 
• Consistently throughout the required period. 
• Correctly, as described below and in any labeling associated with the method. 
Contraception requirements depend in part on the reproductive status of the participant and the 
participant’s partner.  
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Table 10.c 
Acceptable Contraception Methods and Lactation Guidance for This 
Study 
Highly Effective Contraceptives 
Failure rate of <1% per year when used consistently 
and correctly 
Effective Contraceptives a 
Failure rate of >1% per year when used consistently 
and correctly 
User Dependent 
 
• 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition 
of ovulation. b,c 
– 
Oral.  
– 
Intravaginal.  
– 
Transdermal.  
• 
Progestogen only hormonal contraception 
associated with inhibition of ovulation.  
– 
Oral.  
– 
Injectable. 
• 
Sexual abstinence. d  
• 
Refraining from donating sperm. e  
• 
Progestogen-only oral hormonal contraception, 
where inhibition of ovulation is not the primary 
mode of action. 
• 
Male or female condom with or without 
spermicide. f 
• 
Cap, diaphragm or sponge with spermicide. f 
• 
Combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double-
barrier methods). 
Low User Dependency 
 
• 
Implantable progestogen only hormonal 
contraception associated with inhibition of 
ovulation. a,b 
• 
IUD.  
• 
IUS.  
• 
Bilateral tubal occlusion. 
• 
Vasectomy; vasectomized partner. g,h 
 
Measures Intended to Prevent Fetal and Neonatal Exposure via Sperm or Breastmilk 
• 
Participants who are lactating must agree not to use their breastmilk to feed an infant. 
IUD: intrauterine device; IUS: intrauterine hormone-releasing system 
a Effective method of contraception is not applicable in Germany. 
b Hormonal contraceptives must be stabilized for at least 30 days before the start of the screening period. 
c Hormonal contraception may be susceptible to interaction with the intervention, which may reduce the efficacy 
of the contraceptive method. Therefore, 2 highly effective methods of contraception should be used during the 
treatment period and for at least 30 days after the last dose of study treatment. 
d Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
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Table 10.c 
Acceptable Contraception Methods and Lactation Guidance for This 
Study 
Highly Effective Contraceptives 
Failure rate of <1% per year when used consistently 
and correctly 
Effective Contraceptives a 
Failure rate of >1% per year when used consistently 
and correctly 
e Refrain from donating sperm for the duration of the study and within 90 days following the last administration 
of the study drug. 
f A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
g A vasectomy is a highly effective contraceptive method only if the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
h For participants of childbearing ability, having a vasectomized partner is a highly effective contraception 
method provided that the partner is the participant’s sole partner and that the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
 
Table 10.d 
Unacceptable Contraception Methods 
Methods that are unacceptable in any study requiring contraception 
• 
Periodic abstinence (calendar, symptothermal, postovulation methods)  
• 
Withdrawal (coitus interruptus)  
• 
Spermicides only 
• 
Lactational amenorrhea method 
• 
Use of both female condom and male condom together at the same time 
Contraceptives that are effective but have a failure rate of >1% per year when used consistently and 
correctly are unacceptable in a study requiring highly effective contraception (ie, <1% failure rate) 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide 
 
From signing of the ICF and throughout the duration of the study and for 30 days after the last 
dose, participants of childbearing potential (ie, nonsterilized, premenopausal participants) who 
are sexually active must use acceptable methods of contraception.  
Also, from signing of the ICF, throughout the duration of the study, and for 90 days after last 
dose, nonsterilized male participants who are sexually active with a partner of childbearing 
potential must use contraception. 
Participants will be provided information on acceptable methods of contraception as part of the 
participant informed consent process and will be asked to sign an ICF stating that they 
understand the requirements for avoidance of pregnancy during the study. During the study, 
regular urine hCG pregnancy tests will be performed, and participants will receive continued 
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guidance on avoiding pregnancy. At investigator discretion serum (hCG) pregnancy tests can be 
performed at any time during the study (and can be performed instead of urine). 
Female participants of childbearing potential must have a negative urine pregnancy test at 
screening (serum hCG pregnancy test can be performed at investigator discretion) 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. 
In addition, male participants must be advised not to donate sperm from signing of the ICF to 90 
days after the last dose of study drug. 
10.4.3 
Pregnancy 
If any participant is found to be pregnant during the study, the participant should be withdrawn 
and sponsor-supplied intervention should be immediately discontinued. 
If a participant’s partner becomes pregnant during the study or for 30 days after the last dose, the 
participant’s partner should be asked for consent to record and follow the pregnancy.  
If the pregnant participant or the participant’s pregnant partner agrees, the investigator should 
notify their primary care physician that the participant/participant’s partner was participating in a 
clinical study when they became pregnant and provide details about the drug the participant 
received (blinded or unblinded, as applicable). 
If the pregnancy occurs during administration of active study intervention (eg, after Visit 1) or 
within 90 days after the last dose of active study drug, the pregnancy should be reported 
immediately.  
All pregnancies in participants or their partners 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. 
10.5 
Genetics  
Not applicable. 
10.6 
Abnormal Liver-Associated Test Result Monitoring and Follow-up Assessments 
and Study Drug Restart/Rechallenge Guidelines  
Investigators must be vigilant for abnormal liver-associated test results in participants during the 
clinical study. Transient fluctuations in serum aminotransferases occur commonly in clinical 
study participants, but it is crucial that the investigator identifies and evaluates participants with 
possible hepatic injury. This guidance is intended to aid investigations of abnormal liver-
associated test results in clinical study participants who had no known liver disease and had 
either normal or near normal baseline liver test results (ie, ALT <2 × ULN, total bilirubin <1.5 × 
ULN, and alkaline phosphatase <1.5 × ULN) at the time (before) of enrollment (during screening 
period). 
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In evaluating study participants with abnormal liver-associated test results, the investigator 
should perform follow-up laboratory tests to confirm the abnormal test results and monitor the 
participant. If the abnormal liver-associated test results are confirmed, then the participant should 
be monitored and, if necessary, additional diagnostic tests should be performed as shown in 
Figure 10.a. Suggested hepatic investigations are listed in Table 10.e. Criteria for considering 
discontinuation of study drug are shown in Figure 10.b.  
Participants With Combined Elevations in Aminotransferase(s) and Bilirubin 
If a participant has elevated ALT >3 × ULN with concurrent elevated total bilirubin >2 × ULN 
or elevated INR >1.5, the investigator must contact the medical monitor and Takeda study 
clinician within 24 hours. Hepatic investigations as suggested in Table 10.e should be initiated. 
Any event of elevated ALT >3 × ULN with concurrent elevated total bilirubin >2 × ULN or 
elevated INR >1.5 for which an alternative etiology has not been identified must be reported as 
an SAE. 
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Table 10.e 
Hepatic Investigation 
Medical history  
• 
Concomitant medications (including over-the-counter medications, such as 
acetaminophen, and herbal supplements). 
• 
Medical conditions (eg, ischemia, hypotension, severe hypoxemia, congestive 
heart failure, sepsis).  
• 
Alcohol intake.  
• 
Hepatobiliary disorder. 
• 
Previous liver disease or metabolic syndrome (eg, obesity, insulin resistance, 
diabetes, or dyslipidemia). 
• 
Travel history. 
Physical examination 
(symptoms, signs, and 
laboratory results) 
• 
General malaise, fatigue, nausea, or vomiting. 
• 
Right upper quadrant pain or tenderness, fever, jaundice, rash. 
• 
Eosinophilia >5%. 
Hepatic/hepatobiliary 
imaging 
Perform as appropriate (eg, abdominal ultrasound, computed tomography, 
magnetic resonance imaging, or other hepatobiliary imaging). 
Viral hepatitis serology  
• 
Hepatitis A antibody (total and IgM). 
• 
Hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), 
Hepatitis B core antibody (IgM anti-HBc), hepatitis C antibodies (anti-HCV). 
• 
Hepatitis E (IgG and IgM). 
• 
Consider polymerase chain reaction for hepatitis B, C, and E. 
• 
Consider Epstein-Barr virus serology (viral capsid antigen, nuclear antigen, 
early antigen). 
• 
Consider cytomegalovirus serology (IgG and IgM). 
Autoimmune hepatitis 
serology 
• 
Anti-nuclear antibody. 
• 
Anti-smooth muscle antibody. 
• 
Anti-liver-kidney microsomal antibody).  
 
