Clinical trial NCT05284760
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2022-03-11; Completion date: 2022-06-02
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main aim is to see how soticlestat tablets of different strengths work and to compare how it works alone in contrast to administration along with food.

In the study will be 2 groups of participants (part A and part B). Participants in part A will receive 300 mg of soticlestat administered in different kind of tablets (regular tablets, mini-tablets, commercial tablets) and participant in part B will also receive 300 mg of soticlestat in tablets but with food and crushed tablets with applesauce.

Participants will complete several assessments including clinical laboratory evaluations, physical examinations, Columbia-Suicide Severity Rating Scale (C-SSRS) assessment, electrocardiographs (ECGs), and vital signs.

Detailed description:
The drug being tested in this study is called soticlestat (TAK-935). The study will assess the bioequivalence, effect of food and tablet crushing, safety and tolerability following single oral dose of 3 different soticlestat oral tablet formulations in healthy participants.

The study will enroll approximately 96 participants. This study will be conducted in two parts (Part A and Part B) having 6 treatment sequences each. Participants will be randomly assigned (by chance, like flipping a coin) to one of the study parts as per treatment sequence:

* Part A, Sequence 1: Treatment A + Treatment B + Treatment C
* Part A, Sequence 2: Treatment A + Treatment C + Treatment B
* Part A, Sequence 3: Treatment B + Treatment A + Treatment C
* Part A, Sequence 4: Treatment B + Treatment C + Treatment A
* Part A, Sequence 5: Treatment C + Treatment A + Treatment B
* Part A, Sequence 6: Treatment C + Treatment B + Treatment A
* Part B, Sequence 1: Treatment D + Treatment E + Treatment F
* Part B, Sequence 2: Treatment D + Treatment F + Treatment E
* Part B, Sequence 3: Treatment E + Treatment D + Treatment F
* Part B, Sequence 4: Treatment E + Treatment F + Treatment D
* Part B, Sequence 5: Treatment F + Treatment D + Treatment E
* Part B, Sequence 6: Treatment F + Treatment E + Treatment D