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10.8 
Abbreviations and Definitions 
10.8.1 
Abbreviations 
24HC 
24S-hydroxycholesterol 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ARCADE 
TAK-935-18-002 
ASM 
antiseizure medication 
AST 
aspartate aminotransferase 
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 
Clinical Global Impression 
CGI-C 
Clinical Global Impression of Change 
CGI-I 
Clinical Global Impression of Improvement 
CH24H 
cholesterol-24-hydroxylase 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
Clinical Trials Regulation 
CYP 
cytochrome P450 
DEE 
developmental epileptic encephalopathy 
DS 
Dravet syndrome 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
ELEKTRA 
TAK-935-2002 
ENDYMION 1 
TAK-935-18-001 
ENDYMION 2 
TAK-935-3003 
EO 
enzyme occupancy 
EQ-5D-5L 
EQ-5D 5-level version 
EQ VAS 
EQ-5D visual analogue scale 
ET 
early termination 
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EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-tube 
gastrostomy tube 
hCG 
human chorionic gonadotropin 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
IRT 
interactive response technology 
J-tube 
jejunostomy tube 
LFT 
liver function test 
LGS 
Lennox-Gastaut syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMD 
major motor drop 
NG-tube 
nasogastric tube 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QI-Disability 
Quality of Life Inventory-Disability 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
Schedule of Activities 
SOC 
standard of care 
SSR 
special situation reporting 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
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US 
United States 
VNS 
vagus nerve stimulation 
 
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REFERENCES  
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. 
Dravet, C. 2011. Dravet syndrome history. Dev Med Child Neurol, 53 Suppl 2, 1-6. 
Guy, W. 1976. ECDEU Assessment Manual for Psychopharmacology. National Institute of 
Mental Health. Rockville, MD, p. 217-22; 313-31. 
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. 
Richards, K. L., Milligan, C. J., Richardson, R. J., Jancovski, N., Grunnet, M., Jacobson, L. H., 
et al. 2018. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and 
premature death. Proc Natl Acad Sci U S A, 115(34), E8077-E85. 
Shmuely, S., Sisodiya, S. M., Gunning, W. B., Sander, J. W. and Thijs, R. D. 2016. Mortality in 
Dravet syndrome: a review. Epilepsy Behav, 64(Pt A), 69-74. 
 
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Appendix 1 
Strong CYP3A Inducers  
Strong inducers of CYP3A are prohibited, except antiseizure medication. Examples of prohibited 
inducers are listed below. (Source: fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers, Table 3-3 [inducers], accessed 
18 January 2023.) 
Strong CYP3A Inducers (examples) 
Apalutamide 
Enzalutamide 
Mitotane 
Rifampin 
St. John’s wort 
 
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Appendix 2 
Blood Volumes  
The amount of blood from participants at all scheduled visits during the study will be volumes 
not exceeding 2.4 mL/kg during any 4-week period. Additional blood may be drawn for retests 
and unscheduled visits, if any, and will not exceed 2.4 mL/kg of body weight during any 4-week 
period. Topical anesthetics are allowed (if necessary) for the collection of samples. Site will be 
advised not to collect samples on same day if failed twice. Another attempt can be made after 
2 to 4 weeks. 
The approximate blood volume collected at each visit and total blood volume during the study by 
weight will be captured in reference materials eg local laboratory documentation. 
These volumes represent the approximate maximum for visit and weight. Sites will be advised 
not to attempt collection of blood if they fail twice. Another attempt can be made after 2 to 
4 weeks. 
 
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Appendix 3  Minimizing Stress and Pain for Study Participants 
To follow the EU expert group recommendations on Ethical considerations for clinical trials on 
medicinal products conducted with minors (Revision 1 dated 18 September 2017), the following 
measures have been implemented to reduce stress and pain for the study participants. 
For both adult and pediatric participants, the risk associated with the administration of soticlestat 
is low, because it was generally safe and well tolerated in phase 1 and phase 2 studies. The risk 
associated with the diseases under study is mitigated by allowing rescue ASMs to be used during 
the study. 
Study procedures have been streamlined to reduce the risks and burdens to the study participants. 
Most study procedures are usually conducted during an SOC epilepsy clinic visit and induce 
little risk or burden (eg, vital signs, physical examination, neurological examination, clinical 
laboratory tests, ECG). Procedures that are not included in SOC clinic visit, including 
ophthalmological examination with pupil dilation, C-SSRS, and optional genetic testing, do not 
have significant risks or burdens and are designed to collect critical information on AESIs, class 
effect of ASMs, or to provide crucial scientific data.  
Topical anesthetic cream can be applied before taking blood samples. The needles used for blood 
sampling are butterfly needles, which are less painful to use and it is easier to access veins that 
are small or narrow. Butterfly needles with smaller size (23 gauge) are used in participants 
weighing ≤45 kg, while 21 gauge are used in participants weighing > 45 kg. Sites will be advised 
not to attempt collection of blood if they fail twice. Blood volume collected has been minimized 
based on weight in children, as specified in Appendix 2.  
Study visits and procedures have also been designed to minimize the burdens to the 
parents/caregivers. Study visits are infrequent to reduce the burden of traveling to sites. In 
addition, in jurisdictions where home visits by site staff in clinical studies are allowed per the 
discretion of the investigator and permissible by local regulations, home visits may be used as an 
alternative to site visits to further alleviate the parents’/caregivers’ burden. Virtual visits are also 
allowed in case of COVID-19 travel restrictions or other extenuating circumstances, and study 
procedures related to safety examinations are allowed to be performed locally. Parents/caregivers 
need to complete a set of health outcome measures during certain visits and keep a seizure and 
medication diary. The number and complexity of these measures as well as the content of the 
diary have been minimized to reduce their burden.  
In summary, the risks and burdens are low and acceptable in this study. To the study participants 
and their parents/caregivers, the elements of the study are unlikely to cause significant pain, 
discomfort, fear, disturbances of their lives and personal activities, or otherwise unpleasant 
experiences. 
 
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Signature Page for TAK-935-3004 Protocol Amendment 1
Title: Amendment 1 to An Open-label, Nonrandomized, Phase 3 Study to Evaluate th
Document Number: DN-000437198 v2.0
Approval
Clinical
28-Jun-2023 17:21:39 GMT+0000
Approval
Statistics
28-Jun-2023 17:33:35 GMT+0000
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Number: TAK-935-3004  
Study Title: An Open-label, Nonrandomized, Phase 3 Study to Evaluate the Efficacy and Safety 
of Soticlestat in Participants With Dravet Syndrome or Lennox-Gastaut Syndrome Who Have 
Been Exposed to Fenfluramine 
Phase 3 
Version: Original 
Date: 27-JUN-2023 
Prepared by:  
, Ph.D. 
, Neuroscience Statistics 
Based on: 
Protocol Version: Original 
Protocol Date: 10-MAR-2023 
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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Statistical Analysis Plan Original 
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CONFIDENTIAL 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original Version 
See signature page 
Not Applicable 
 
 
 