This single center trial will be conducted in the United States. The overall duration of the study is approximately 51 days. Participants will be followed up for 14 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: Soticlestat T4 tablets 300 mg, orally, once on Day 1 of Period 1 under fasted condition as Treatment A, followed by soticlestat T3 mini-tablets 300 mg, orally, once on Day 1 of Period 2 under fasted condition as Treatment B, and followed by soticlestat T3 commercial tablets 300 mg, orally, once on Day 1 of Period 3 under fasted condition as Treatment C. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 2: Soticlestat T4 tablets 300 mg, orally, once on Day 1 of Period 1 under fasted condition as Treatment A, followed by soticlestat T3 commercial tablets 300 mg, orally, once on Day 1 of Period 2 under fasted condition as Treatment C, and followed by soticlestat T3 mini-tablets 300 mg, orally, once on Day 1 of Period 3 under fasted condition as Treatment B. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 3: Soticlestat T3 mini-tablets 300 milligram (mg), orally, once on Day 1 of Period 1 under fasted condition as Treatment B, followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 2 under fasted condition as Treatment A, and followed by soticlestat T3 commercial tablets 300 mg, orally, once on Day 1 of Period 3 under fasted condition as Treatment C. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 4: Soticlestat T3 mini-tablets 300 mg, orally, once on Day 1 of Period 1 under fasted condition as Treatment B, followed by soticlestat T3 commercial tablets 300 mg, orally, once on Day 1 of Period 2 under fasted condition as Treatment C, and followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 3 under fasted condition as Treatment A. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 5: Soticlestat T3 commercial tablets 300 mg, orally, once on Day 1 of Period 1 under fasted condition as Treatment C, followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 2 under fasted condition as Treatment A, and followed by soticlestat T3 mini-tablets 300 mg, orally, once on Day 1 of Period 3 under fasted condition as Treatment B. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 6: Soticlestat T3 commercial tablets 300 mg, orally, once on Day 1 of Period 1 under fasted condition as Treatment C, followed by soticlestat T3 mini-tablets 300 mg, tablets, orally, once on Day 1 of Period 2 under fasted condition as Treatment B, and followed by soticlestat T4 tablets 300 mg, orally, once on Day 1 of Period 3 under fasted condition as Treatment A. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 7: Soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 1 under fasted condition as Treatment D, followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 2 under fed condition as Treatment E, and followed by soticlestat T4 300 mg tablets crushed and mixed with applesauce, orally, once on Day 1 of Period 3 under fasted condition as Treatment F. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 8: Soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 1 under fasted condition as Treatment D, followed by soticlestat T4 300 mg, tablets crushed and mixed with applesauce, orally, once on Day 1 of Period 2 under fasted condition as Treatment F, and followed by soticlestat T4 300 mg, orally, once on Day 1 of Period 3 under fed condition as Treatment E. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 9: Soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 1 under fed condition as Treatment E, followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 2 under fasted condition as Treatment D, and followed by soticlestat T4 300 mg, tablets crushed and mixed with applesauce, orally, once on Day 1 of Period 3 under fasted condition as Treatment F. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 10: Soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 1 under fed condition as Treatment E, followed by soticlestat T4 300 mg tablets crushed and mixed with applesauce, orally, once on Day 1 of Period 2 under fasted condition as Treatment F, and followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 3 under fasted condition as Treatment D. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 11: Soticlestat T4 300 mg tablets crushed and mixed with applesauce, orally, once on Day 1 of Period 1 under fasted condition as Treatment F, followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 2 under fasted condition as Treatment D, and followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 3 under fed condition as Treatment E. A washout interval of exactly 4 days will be maintained between each Treatment Period. arm 12: Soticlestat T4 300 mg tablets, crushed and mixed with applesauce, orally, once on Day 1 of Period 1 under fasted condition as Treatment F, followed by soticlestat T4 300 mg, tablets, orally, once on Day 1 of Period 2 under fed condition as Treatment E, and followed by soticlestat T4 300 mg tablets, orally, once on Day 1 of Period 3 under fasted condition as Treatment D. A washout interval of exactly 4 days will be maintained between each Treatment Period.
Interventions: intervention 1: Soticlestat intervention 2: Soticlestat intervention 3: Soticlestat
Intervention descriptions: intervention 1: Soticlestat T4 tablets. intervention 2: Soticlestat T3 mini-tablets. intervention 3: Soticlestat commercial tablets.