 
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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 
Additional Objectives ............................................................................................8 
1.1.2.1 
Exploratory Objectives..................................................................................8 
1.2 
Endpoints .......................................................................................................................8 
1.2.1 
Primary Endpoint(s) ..............................................................................................8 
1.2.2 
Exploratory Endpoints ...........................................................................................8 
Safety Endpoints include .....................................................................................................9 
1.3 
Estimand(s) ....................................................................................................................9 
1.3.1 
Primary Estimand ..................................................................................................9 
2.0 
STUDY DESIGN.................................................................................................................9 
2.1 
Overall Study Design .....................................................................................................9 
2.1.1 
Dose Titration Period (4 Weeks) .........................................................................12 
2.1.2 
Maintenance Period (Approximately 48 Weeks) ................................................12 
2.1.3 
Study Discontinuation/Completion .....................................................................13 
2.1.4 
Period of Evaluation and Schedule of Study Assessment ...................................13 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................13 
3.1 
Statistical Hypotheses ..................................................................................................13 
3.2 
Statistical Decision Rules ............................................................................................13 
3.3 
Multiplicity Adjustment ...............................................................................................13 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................14 
5.0 
ANALYSIS SETS .............................................................................................................14 
5.1 
Intent-to-treat (ITT) Analysis Set ................................................................................14 
5.2 
Modified Intent-to-treat (mITT) Analysis Set .............................................................14 
5.3 
Safety Analysis Set ......................................................................................................14 
5.4 
Full Analysis Set ..........................................................................................................14 
5.5 
Per-Protocol Analysis Set ............................................................................................14 
5.6 
Pharmacokinetic Analysis Set......................................................................................15 
6.0 
STATISTICAL ANALYSIS .............................................................................................15 
6.1 
General Considerations ................................................................................................15 
6.1.1 
Handling of Treatment Misallocations ................................................................16 
6.2 
Disposition of Subjects ................................................................................................16 
6.3 
Demographic and Other Baseline Characteristics .......................................................17 
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6.3.1 
Demographics ......................................................................................................17 
6.3.2 
Baseline Characteristics .......................................................................................17 
6.3.3 
Medical History and Concurrent Medical Conditions .........................................18 
6.4 
Medication History and Concomitant Medications .....................................................18 
6.4.1 
Prior Medications ................................................................................................18 
6.4.2 
Concomitant Medications ....................................................................................19 
6.5 
Efficacy Analysis .........................................................................................................19 
6.5.1 
Primary Endpoint(s) Analysis .............................................................................19 
6.5.1.1 
Derivation of Endpoint(s) ...........................................................................19 
6.5.1.2 
Main Analytical Approach ..........................................................................21 
6.5.2 
Secondary Endpoint(s) Analysis .........................................................................21 
6.5.3 
Exploratory Endpoints Analysis ..........................................................................21 
6.5.3.1 
Percent change from baseline in convulsive (DS) or MMD (LGS) 
seizure frequency per 28 days during every 12 weeks after the initial 12 
weeks of the maintenance period. ...............................................................21 
6.5.3.2 
Percent change from baseline in convulsive (DS) or MMD (LGS) 
seizure frequency per 28 days during the initial 16 weeks of the 
treatment period (4 weeks of titration period + 12 weeks of 
maintenance period). ...................................................................................22 
6.5.3.3 
Percent change from baseline in total seizure frequency per 28 days of 
all seizure types during the initial 12 weeks of the maintenance period. ....22 
6.5.3.4 
Percent change from baseline in total seizure frequency per 28 days of 
all seizure types every 12 weeks after the initial 12 weeks of the 
maintenance period. ....................................................................................23 
6.5.3.5 
Percent change from baseline in total seizure frequency per 28 days of 
all seizure types during the initial 16 weeks of the treatment period (4 
weeks of titration period + 12 weeks of maintenance period). ...................23 
6.5.3.6 
Percent change from baseline in seizure frequency per 28 days of each 
seizure type identified at the time of screening or baseline during the 
maintenance period and full treatment period (52 weeks). .........................24 
6.5.3.7 
Treatment response as defined by ≥50% reduction in convulsive (DS) 
or MMD (LGS) seizure frequency per 28 days from baseline every 12 
weeks after the initial 12 weeks of the maintenance period........................24 
6.5.3.8 
Treatment response as defined by ≥50% reduction in convulsive (DS) 
or MMD (LGS) seizure frequency per 28 days from baseline during the 
initial 16 weeks of the full treatment period (4 weeks of titration period 
+ 12 weeks of maintenance period). ...........................................................25 
6.5.3.9 
Clinical Global Impression of Improvement (CGI-I) (clinician). ...............25 
6.5.3.10 Caregiver Global Impression of Improvement (Care GI-I). .......................25 
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6.5.3.11 CGI-I Seizure Intensity and Duration. ........................................................26 
6.5.3.12 CGI-I Nonseizure Symptoms completed by clinician with input from 
the caregivers. .............................................................................................26 
6.5.3.13 Quality of Life Inventory-Disability (QI-Disability). .................................26 
6.5.3.14 Change in EQ-5D 5-level version (EQ-5D-5L) and EQ-5D visual 
analogue scale (EQ VAS) scores. ...............................................................27 
6.5.3.15 Caregiver satisfaction questionnaire. ..........................................................28 
6.5.3.16 Days when rescue ASM is used. .................................................................28 
6.5.4 
Subgroup Analyses (if applicable) ......................................................................29 
6.6 
Safety Analysis ............................................................................................................29 
6.6.1 
Adverse Events ....................................................................................................29 
6.6.2 
Adverse Events of Special Interest ......................................................................30 
6.6.3 
Other Safety Analysis (if applicable) ..................................................................31 
6.6.3.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................31 
6.6.3.2 
Ophthalmological evaluations. ....................................................................31 
6.6.4 
Extent of Exposure and Compliance ...................................................................32 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................33 
6.7.1 
Pharmacokinetic Analysis ...................................................................................33 
6.7.2 
Pharmacodynamic Analysis ................................................................................33 
6.7.3 
Biomarker Analysis .............................................................................................33 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................33 
6.9 
Other Analyses .............................................................................................................33 
6.10 
Interim Analyses ..........................................................................................................33 
6.11 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] .................................................................................................................33 
7.0 
REFERENCES ..................................................................................................................33 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................33 
9.0 
APPENDIX ........................................................................................................................34 
9.1 
Changes From the Previous Version of the SAP .........................................................34 
9.2 
Data Handling Conventions .........................................................................................34 
9.2.1 
Definition of Baseline ..........................................................................................34 
9.2.2 
Definition of Visit Windows ...............................................................................34 
9.3 
Analysis Software ........................................................................................................35 
 
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LIST OF IN-TEXT TABLES 
Table 2.a 
Dosing Schedules by Weight .................................................................................11 
Table 6.a Grouping Rules for Endpoints .......................................................................................16 
 
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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ASM 
antiseizure medication 
ATC 
anatomic therapeutic chemical 
BID 
twice daily 
BMI 
Body mass index 
Care GI-I 
Caregiver Global Impression of Improvement 
CGI-I 
Clinical Global Impression of Improvement 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019  
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
DS 
Dravet syndrome 
eCRF 
electronic case report form 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
EQ-VAS 
visual analogue scale 
ET 
early termination 
ITT 
intention-to-treat 
MMD 
major motor drop 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
OLE 
open-label extension 
PK 
pharmacokinetic 
PT 
Preferred Term (MedDRA) 
Q1 
25th percentile 
Q3 
75th percentile 
QI-Disability 
Quality of Life Inventory-Disability 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 
SOC 
System Organ Class 
TEAE  
treatment-emergent adverse event 
WHO 
World Health Organization 
 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
To assess the efficacy of soticlestat in participants with DS or LGS who have been exposed to 
fenfluramine. 
1.1.2 
Additional Objectives 
1.1.2.1 
Exploratory Objectives 
• To explore effects of soticlestat on seizure frequency, quality of life and non-seizure 
symptoms in participants with DS or LGS who have been exposed to fenfluramine. 
• To explore safety and tolerability of soticlestat in participants with DS or LGS who have 
been exposed to fenfluramine. 
1.2 
Endpoints 
1.2.1 
Primary Endpoint(s) 
• For DS cohort:  Percent change from baseline in convulsive seizure frequency per 28 days 
during the initial 12 weeks of the maintenance period. 
• For LGS cohort:  Percent change from baseline in major motor drop (MDD) seizure 
frequency per 28 days during the initial 12 weeks of the maintenance period. 
1.2.2 
Exploratory Endpoints 
• Percent change from baseline in convulsive (DS) or MMD (LGS) seizure frequency per 28 
days during every 12 weeks after the initial 12 weeks of the maintenance period. 
• Percent change from baseline in convulsive (DS) or MMD (LGS) seizure frequency per 28 
days during the initial 16 weeks of the treatment period (4 weeks of titration + initial 12 
weeks of maintenance). 
• Percent change from baseline in total seizure frequency per 28 days of all seizure types 
during the initial 12 weeks of the maintenance period. 
• Percent change from baseline in total seizure frequency per 28 days of all seizure types 
during every 12 weeks after the initial 12 weeks of the maintenance period. 
• Percent change from baseline in total seizure frequency per 28 days of all seizure types 
during the initial 16 weeks of the treatment period (4 weeks of titration + initial 12 weeks of 
maintenance). 
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• Percent change from baseline in seizure frequency per 28 days of each seizure type identified 
at the time of screening or baseline during the maintenance period and full treatment period 
(52 weeks). 
• Treatment response as defined by ≥50% reduction in convulsive (DS) or MMD (LGS) seizure 
frequency per 28 days from baseline every 12 weeks after the initial 12 weeks of the 
maintenance period. 
• Treatment response as defined by ≥50% reduction in convulsive (DS) or MMD (LGS) seizure 
frequency per 28 days from baseline during the initial 16 weeks of the full treatment period 
(4 weeks of titration period + 12 weeks of maintenance period). 
• Clinical Global Impression of Improvement (CGI-I) (clinician).  
• Caregiver Global Impression of Improvement (Care GI-I). 
• CGI-I Seizure Intensity and Duration. 
• CGI-I Non-seizure Symptoms completed by clinician with input from the caregivers. 
• Quality of Life Inventory-Disability (QI-Disability). 
• Change in EQ-5D 5-level version (EQ-5D-5L) and EQ-5D visual analogue scale (EQ VAS) 
scores.  
• Caregiver satisfaction questionnaire. 
• Days when rescue anti-seizure medication (ASM) is used. 
Safety Endpoints include  
• Incidence of treatment- emergent adverse events (TEAEs). 
• Columbia-Suicide Severity Rating Scale (C-SSRS).  
• Ophthalmological evaluations.  
1.3 
Estimand(s) 
1.3.1 
Primary Estimand 
Since this is a descriptive study, an estimand framework is not necessary. 
2.0 
STUDY DESIGN 
2.1 
Overall Study Design  
This is a phase 3, open-label, nonrandomized, single-arm study in participants with DS or LGS 
who have been exposed to fenfluramine.  
“Exposure” is defined as participants who are current or prior users of fenfluramine. 
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Note: Participants who have discontinued fenfluramine for reasons of lack of efficacy or 
intolerability are eligible as prior users. 
Approximately 15 participants with DS and 30 participants with LGS will be enrolled in the study. 
The study will consist of the following periods: 
• A 4- to 6-week screening/baseline period.  
• Approximately 52-week full treatment period including:  
– A 4-week titration period.  
– Approximately 48-week maintenance period. 
• A taper period (up to 1 week) and follow-up period (1 week after the taper period concludes); 
this will not be required for participants enrolling in the extension study (ENDYMION 2).  
• Follow-up visit/call occurs approximately 1 week after the taper period concludes.  
This is an open-label study to receive standard-of-care plus soticlestat in participants who have 
been exposed to fenfluramine. Soticlestat added to current antiseizure therapy will be administered 
orally BID with or without food (oral or enteral feeds including but not limited to nasogastric tube 
[NG-tube] or via gastrostomy tube [G-tube] or low-profile gastric tube (Mic-Key Button), or a 
jejunostomy tube [J-tube]).  
A schematic of the study design is shown in Figure 2.a. A schedule of assessments is presented in 
Section 1.3 of the protocol.  
Figure 2.a Schematic of Study Design 
 