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


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the Bioequivalence of 
Soticlestat Oral Tablet Formulations and the Effect of Food and Tablet Crushing on the 
Pharmacokinetics of Soticlestat in Healthy Adult Participants
Study Identifier:
TAK-935-1014
Compound:
Soticlestat (TAK-935)
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington, MA 02421
IND No.:
133,627
Date:
17 March 2022
Version/Amendment 
Number:
Amendment 1 Protocol
Amendment History:
Date
Amendment Number
Amendment Type
Region
18 February 2022
Initial Version
United States
17 March 2022
01
Not Applicable
United States
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................12
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................16
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.2
Rationale for the Proposed Study.............................................................................22
4.2.1
Rationale for Part A ...........................................................................................24
4.2.2
Rationale for Part B............................................................................................24
4.3
Benefit/Risk Profile .................................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................25
5.1
Hypothesis...............................................................................................................25
5.2
Study Objectives......................................................................................................25
5.2.1
Study Primary Objectives...................................................................................25
5.2.2
Study Secondary Objective ................................................................................26
5.2.3
Study Exploratory Objectives.............................................................................26
5.3
Endpoints.................................................................................................................26
5.3.1
Primary Endpoints .............................................................................................26
5.3.2
Secondary Endpoint ...........................................................................................26
5.3.3
Exploratory Endpoints .......................................................................................26
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................27
6.1
Study Design ...........................................................................................................27
6.2
Dose Escalation .......................................................................................................28
6.3
Stopping Rules.........................................................................................................28
6.4
Rationale for Study Design, Dose, and Endpoints ....................................................28
6.4.1
Rationale of Study Design..................................................................................28
6.4.2
Rationale for Dose .............................................................................................28
6.4.3
Rationale for Endpoints......................................................................................29
6.4.4
Future Biomedical Research...............................................................................29
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures...............29
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.6
Study Beginning and End/Completion .....................................................................29
6.6.1
Definition of Beginning of the Study..................................................................29
6.6.2
Definition of End of the Study ...........................................................................30
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6.6.3
Definition of Study Completion .........................................................................30
6.6.4
Definition of Study Discontinuation...................................................................30
6.6.5
Criteria for Premature Termination or Suspension of the Study..........................30
6.6.6
Criteria for Premature Termination or Suspension of a Site................................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .....31
7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................31
7.3
Excluded Medications, Supplements, Dietary Products............................................33
7.4
Diet, Fluid, Activity.................................................................................................34
7.4.1
Diet and Fluid ....................................................................................................34
7.4.2
Activity..............................................................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Participant......................................36
7.6
Procedures for Discontinuation or Withdrawal of a Participant ................................37
7.7
Participant Replacement ..........................................................................................37
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................37
8.1
Clinical Study Drug .................................................................................................37
8.1.1
Clinical Study Drug Labeling.............................................................................38
8.1.2
Clinical Study Drug Inventory and Storage ........................................................38
8.1.3
Clinical Study Drug Blinding.............................................................................38
8.1.4
Randomization Sequence ...................................................................................38
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure...................................39
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................39
9.0
STUDY PROCEDURES...............................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent Procedure..............................................................................39
9.1.2
Inclusion and Exclusion .....................................................................................40
9.1.3
Medical History/Demography ............................................................................40
9.1.4
Concomitant Medications...................................................................................40
9.2
Clinical Procedures and Assessments.......................................................................40
9.2.1
Physical Exam ...................................................................................................40
9.2.2
Height and Weight .............................................................................................40
9.2.3
BMI ...................................................................................................................40
9.2.4
Vital Signs .........................................................................................................41
9.2.5
12-Lead ECG.....................................................................................................41
9.2.6
Study Drug Administration ................................................................................41
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9.2.7
C-SSRS..............................................................................................................42
9.2.8
AE Monitoring...................................................................................................42
9.2.9
Laboratory Procedures and Assessments ............................................................42
9.3
Pharmacokinetic Samples ........................................................................................44
9.3.1
Pharmacokinetic Measurements.........................................................................45
9.3.2
Biomarker Measurements...................................................................................46
9.3.3
PGx Measurements ............................................................................................46
9.3.4
Confinement ......................................................................................................46
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions and Elements of AEs .............................................................................47
10.1.1 SAEs..................................................................................................................49
10.1.2 Special Interest AEs...........................................................................................50
10.2
AE Procedures.........................................................................................................50
10.2.1 Assigning Severity/Intensity of AEs...................................................................50
10.2.2 Assigning Causality of AEs................................................................................51
10.2.3 Start Date...........................................................................................................51
10.2.4 End Date............................................................................................................51
10.2.5 Pattern of Adverse Event (Frequency)................................................................51
10.2.6 Action Taken With Study Treatment..................................................................52
10.2.7 Outcome ............................................................................................................52
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................52
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....54
11.0
STATISTICAL METHODS..........................................................................................55
11.1
Statistical and Analytical Plans ................................................................................55
11.1.1 Analysis Sets......................................................................................................55
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................55
11.1.3 PK Analysis .......................................................................................................55
11.1.4 PD Analysis .......................................................................................................56
11.1.5 Safety Analysis ..................................................................................................56
11.2
Interim Analysis and Criteria for Early Termination ................................................57
11.3
Determination of Sample Size..................................................................................57
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................58
12.1
Study-Site Monitoring Visits ...................................................................................58
12.2
Protocol Deviations..................................................................................................58
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
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13.0
ETHICAL ASPECTS OF THE STUDY........................................................................59
13.1
IRB and/or IEC Approval ........................................................................................59
13.2
Participant Information, Informed Consent, and Participant Authorization...............60
13.3
Participant Confidentiality .......................................................................................61
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................62
13.4.1 Publication and Disclosure.................................................................................62
13.4.2 Clinical Study Registration.................................................................................62
13.4.3 Clinical Study Results Disclosure.......................................................................63
13.5
Insurance and Compensation for Injury....................................................................63
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................63
14.1
Administrative Information......................................................................................63
14.1.1 Study Contact Information .................................................................................63
14.1.2 INVESTIGATOR AGREEMENT......................................................................64
14.1.3 Study-Related Responsibilities...........................................................................65
14.1.4 List of Abbreviations .........................................................................................65
15.0
DATA HANDLING AND RECORD KEEPING...........................................................67
15.1
CRFs (Electronic and Paper)....................................................................................67
15.2
Record Retention .....................................................................................................67
16.0
REFERENCES..............................................................................................................68
17.0
APPENDICES...............................................................................................................69
LIST OF IN-TEXT TABLES
Table 2.a
Study Design for Part A .....................................................................................12
Table 2.b
Study Treatments for Part A...............................................................................13
Table 2.c
Study Design for Part B .....................................................................................14
Table 2.d
Study Treatments for Part B...............................................................................15
Table 3.a
Part A ................................................................................................................16
Table 3.b
Part B.................................................................................................................18
Table 4.a
Soticlestat Tablet Formulations Utilized in Phase 2 and Phase 3 Clinical 
Studies ...............................................................................................................22
Table 4.b 
......................................................24
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................34
Table 8.a
Randomization Sequence in Part A ....................................................................38
Table 8.b
Randomization Sequence in Part B.....................................................................39
Table 9.a
Primary Specimen Collections ...........................................................................45
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Table 10.a
Takeda Medically Significant AE List................................................................50
LIST OF IN-TEXT FIGURES
Figure 4.a
Dissolution Profile of 20 mg Tablets (T3) ..........................................................23
Figure 4.b
Dissolution Profile of 100 mg Tablets (T2, T4)..................................................23
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................69
Appendix B
Elements of the Participant Informed Consent....................................................71
Appendix C
Investigator Consent to the Use of Personal Information ....................................74
Appendix D
Pregnancy and Contraception.............................................................................75
Appendix E
Summary of Changes from Previous Version.....................................................77
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDCA)
95 Hayden Avenue
Lexington, MA 02421
Telephone: +1 (617) 679-7000
Compound:
Soticlestat (TAK-935)
Study Identifier: TAK-935-1014
Phase: 1
Protocol Title: A Phase, 1 Open-Label, Randomized, Crossover Study to Evaluate the Bioequivalence of Soticlestat 
Oral Tablet Formulations and the Effect of Food and Tablet Crushing on the Pharmacokinetics of Soticlestat in 
Healthy Adult Participants
Study Design:
This is a 2-part, open-label study conducted in healthy adult participants. Part A will evaluate the bioequivalence 
(BE) of 3 different soticlestat oral tablet formulations. Part B will evaluate the effect of food and tablet crushing on 
soticlestat pharmacokinetics (PK).
Each part will be conducted independently as a randomized, 3-period, crossover design. Study schematics of the 
study design are shown in Table 2.a, Table 2.b, Table 2.c, and Table 2.d. A schedule of assessments is shown in 
Schedule of Study Procedures (Section 3.0).
The two study parts may be conducted concurrently. Participants can only participate in one study part.
Part A:
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first dosing on Day 1 of 
Period 1). Upon completion of screening, qualified participants will be admitted to the study site on Day -1 of Period 
1 and will remain confined until completion of study procedures on Day 5 of Period 3. Participants may be admitted 
earlier than Day -1 for COVID-19 testing not related to study protocol, as per CRU requirements.
In each period, on Day 1, participants will receive a single oral dose of 300 mg soticlestat administered as T4 tablets 
(Treatment A), T3 mini-tablets (Treatment B), or commercial tablets (Treatment C), in a 3-way crossover fashion. 
Blood samples for the PK of soticlestat 
 will be collected at scheduled time points from 
predose through 96 hours postdose. There will be a washout period of exactly 4 days between each soticlestat doses.
Safety and tolerability will be assessed throughout the study by treatment-emergent adverse events (TEAEs), clinical 
laboratory evaluations, physical examinations, Columbia-Suicide Severity Rating Scale (C-SSRS), 12-lead 
electrocardiograms (ECGs), and vital signs.
After discharge, the Clinical Research Unit (CRU) will contact all participants (including participants who terminate 
the study early) 14 (±3) days after the last soticlestat administration by telephone or other methods per CRU 
standards to determine if any adverse events (AEs) have occurred and/or any concomitant medications were taken 
since the last study visit. If clinically significant findings are observed upon discharge, participants may return to the 
CRU for re-evaluation per Investigator’s discretion.
Part B: 
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first dosing on Day 1 of 
Period 1). Upon completion of screening, qualified participants will be admitted to the study site on Day -1 of Period 
1 and will remain confined until completion of study procedures on Day 5 of Period 3. Participants may be admitted 
earlier than Day -1 for COVID-19 testing not related to study protocol, as per CRU requirements.
In each period, on Day 1, participants will receive a single oral dose of 300 mg soticlestat administered as intact T4 
tablets under fasting conditions (Treatment D), intact T4 tablets fed conditions (Treatment E), or as crushed T4 
tablets mixed with applesauce under fasting conditions (Treatment F), in a 3-way crossover fashion. Blood samples 
for the PK of soticlestat 
 will be collected at scheduled time points from predose through 96 
hours postdose. There will be a washout period of exactly 4 days between each soticlestat doses.
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Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory evaluations, physical 
examinations, C-SSRS, 12-lead ECGs, and vital signs.
After discharge, the CRU will contact all participants (including participants who terminate the study early) 14 (±3) 
days after the last soticlestat administration by telephone or other methods per CRU standards to determine if any 
AEs have occurred and/or any concomitant medications were taken since the last study visit. If clinically significant 
findings are observed upon discharge, participants may return to the CRU for re-evaluation per Investigator’s 
discretion.
Study Primary Objectives:
Part A: 