 
The total daily dose of study drug (soticlestat) will be calculated on the basis of body weight at 
Visit 1 (screening visit) and given BID. The dosing schedules by weight are shown in Table 2.a. 
The minimum dose allowed during the study is 100 mg BID (or 100 mg BID equivalent weight-
based dosing for weight <45 kg). Participants who cannot tolerate the minimal dose will be 
discontinued from the study. Participants weighing <45 kg will be dispensed 20 mg mini-tablets. 
Participants weighing ≥45 kg may be dispensed 20 mg mini-tablets or 100 mg tablets.  
Intermediate doses between dose levels may be allowed after discussing with the medical monitor.  
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Table 2.a 
Dosing Schedules by Weight 
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 
10 to <15 kg Weight Reference Dose 
Soticlestat 
40 mg 
BID 
2 mini-tablets 
soticlestat BID 
60 mg 
BID 
3 mini-tablets 
soticlestat BID 
100 mg 
BID 
5 mini-tablets 
soticlestat BID 
15 to <30 kg Weight Reference Dose 
Soticlestat 
60 mg 
BID 
3 mini-tablets 
soticlestat BID 
120 mg 
BID 
6 mini-tablets 
soticlestat BID 
200 mg 
BID 
10 mini-tablets 
soticlestat BID 
30 to <45 kg Weight Reference Dose 
Soticlestat 
80 mg 
BID 
4 mini-tablets 
soticlestat BID 
140 mg 
BID 
7 mini-tablets 
soticlestat BID 
200 mg 
BID 
10 mini-tablets 
soticlestat BID 
≥45 kg Weight Reference Dose 
Soticlestat 
100 mg 
BID 
1 tablet soticlestat 
BID  
OR 
5 mini-tablets 
soticlestat BID 
200 mg 
BID 
2 tablets 
soticlestat BID 
OR 
10 mini-tablets 
soticlestat BID 
300 mg 
BID 
3 tablets 
soticlestat BID 
OR 
15 mini-tablets 
soticlestat BID 
BID: twice daily. 
Participants <45 kg may request adult size tabs for Dose 3 only. 
The dose can be adjusted according to the participant’s weight change after completing the initial 
12 weeks of the maintenance period, per investigator judgement. 
ASMs taken as SOC, should remain stable for initial 12 weeks of the maintenance period, after 
which, doses can be adjusted based on SOC and investigator judgement.  
Rescue medication dose can be adjusted throughout the study as per SOC. 
Soticlestat doses should also remain stable for initial 12 weeks of maintenance period, after which 
it can be adjusted according to participant weight changes and investigator judgement. 
The study design allows virtual visits to be conducted via phone or an appropriate platform(s) as 
long as approved and aligned with institutional or local guidelines. The decision to perform a visit 
virtually is at the discretion of the investigator. 
Screening (Visit 1), Visit 7 and final visit/early termination (ET) must be conducted in clinic or in 
person (home visits). Safety calls may be conducted virtually.  
All other visits can be virtual (visits including assessment of Clinical Global Impression [CGI] 
scale[s] should be conducted via video, not phone), at investigator discretion and if permitted by 
local regulations. Additionally, home health visits may be conducted by site staff, if permitted by 
local regulations. Visit assessment of CGI scale(s) should be conducted via video and not phone. 
In addition, any visit identified as virtual in this protocol may be conducted in clinic and in 
person if requested by the participant/parent or guardian and/or at the investigator’s discretion. 
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Caregivers or principal investigator can request home visits to be conducted by site staff if 
permissible by local regulations.  
2.1.1 
Dose Titration Period (4 Weeks)  
Participants will take the initial dose of study drug, that is, Dose 1 (100 mg BID adult reference 
dose, weight-based dosing for weight <45 kg) the morning after the enrollment day (Day -1). 
Participants receiving the study drug at home through a courier should take it the morning after 
they receive it.  
Approximately 7 days after starting Dose 1, study drug dose will be increased to Dose 2 (200 mg 
BID adult reference dose, weight-based dosing for weight <45 kg) and continued for 
approximately 7 days. Seven days after receiving Dose 2, the drug dose can be increased to, Dose 
3 (300 mg BID adult reference dose, weight-based dosing for weight <45 kg). If the participants 
do not experience any tolerability issues, they will continue Dose 3 for the remainder of the 
titration period. 
Participants will only be allowed to increase their dose within the 4-week titration period. A 
decrease in dose level (to Dose 2 or Dose 1) is allowed during the titration period if required for 
safety and tolerability. Intermediate doses between scheduled dose levels may be allowed after 
discussing with the medical monitor. 
Participants who cannot tolerate the minimum dose of 100 mg BID (or weight-based equivalent 
dosing for participants weighing <45 kg) will be discontinued from the study. The maximum 
allowed dose is 300 mg BID (or weight-based equivalent dosing for participants weighing <45 
kg). 
The participants/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 and again at the 
end of the titration period for that dose. The final dose tolerated by the end of the 4-week titration 
period should be maintained during the initial 12 weeks of the maintenance period unless 
tolerability issues arise.  
Any changes to the dose levels provided in Table 2.a may be allowed after further discussion 
with medical monitor. 
2.1.2 
Maintenance Period (Approximately 48 Weeks)  
In the absence of safety or tolerability considerations, the final dose level at the end of the titration 
period should be maintained for the first 12 weeks of the maintenance period. The dose can be 
adjusted according to the participant’s weight change after completing the initial 12 weeks of the 
maintenance period. 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 (300 mg BID 
adult reference dose, weight-based dosing for weight <45 kg) may be reduced to Dose 2 (200 mg 
BID adult reference dose, weight-based dosing for weight <45 kg), and Dose 2 may be reduced to 
Dose 1 (100 mg BID adult reference dose, weight-based dosing for weight <45 kg). The minimum 
dose is Dose 1; participants who cannot tolerate the minimum dose will be discontinued from the 
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study. The dose may be decreased during the initial 12 weeks maintenance period for safety or 
tolerability reasons as assessed by the investigator; however, if possible, dose changes should be 
discussed with the sponsor/designee. After the initial 12 weeks of maintenance period, 
intermediate doses between dose levels may be allowed after discussion with the medical monitor. 
2.1.3 
Study Discontinuation/Completion 
At the end of overall maintenance period, at Visit 10, participants will have the option to enroll 
the OLE study ENDYMION 2 on the dose they are receiving in the maintenance period in TAK-
935-3004, as deemed appropriate by the investigator.  
Participants not entering ENDYMION 2, will begin a 1-week taper period (unless already at the 
lowest dose). During the 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) no more frequently than every 3 days until the 
study drug is discontinued. On completion of the taper period a safety phone call or visit will be 
completed approximately 2 weeks after the participant’s final visit/ET.  
Participants who terminate the study early for reasons other than safety/tolerability may also 
have the opportunity to join ENDYMION 2 study at sponsor discretion. 
2.1.4 
Period of Evaluation and Schedule of Study Assessment 
Approximately 60 weeks, including up to 6-week screening/baseline period, 52-week treatment 
period [4-week titration and 48-week maintenance periods], 1-week taper period for those 
discontinuing study drug, followed by a safety follow-up visit/call 1 week after the taper period 
ends. 
For a schematic of the study design, see Section Error! Reference source not found.. For the 
Schedule of Activities (SoA), see Section Error! Reference source not found.. 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
The primary study objective is descriptive and does not include any formal hypothesis testing. 
Therefore, there will be no gatekeeping procedure and all the exploratory objectives will be 
presented regardless of the results of any proceeding objectives. 
3.1 
Statistical Hypotheses 
Not Applicable. 
3.2 
Statistical Decision Rules 
Not Applicable. 
3.3 
Multiplicity Adjustment 
Not Applicable. 
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4.0 
SAMPLE-SIZE DETERMINATION 
This study plans to enroll approximately 15 participants with DS and 30 participants with LGS. 
The study is not powered for hypothesis testing. The sample size is based on an estimation 
approach to ensure adequate precision to estimate the median change from baseline in convulsive 
(DS) or MMD (LGS) seizure frequency per 28 days during the first 12 weeks of the maintenance 
period. With the planned sample sizes, the expected half width of the 95% CI for the median is 
commensurate with the expected magnitude of the median. 
With 15 participants in the DS cohort treated with soticlestat, the expected median percent change 
from baseline in convulsive seizure frequency during the first 12 weeks of the maintenance period 
is 35% and expected half width of the 95% CI is 30%.  
With 30 participants in the LGS cohort, the expected median percent change from baseline in 
MMD seizure frequency during the first 12 weeks of the maintenance period is 37% and the 
expected half width of the 95% CI is 29%.  
To determine the expected median and 95% CI half width, simulations were performed assuming 
the data follow a log normal distribution, and the distribution of the underlying parameters (i.e., 
mean and SD of the log transform of the data distribution) was developed using results of the phase 
2 ELEKTRA study. 
5.0 
ANALYSIS SETS 
5.1 
Intent-to-treat (ITT) Analysis Set 
All participants who enroll in the study. 
5.2 
Modified Intent-to-treat (mITT) Analysis Set 
All enrolled participants who take at least 1 dose of study drug and are assessed for seizures for 
at least 1 day in the treatment period. 
The mITT analysis set will be used for all efficacy analyses. Subjects who do not enter the 
maintenance period will not be included in the analyses pertinent to the maintenance period.  
5.3 
Safety Analysis Set 
All participants who take at least 1 dose of study drug. 
5.4 
Full Analysis Set 
Not Applicable. 
5.5 
Per-Protocol Analysis Set  
Not Applicable. 
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5.6 
Pharmacokinetic Analysis Set  
There are no PK (pharmacokinetic) data collected.  Hence this population is not applicable. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
The analyses are descriptive in nature. No formal hypothesis testing is planned.  
Where applicable, variables will be summarized descriptively by cohort (DS and LGS) and by 
visit. 
Categorical variables will be summarized using count (n) and percent (%). Unless otherwise stated, 
the denominator for percentages is the number of subjects in the group within that analysis set. For 
any summary statistics by visit, the denominator is the number of subjects that were assessed at 
that visit. 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, Q1, 
Q3, minimum, and maximum values will be provided. 
Mean and median will be presented to 1 more decimal place than the recorded data. The SDs will 
be presented to 2 more decimal places than the recorded data. Confidence intervals (CIs) will be 
presented using the same number of decimal places as the parameter estimate. 
Descriptive summaries for primary, exploratory and safety endpoints will be provided by the 
following groupings (see Table 6.a), unless indicated otherwise. 
 
 
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Table 6.a Grouping Rules for Endpoints 
 
6.1.1 
Handling of Treatment Misallocations 
The is a single arm study and there is only one allocated treatment. All participants enrolled in the 
study are included in the ITT Analysis Set. However, for the subject to be included in mITT and 
Safety Analysis Sets, they need to have taken at least 1 dose of study drug. Further details on mITT 
and Safety Analysis Sets are presented in sections 5.2 and 5.3. 
6.2 
Disposition of Subjects 
The following summaries will be provided based on the ITT analysis set: 
Endpoints  
Diagnosis  
 
DS 
LGS 
DS and LGS 
combined 
Disposition, Demographics and 
Baseline 
DS 
LGS 
Overall 
Efficacy (seizure) 
DS  
Seizure types:  
Convulsive seizures 
All seizures 
LGS  
Seizure types:  
Major motor drop 
(MMD) seizures 
All seizures 
Overall  
(All seizures 
only) 
Exploratory (seizure) 
 
 
DS  
 
LGS  
Overall,  
(All seizures 
only) 
Exploratory (treatment response) 
 
DS  
 
LGS  
- 
Exploratory (other than seizure and 
treatment response) 
DS  
LGS  
- 
Medical History, and Prior and 
Concomitant Medications 
DS  
LGS  
Overall 
Safety 
DS  
LGS  
Overall 
Extent of exposure 
DS 
LGS 
Overall 
Compliance 
DS 
LGS 
Overall 
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• The summary for study disposition including count/percentage of participants who have 
completed the study vs. count/percentage of participants who have prematurely withdrawn 
from the study, as well as the primary reasons for withdrawal. 
• Summary of treatment discontinuation by visit window (1-4 weeks; and every 12 weeks from 
thereafter) 
• Other summaries: 
– Number of subjects enrolled by country, and site  
– Analysis Sets 
– Major or significant protocol deviations 
If relevant, 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.).  
All protocol deviations will be listed. If relevant, a separate listing will be created for protocol 
deviations due to COVID-19 and a listing of visits affected by COVID-19 will be presented. 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
Patient demographic characteristics will be summarized and listed using the safety analysis 
set.  The variables summarized will include: 
• Age 
• Age categories (children [2-5 years], children [6-11 years], adolescents [12-17 years] and 
adults [18-64 years]) 
• Sex 
• Ethnicity 
• Race 
• Country 
6.3.2 
Baseline Characteristics 
Baseline characteristics will be summarized and listed using the safety analysis set. Variables 
include: 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI (kg/m2)) 
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• Number of anti-seizure medications (ASM) taken per subject summarized as 0, 1, 2, 3, 
etc. 
• Convulsive seizure frequency during Baseline Period (DS) 
• MMD seizure frequency during Baseline Period (LGS) 
• All seizure frequency during Baseline Period (DS, LGS) 
6.3.3 
Medical History and Concurrent Medical Conditions 
Medical history to be obtained will include determining whether the participant has any significant 
conditions or diseases relevant to the disease under study that resolved before the participant 
signed the informed consent form. Ongoing conditions are considered concurrent medical 
conditions. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present when informed consent is provided. This includes clinically significant laboratory, 
physical examination, and/or vital signs abnormalities noted at screening examination, according 
the judgment of the investigator. The condition (i.e., diagnosis) should be described. 
Coding of medical history and concurrent medical conditions will be based on the Medical 
Dictionary for Regulatory Activities (MedDRA, version 24.0 or higher) and will be summarized 
using System Organ Class (SOC) and MedDRA preferred term. The actual version of the 
MedDRA coding dictionary used will be noted in the clinical study report. The summary 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. 
Summaries of medical history and concurrent medical conditions will be based on the Safety 
Analysis Set. 
6.4 
Medication History and Concomitant Medications  
6.4.1 
Prior Medications 
Prior medications are defined as those that were Stopped at or within 90 days before signing the 
ICF (note: all prior ASMs including fenfluramine use or its reason for discontinuation [if 
applicable] will be documented regardless of when it was stopped).  
Prior medications will be coded with World Health Organization Drug Dictionary Enhanced and 
summarized by WHO drug Anatomic Therapeutic Chemical (ATC) class level 4 and preferred 
terms. 
Prior and concomitant medications will be listed. 
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Prior medications will be summarized by summarized by Therapeutic Class ATC4 and 
preferred term. In addition, prior ASMs will be summarized by ATC level 4 and preferred 
terms. 
6.4.2 
Concomitant Medications 
Concomitant medications/treatments are defined as those given in addition to the study drug:  
• 
Between the signing of the ICF and participant completion. 
• 
Between the first dose of study drug and the end of the follow-up period, inclusive. 
• 
Starting before the signing of the ICF and continuing during the study. 
 
Concomitant medications will be coded with World Health Organization Drug Dictionary 
Enhanced and summarized by WHO drug Anatomic Therapeutic Chemical (ATC) class level 4 
and preferred terms. 
Concomitant medications will be summarized by ATC class level 4, and preferred term. 
Concomitant ASMs will also be summarized by ATC class level 4, and preferred term by 
decreasing frequency of incidence as per Table 6.a. 
Concomitant medications will be listed. 
 
6.5 
Efficacy Analysis 
All efficacy analysis will be based on the mITT Analysis Set. 
6.5.1 
Primary Endpoint(s) Analysis 
The Primary endpoint is: 
• For DS cohort:  Percent change from baseline in convulsive seizure frequency per 28 days 
during the initial 12 weeks of the maintenance period. 
• For LGS cohort:  Percent change from baseline in major motor drop seizure frequency per 28 
days during the initial 12 weeks of the maintenance period. 
6.5.1.1 
Derivation of Endpoint(s) 
For subjects with DS diagnosis percent change from baseline in convulsive seizure frequency per 
28 days and total seizure frequency per 28 days will be calculated for the initial 12 weeks of the 
maintenance period.  
For subjects with LGS diagnosis percent change from baseline in MMD seizure frequency per 28 
days and total seizure frequency per 28 days will be calculated for the initial 12 weeks of the 
maintenance period. 
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Convulsive seizures include the following codes and the descriptions: 
• A - Hemiclonic or Focal Clonic 
• B - Focal to Bilateral Tonic-Clonic 
• C - Generalized Tonic-Clonic 
• D - Bilateral Clonic 
• E - Convulsive Status Epilepticus 
MMD seizures include the following codes and the descriptions: 
• 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., Hyper motor 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 
 
Seizure frequency (SF) for each time period and a specified set of seizure types (e.g., convulsive, 
MMD, all) is calculated using only available (non-missing) data during that period. For example, 
seizure frequency (SF) per 28 days will be calculated as follows: 
SF per 28 days = Total number of the specific seizure(s) type during the specified period
Number of non-missing diary days in the specified period
× 28 
 