To assess the BE of 300 mg soticlestat administered as T3 mini-tablets (Treatment B) compared to 300 mg 
soticlestat administered as T4 tablets (Treatment A).

To assess the BE of 300 mg soticlestat administered as commercial tablets (Treatment C) compared to 300 mg 
soticlestat administered as T4 tablets (Treatment A).
Part B:

To assess the effect of food on the bioavailability (BA) of 300 mg soticlestat administered as T4 tablets under 
fed condition (Treatment E) compared to fasting condition (Treatment D).

To assess the effect of tablet crushing on the PK of 300 mg soticlestat administered as T4 tablets crushed and 
mixed with applesauce (Treatment F) compared to whole T4 tablets (Treatment D).
Study Secondary Objective:

To evaluate the safety and tolerability of soticlestat following single oral dose of 300 mg soticlestat in 
Treatments A, B, C, D, E, and F.
Study Exploratory Objectives: 
Study Participant Population: Healthy male and female participants aged 18 to 55 years inclusive, at screening. 
Body Mass Index (BMI) 18.0-32.0 kg/m2, inclusive, at screening
Planned Number of Participants:
96 participants will be enrolled (72 participants in Part 
A and 24 participants in Part B)
Planned Number of Sites:
1 
Dose Levels:
Treatment A, Treatment D, Treatment E, and 
Treatment F:
300 mg (3 x 100 mg strength T4 tablets)
Treatment B:
300 mg (15 x 20 mg strength T3 mini-tablets).
Treatment C:
300 mg (1 x 300 mg strength commercial tablet)
Route of Administration:
Oral
Duration of Treatment:
Single-dose of soticlestat on Day 1 of each period.
Planned Study Duration:
Approximately 51 days including screening period and 
follow-up.
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Criteria for Inclusion:
Participants must fulfill the following inclusion criteria prior to the first dosing to be eligible for participation in the 
study:
1.
Healthy, adult, male or female of non-childbearing potential (Appendix D), 18 to 55 years of age, inclusive, at 
screening.
2.
Male agrees to comply with any applicable contraceptive requirements of the protocol as detailed in 
Appendix D.
3.
Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. 
4.
Continuous non-smoker who has not used nicotine-containing products for at least 90 days prior to the first 
dosing.
5.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs, and ECGs, as deemed by the Investigator or designee.