Percent change from baseline in seizure frequency per 28 days during a period will be defined as 
 
(SF per 28 days during period) −(SF per 28 days during Baseline Period)
SF per 28 days during Baseline Period
× 100 
 
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Note that the denominator is same for all types of seizures for a specified interval of time for 
a given subject. 
6.5.1.2 
Main Analytical Approach 
All seizure diary data collected during the Treatment Period will be used even if collected after an 
intercurrent event. Moreover, for the analysis of primary endpoint, only available diary data from 
the relevant periods (i.e., non-missing diary days) are used in the calculation of seizure frequency. 
This approach assumes that the seizure frequency during the missing diary days is equal to the 
seizure frequency during the non-missing diary days. 
Descriptive summaries for percent change in seizure frequencies during the initial 12 weeks of the 
maintenance period from baseline per 28 days will include mean, SD, median, Q1, Q3, minimum, 
maximum, and distribution-free 95% CI for the median. Proc univariate with CIPCTLDF option 
in SAS will be used to obtain the CIs. Descriptive statistics for baseline and maintenance period 
will also be provided (without CIs).  
Results will be presented according to the grouping scheme presented in Table 6.a. 
A listing including patient identifier, visit, study day, seizure frequency, percent change from 
baseline in seizure frequency will be provided. 
6.5.2 
Secondary Endpoint(s) Analysis 
Not applicable. 
6.5.3 
Exploratory Endpoints Analysis  
6.5.3.1 
Percent change from baseline in convulsive (DS) or MMD (LGS) seizure frequency 
per 28 days during every 12 weeks after the initial 12 weeks of the maintenance 
period. 
The calculation of seizure frequency will be based on approach described in per Section Error! 
Reference source not found.. 
For subjects with DS diagnosis, percent change from baseline in frequency per 28 days of 
convulsive seizure for each 12-week period starting from the date after the initial 12-week 
maintenance will include:  
1. Week 13 to 24 (inclusive) of the maintenance period. 
2. Week 25 to 36 (inclusive) of the maintenance period. 
3. Week 37-48 (inclusive) of the maintenance period. 
For subjects with LGS diagnosis, percent change from baseline in frequency per 28 days of MMD 
seizure for each 12-week period starting from the date after the initial 12-week maintenance will 
include: 
1. Week 13 to 24 (inclusive) of the maintenance period. 
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2. Week 25 to 36 (inclusive) of the maintenance period. 
3. Week 37-48 (inclusive) of the maintenance period. 
 
Descriptive summaries for percent change in seizure frequencies per 28 days from baseline at for 
each 12-week period starting from the date after the initial 12-week maintenance will include mean, 
SD, median, Q1, Q3, minimum, maximum, and distribution-free 95% CI for the median. Proc 
univariate with CIPCTLDF option in SAS will be used to obtain the CIs. Descriptive statistics for 
each 12-week period starting from the date after the initial 12-week maintenance will also be 
provided (without CIs).  
In addition, the line graphs plotting percent change from baseline in seizure frequency will be 
provided, with x-axis as time intervals (every 12 weeks during the maintenance period of the study 
after the initial 12-week), y-axis as percent change from baseline of seizure frequency. 
If a subject has seizure data missing for more than 8 weeks in any 12 weeks of assessment interval 
after the initial 12 weeks of maintenance, the subject will not be included in the analysis for that 
interval. 
6.5.3.2 
Percent change from baseline in convulsive (DS) or MMD (LGS) seizure frequency 
per 28 days during the initial 16 weeks of the treatment period (4 weeks of titration 
period + 12 weeks of maintenance period). 
The calculation of seizure frequency will be based on approach described in per Section Error! 
Reference source not found.. 
For subjects with DS diagnosis, the endpoint for this analysis will be percent change from baseline 
in frequency per 28 days of convulsive seizure for the initial 16 weeks of the treatment period (4 
weeks of titration period + 12 weeks of maintenance period). 
For subjects with LGS diagnosis, the endpoint for this analysis will be percent change from 
baseline in frequency per 28 days of MMD seizure for the initial 16 weeks of the treatment period 
(4 weeks of titration period + 12 weeks of maintenance period). 
Descriptive summaries for percent change from baseline in convulsive (DS) and MMD (LGS) 
seizure frequency per 28 days during the initial 16 weeks of the treatment period (4 weeks of 
titration period + 12 weeks of maintenance period) per 28 days will include mean, SD, median, 
Q1, Q3, minimum, maximum, and distribution-free 95% CI for the median. Proc univariate with 
CIPCTLDF option in SAS will be used to obtain the CIs. Descriptive statistics for the initial 16 
weeks of the treatment period (4 weeks of titration period + 12 weeks of maintenance period will 
also be provided (without CIs).  
Results will be presented according to the grouping presented in Table 6.a. 
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6.5.3.3 
Percent change from baseline in total seizure frequency per 28 days of all seizure 
types during the initial 12 weeks of the maintenance period. 
Percent change from baseline in frequency per 28 days of all seizure types for the initial 12 weeks 
of maintenance period will be based on approach described in per Section Error! Reference 
source not found.. 
Descriptive summaries for percent change from baseline in all seizure types frequency per 28 days 
during the initial 12 weeks of maintenance period per 28 days will include mean, SD, median, Q1, 
Q3, minimum, maximum, and distribution-free 95% CI for the median. Proc univariate with 
CIPCTLDF option in SAS will be used to obtain the CIs. Descriptive statistics for the initial 12 
weeks of the maintenance period will also be provided (without CIs).  
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.4 
Percent change from baseline in total seizure frequency per 28 days of all seizure 
types every 12 weeks after the initial 12 weeks of the maintenance period. 
Percent change from baseline in frequency per 28 days of all seizure types for each 12-week period 
starting from the date after the initial 12-week maintenance will be calculated based on approach 
described in per Section Error! Reference source not found.. The 12-week periods will include  
1. Week 13 to 24 (inclusive) of the maintenance period. 
2. Week 25 to 36 (inclusive) of the maintenance period. 
3. Week 37-48 (inclusive) of the maintenance period. 
Descriptive summaries for percent change in all seizure types frequencies per 28 days from 
baseline at for each 12-week period starting from the date after the initial 12-week maintenance 
will include mean, SD, median, Q1, Q3, minimum, maximum, and distribution-free 95% CI for 
the median. Proc univariate with CIPCTLDF option in SAS will be used to obtain the CIs. 
Descriptive statistics for each 12-week period starting from the date after the initial 12-week 
maintenance will also be provided (without CIs).  
In addition, the line graphs plotting percent change from baseline in all seizure types frequency 
will be provided, with x-axis as time intervals (every 12 weeks during the maintenance period of 
the study after the initial 12-week), y-axis as percent change from baseline of seizure frequency. 
If a subject has seizure data missing for more than 8 weeks in any 12 weeks of assessment interval 
after the initial 12 weeks of maintenance, the subject will not be included in the analysis for that 
interval. 
Results will be presented according to the grouping presented in  
 
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Table 6.a. 
6.5.3.5 
Percent change from baseline in total seizure frequency per 28 days of all seizure 
types during the initial 16 weeks of the treatment period (4 weeks of titration period 
+ 12 weeks of maintenance period). 
Percent change from baseline in frequency per 28 days of all seizure types for the period 
comprising the 4 weeks of the titration period and first 12 weeks of the maintenance period will 
be calculated based on approach described in per Section Error! Reference source not found.. 
Descriptive summaries for percent change from baseline in all seizure types frequency per 28 days 
during the initial 16 weeks of the treatment period (4 weeks of titration period + 12 weeks of 
maintenance period) per 28 days will include mean, SD, median, Q1, Q3, minimum, maximum, 
and distribution-free 95% CI for the median. Proc univariate with CIPCTLDF option in SAS will 
be used to obtain the CIs. Descriptive statistics for the initial 16 weeks of the treatment period (4 
weeks of titration period + 12 weeks of maintenance period will also be provided (without CIs).  
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.6 
Percent change from baseline in seizure frequency per 28 days of each seizure type 
identified at the time of screening or baseline during the maintenance period and full 
treatment period (52 weeks). 
Percent change from baseline in frequency per 28 days of each seizure type during the full 
Treatment Period (52 weeks) will be calculated using the approach described in Section Error! 
Reference source not found.. For each seizure type, only subjects who experience at least 1 
seizure of that type during the screening period (i.e., individuals with a seizure frequency of > 0 at 
baseline for that type of seizure) will be included in the analysis.  
Descriptive summaries for percent change from baseline in for each seizure types (identified at the 
time of screening or baseline) frequency per 28 days during the full Treatment Period (52 weeks) 
will include mean, SD, median, Q1, Q3, minimum, maximum, and distribution-free 95% CI for 
the median. Proc univariate with CIPCTLDF option in SAS will be used to obtain the CIs. 
Descriptive statistics for each seizure types (identified at the time of screening or baseline) 
frequency per 28 days during the full Treatment Period (52 weeks) will also be provided (without 
CIs).  
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.7 
Treatment response as defined by ≥50% reduction in convulsive (DS) or MMD 
(LGS) seizure frequency per 28 days from baseline every 12 weeks after the initial 12 
weeks of the maintenance period. 
Subjects with ≥50% reduction from baseline in convulsive (DS) and MMD (LGS) seizure 
frequency per 28 days during each of the 12-week maintenance periods will be considered 
responders for that period. 
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Descriptive statistics for responder proportions for each period will include count and percentage 
for proportions for subjects with DS and LGS diagnosis separately. Two-sided 95% CIs will be 
provided for responder proportions using exact method for each period. 
If a subject has seizure data missing for more than 8 weeks in any 12 weeks of assessment interval 
after the initial 12 weeks of maintenance, the subject will not be included in the analysis for that 
interval. 
6.5.3.8 
Treatment response as defined by ≥50% reduction in convulsive (DS) or MMD 
(LGS) seizure frequency per 28 days from baseline during the initial 16 weeks of the 
full treatment period (4 weeks of titration period + 12 weeks of maintenance period). 
Subjects with ≥50% reduction from baseline in convulsive (DS) and MMD (LGS) seizure 
frequency per 28 days during the initial 16 weeks of the full treatment period will be considered 
responders for that period. 
Descriptive statistics for responder proportions for each period will include count and percentage 
for proportions for subjects with DS and LGS diagnosis separately. Two-sided 95% CIs will be 
provided for responder proportions using exact method. 
In addition, the responder proportion will be summarized for the initial 12 weeks of the 
maintenance period. 
6.5.3.9 
Clinical Global Impression of Improvement (CGI-I) (clinician).  
The CGI-I (clinician) is a 7-point Likert scale that the investigator uses to rate a participant’s 
change (improvement) in overall seizure control, nonseizure symptoms, and behavior, as well as 
how well the participant is tolerating study drug and side effects, compared with baseline (before 
treatment with the study drug). The participant 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 V6, V7, 
and V10. The baseline visit for this assessment occurs at visit V2. For assessing baseline disease 
severity to inform subsequent CGI-I, the investigator or designee will complete the CGI Baseline 
questionnaire. The investigator or designee will record their overall clinical impression of disease 
severity at baseline. They will interview the participant (if appropriate) or parent/caregiver and 
use input from the participant or parent/caregiver to inform their overall clinical impression 
assessment (Guy 1976). 
For each visit, count and percentage for proportions for each of the 7-point Likert scale categories 
will be presented. Responses will be dichotomized as improvement (scores 1, 2, and 3) or “no 
improvement or worse” (scores 4, 5, 6, and 7) and the count and percentage of these two categories 
will be provided by visit. Two-sided 95% CIs will be provided for percentage of improvement 
using exact method at each visit. 
The baseline questionnaire data will not be used in the analyses. 
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6.5.3.10 
Caregiver Global Impression of Improvement (Care GI-I). 
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 participant 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 Visit V6, V7, and V10. The baseline visit for this assessment occurs at visit V2. 
For assessing Care GI Baseline of overall illness severity, investigator or designee will record 
on behalf of the participant (if appropriate) or parent/caregiver’s assessment of the participant’s 
overall condition using the same questionnaire.  
The analysis and data summaries will follow the same approach as for the CGI-I (clinician) 
analysis, per Section 6.5.3.9. 
Results will be presented according to the grouping presented in Table 6.a 
 
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Table 6.a. 
6.5.3.11 
CGI-I Seizure Intensity and Duration. 
The CGI-I Seizure Intensity and Duration instrument is used by the investigator (with input from 
the parent/caregiver as needed) to rate changes in intensity and/or duration of the most impactful 
seizures compared with the baseline assessment. The participant’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 investigator or designee will 
complete the CGI-I Seizure Intensity and Duration in consultation with the primary caregiver at 
Visits V6, V7, and V10. The baseline visit for this assessment occurs on visit V2. 
The analysis and data summaries will follow the same approach as for the CGI-I (clinician) 
analysis, per Section 6.5.3.9. 
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.12 
CGI-I Nonseizure Symptoms completed by clinician with input from the caregivers. 
The CGI-I Nonseizure Symptoms instrument is a series of single-item assessments that the 
investigator (with input from the parent/caregiver as needed) uses to rate improvement in the 
symptoms and impacts in select nonseizure domains (including communication, alertness, and 
disruptive behaviors) since initiating the study drug at baseline. The participant 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).  
The investigator or designee will complete the CGI-I Nonseizure Symptoms instrument in 
consultation with the primary caregiver at Visits V6, V7, and V10. The baseline visit for this 
assessment occurs on visit V2. 
The analysis and data summaries will follow the same approach as for the CGI-I (clinician) 
analysis, per Section 6.5.3.9. 
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.13 
Quality of Life Inventory-Disability (QI-Disability). 
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 (4 items), positive emotions (4 items), negative emotions (7 items), social 
interaction (7 items), leisure and the outdoors (5 items), and independence (5 items).  
Items are rated on a Likert scale of: Never = 0, Rarely=25, Sometimes=50, Often=75 and Very 
Often=100; the Negative Emotions domain items are reverse coded (i.e., Never=100, Rarely=75, 
Sometimes=50, Often=25 and Very Often=0). 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 
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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. 
The parent/caregiver-reported questionnaires will be administered at Visits V2 (baseline), V7, 
and V10. 
The change from baseline (in total score) will be summarized descriptively by visits as a 
continuous variable. Mean, SD, median, Q1, Q3, minimum, maximum, and distribution-free 95% 
CI for the median will be provided at each visit.  
The line graph plotting median and 95% CI for the percent change from baseline QI-Disability 
score will be provided, with x-axis as time. 
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.14 
Change in EQ-5D 5-level version (EQ-5D-5L) and EQ-5D visual analogue scale 
(EQ VAS) scores. 
The EQ-5D-5L is the 5–response level version of the EQ-5D instrument. The EQ-5D-5L is a 
preference-based measure of health status suitable for calculating quality-adjusted life years to 
inform economic evaluations. It consists of 2 sections, a descriptive system questionnaire and the 
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 selecting the most appropriate statement in each of the dimensions. 
In addition, the EQ VAS is used to indicate the general health status by rating their health “today” 
from 0 (worst) to 100 (best health you can imagine). These questionnaires will be administered at 
Visits V2 (baseline), V7, and V10. 
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 visit including baseline by presenting the count 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 over time. A shift table 
will be provided by comparing the results (dichotomous category) at each scheduled post-baseline 
visit with those at the baseline visit. The count and percentages in each category based on 
dichotomization will be provided over time. 
EQ-VAS scores will be summarized descriptive by visit. Change in EQ-VAS from baseline will 
be summarized descriptively as a continuous variable. Mean, SD, median, Q1, Q3, minimum, 
maximum, and distribution-free 95% CI for the median will be provided at each visit.  
The line graph plotting median and 95% CI for the percent change from baseline EQ-VAS score 
will be provided, with x-axis as time. 
Results will be presented according to the grouping presented in Table 6.a. 
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6.5.3.15 
Caregiver satisfaction questionnaire. 
The caregiver satisfaction questionnaire is a 7-point Likert scale that the caregiver uses to rate 
overall satisfaction with soticlestat. The parent/caregiver is asked to consider the study 
participant’s symptoms over the past 4 weeks and rate overall satisfaction with soticlestat using 
the following rating options: extremely satisfied, very satisfied, satisfied, neither satisfied nor 
dissatisfied, dissatisfied, very dissatisfied, extremely dissatisfied.  
The parent/caregiver will complete the caregiver satisfaction questionnaire at Visit V7.  
Response will be summarized descriptively by presenting count and percentage of responses in 
each level. In addition, a dichotomization based on satisfied (extremely satisfied, very satisfied, 
satisfied) vs not satisfied (neither satisfied nor dissatisfied, dissatisfied, very dissatisfied, 
extremely dissatisfied) will be summarized using count and percentage. Two-sided 95% CIs will 
be provided for proportion satisfied using exact method. 
Results will be presented according to the grouping presented in Table 6.a. 
6.5.3.16 
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 study 
when rescue ASM is used will be derived. The proportion of days during the study period will also 
be calculated, using the number of days during the study between date of first dose (included) and 
date of the End of Maintenance (or Early Termination) visit as the denominator (included). The 
number of days when rescue ASM is used will be summarized descriptively.  
For this analysis, missing dates will be imputed in the most conservative manner. The missing start 
dates for rescue ASM will be imputed to the first day of the month or the first day of the study 
(whichever is later) if day is missing but month and year are known, and to the first day of the year 
or the first day of the study (whichever is later) 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 study. Missing end dates for rescue ASM will be imputed to the last day of the month or the 
last day of the study (whichever is earlier) if day is missing but month and year are known, and to 
the last day of the year or the last day of the study (whichever is earlier) 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 study. 
Results will be presented according to the grouping presented in Table 6.a. 
6.5.4 
Subgroup Analyses (if applicable) 
Not applicable. 
6.6 
Safety Analysis 
Safety analyses will be performed using the safety analysis set. Results will be presented 
descriptively. AEs will be coded using the Medical Dictionary for Regulatory Activities 
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(MedDRA). TEAEs will be summarized using Preferred Terms and primary System Organ 
Classes. 
Data summaries will be displayed for incidence of TEAEs, clinical laboratory variables, and 
vital sign parameters. Descriptive statistics such as mean, median, SD, Q1, Q3, minimum, 
maximum etc. will be provided, as appropriate. For change from baseline and percent change 
from baseline, median and distribution-free two sided 95% CIs will be provided, as appropriate.  
For AEs, counts and percentages will be presented by SOC and PT. 
Ophthalmological evaluations and C-SSRS will be listed by participant. 
6.6.1 
Adverse Events 
Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by preferred term (PT) and system organ class (SOC) categories. 
Serious AEs and AEs leading to study discontinuation will also be summarized. 
The following definitions will be used for AEs: 
• A Treatment-emergent adverse event (TEAE) is defined as any AE that starts or increases in 
severity on or after the first dose of the study drug of 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. 
• Treatment-emergent SAE: A TEAE that is serious. 
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 intensity or relatedness summaries, if a subject reports multiple AEs coded to the same SOC 
or PT, the AE with maximum intensity or strongest relationship will be included in the summary. 
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the event 
will be considered to have been related. 
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 the 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 the study medication and the stop date is not prior to the 
date of the first dose, then the date of first dose will be used for the start date. 
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• 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 the first dose, then the date of first dose will be used 
for start date. 
In general, AEs will be tabulated by group specified in Table 6.a. The summary tables will include 
the count and percentage [n (%)] of subjects. The tables will include number of events, as 
appropriate. 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 all subjects) TEAEs by PT (the 5% cut-off value will be 
applied to total before rounding) 
• 
TEAEs by Maximum Severity, SOC and PT 
• 
Drug-Related TEAEs by SOC and PT  
• 
TEAEs leading to 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 TEAEs, TEAEs leading to study drug discontinuation, SAEs, 
and TEAEs that resulted in death. 
In addition, a list of AEs in subjects with concomitant perampanel will be provided. 
6.6.2 
Adverse Events of Special Interest 
The following AEs of special interest will be summarized. Please refer to the protocol for details. 
• Potential drug-drug interaction between soticlestat and perampanel leading to increased 
seizure frequency             
• Cataracts 
• Psychosis 
AESIs must be recorded as AEs in the eCRF within 24 hours. An evaluation form along with all 
documentation must be submitted to the sponsor. 
The number and percentage of AEs of special interest and number of events will be presented by 
groups similar to TEAEs. Adverse events of special interests will be categorized and presented by 
SOC and PT in the same manner that described in Section Error! Reference source not found. 
and per the grouping presented in Table 6.a. 
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6.6.3 
Other Safety Analysis (if applicable) 
6.6.3.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidal ideation and behavior will be assessed in participants aged ≥6 years by use of the C-SSRS. 
The C-SSRS is a 3-part scale that measures suicidal ideation (eg, participant 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). 
C-SSRS will be listed by participant. 
6.6.3.2 
Ophthalmological evaluations.  
An ophthalmologic evaluation will be conducted by a pediatric ophthalmologist or 
neuroophthalmologist preferably, although an adult ophthalmologist or an optometrist 
experienced with examining children may be allowed after discussion with the medical monitor. 
The ophthalmologic evaluation may include: 
1. Age and developmentally appropriate quantitative visual acuity. 
If the participant 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. 
These evaluations are to be conducted at baseline (V1) (between the screening and enrollment 
visits), at Day 112 (±2 weeks) (V7) and at Day 364 (±1 weeks) (V10) or at the ET visit for those 
participants who do not complete the study. 
Additional unscheduled ophthalmological assessments may be conducted during the course of this 
study, if recommended by the ophthalmologist. 
The parameters, visual acuity, cataract screening and fundoscopic examination in 
ophthalmological evaluations for each group (as per Table 6.a) will be summarized for baseline, 
and each post-baseline visit.  
The number and percentages of subjects having significantly declined visual acuity will be 
provided over time. Similarly, subjects having anterior or posterior lens opacities in cataract 
screening and subjects having optic nerve exam as abnormal in fundoscopic examination will be 
summarized. 
All ophthalmological evaluation data will be listed. 
6.6.4 
Extent of Exposure and Compliance 
Extent of exposure (in weeks) of study medication is defined as (date of last dose – date of first 
dose +1)/7. Total actual dose is defined as the sum of actual doses (all non-missed doses are 
considered full dose). 
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• Total dose given, average daily dose, and duration of exposure (treatment duration in weeks) 
will be summarized (descriptive statistics such as N, mean, SD, median, minimum, and 
maximum) for all patients by group specified in Table 6.a. 
• Median/range of treatment duration in the study for subjects who withdraw under each 
category will be provided. 
In addition, number and percentage of subjects will be provided by dose level (1. 2. 3) at each visit. 
The primary method of assessing compliance will be based on the number of returned tablets. 
The percentage of study drug compliance will be defined in two ways: 
1) Using the electronic daily seizure and medication diary, as  
%𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= (𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑎𝑠 𝑇𝑎𝑘𝑒𝑛
𝑇𝑜𝑡𝑎𝑙 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐷𝑜𝑠𝑒
) × 100% 
2) Using number of returned tablets,  
%𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= (𝐷𝑜𝑠𝑒 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝐷𝑜𝑠𝑒 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝑇𝑜𝑡𝑎𝑙 𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐷𝑜𝑠𝑒
) × 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%, 
80% to < 100%, 100% to < 120% and ≥ 120%) and the number of subjects in each compliance 
category will be presented. Study medication compliance will also be summarized as a continuous 
variable using descriptive statistics (n, mean, SD, median, minimum, and maximum). In addition, 
Number, and percentage of subjects with seizure diary compliance will be summarized by <80% 
and >=80%. The drug compliance will be based on the safety analysis set. 
Seizure diary compliance is assessed over the period starting from date of first dose and ending 
on the date of the follow-up visit. Seizure diary compliance will be summarized in a similar 
fashion. Compliance is calculated as:  
(Number of days in this period with seizure diary data
𝑇otal number of  days in this period
) × 100% 
 
The Baseline Period for the purpose of percent 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. 
Seizure diary compliance will be based on the mITT analysis set. 
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6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.7.1 
Pharmacokinetic Analysis 
Not applicable. 
6.7.2 
Pharmacodynamic Analysis 
Not applicable. 
6.7.3 
Biomarker Analysis 
Not applicable. 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
Not applicable. 
6.9 
Other Analyses 
Not applicable. 
6.10 
Interim Analyses 
Interim data cuts from this ongoing study will be analyzed to support any regulatory submissions. 
Since there is no hypothesis testing involved, any interim analysis performed will not require any 
type-I error adjustment. 
6.11 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
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 
Not applicable. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Not applicable. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
Not applicable. 
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9.2 
Data Handling Conventions  
9.2.1 
Definition of Baseline 
Unless otherwise specified, baseline is defined as the last non-missing assessment prior to the 
first dose of the study drug. In the case where the last non-missing measurement (except AE and 
concomitant medications) and the first dose coincide at the same time, or the same date if time of 
the measurement is not collected, that measurement will be considered as baseline value. For 
seizure frequency, the prospective 4 to 6- week baseline period of the study will be used to 
compute the baseline frequency. 
9.2.2 
Definition of Visit Windows  
Unless otherwise specified, all the summary tables by visit will use the values (post-baseline) 
selected from analysis visit windows. A windowing convention using the midpoint technique 
(based on study days for each assessment as specified in the protocol schedule of assessments) will 
be used to determine the mapping of a datapoint to an analysis visit window. When more than one 
record falls into one analysis visit window, the rules specified below will be applied to select the 
appropriate record for summary tables. Note that, if multiple measurements are recorded at the 
same day and time, then the average of these measurements (for continuous data) or the worst 
among these measurements (for categorical data) can be used.  
Safety (Lab, Vitals, ECG etc.): 
• When more than one record for a parameter is obtained in an analysis visit window, the 
latest one will be used for summary.  
Other (Care GI-I, CGI-I, etc.): 
• If multiple assessments occur in the same window, the assessment done at the scheduled 
visit will be summarized at the corresponding analysis visit.  
• If only unscheduled visits are available, the assessment within the window and closest to 
the scheduled visit (i.e., the corresponding study day of the scheduled visit per protocol 
schedule of assessments) will be used for summary.  
• If there are two unscheduled assessments within the window and they are equally close to 
the scheduled visit, the later assessment will be used for summary. 
Listings will include all assessments. 
 
9.3 
Analysis Software  
SAS System® Version 9.4 or higher will be used in the statistical analysis. 
 
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Signature Page for Statistical_Analysis_Plan_TAK-935-3004
Title: SAP
Document Number: TDN-000187382 v1.0
Approval
Statistics
29-Jun-2023 06:17:17 GMT+0000
For non-commercial use only