Supine blood pressure is ≥90/40 mmHg and ≤140/90 mmHg at screening;

Supine heart rate is ≥45 bpm and ≤100 bpm at screening;

QT interval corrected for pulse rate using Fridericia’s formula (QTcF) is ≤450 msec (males) or 
≤470 msec (females) and ECG findings considered normal or not clinically significant by the Investigator 
or designee at screening;

Estimated creatinine clearance ≥80 mL/min at screening.

Liver function tests (LFT) including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≤1.5 X the upper limit of normal (ULN) at screening and check-in.
6.
Able to swallow multiple tablets.
7.
Understands the study procedures in the Informed Consent Form (ICF), and be willing and able to comply with 
the protocol.
Criteria for Exclusion: 
Participants must not be enrolled in the study if they meet any of the following criteria prior to the first dosing: 
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
Investigator or designee.
3.
History or presence of gastritis, gastrointestinal (GI) tract, gastric bypass surgery, or hepatic disorder or other 
clinical condition which, in the opinion of the Investigator or designee, may affect the absorption, distribution, 
metabolism, or elimination of study drug.
4.
History or presence of any of the following, deemed clinically significant by the Investigator or designee:

GI disorder (eg peptic ulcer disease, gastroesophageal reflux disease, impaction, chronic constipation, 
inflammatory bowel disease, ischemic colitis, vascular intestinal atherosclerosis, previous bowel resection, 
bowel obstruction, bariatric surgery, cholecystitis, intestinal ulceration or inflammation);

GI bleeding or perforation;

Recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding).
5.
History or presence of cataracts. 
6.
History or presence of other clinically significant vision disturbances as judged by the Investigator or designee.
7.
History or presence of epilepsy, seizure, or convulsion, tremor or related symptoms that are deemed clinically 
significant by the Investigator or designee.
8.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study 
or poses an additional risk to the participant by their participation in the study.
9.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
10. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.
11. Any positive responses on the C-SSRS that in the clinical judgement of the Investigator has a risk of suicide or 
has made a suicide attempt in the previous 12 months prior to the first dosing.
12. Female participant of childbearing potential.
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2.0
STUDY SCHEMATIC
Table 2.a
Study Design for Part A
S
Period 1
Period 2
Period 3
FU
C-I and 
Predose 
Assessment
Soticlestat 
Dosing, PK 
Sampling, and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling, and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Study Exit a
(PK Sampling 
and Study 
Assessments)
Within 
28 days 
prior to 
first 
dosing
Day -1
Day 1
Day 2 – 5 b
Day 1 b
Day 2 – 5 b
Day 1 b
Day 2 – 4
Day 5
14 (±3) 
days 
following 
last 
soticlestat 
dose
--------------------------------- Confinement c---------------------------------
a Study Exit is defined as the end of last treatment period.
b Day 5 of Period 1 and Period 2 will also be considered Day 1 of Period 2 and Period 3, respectively. Procedures scheduled on both days will only be performed 
once.
c Participants will start the confinement on Day -1 of Period 1 and will remain confined until Day 5 of Period 3. Participants may be admitted earlier than Day 1 
for COVID-19 testing not related to study protocol, as per CRU requirements.
Abbreviations: C-I = Check-in, FU = Follow-up, PK = Pharmacokinetics, S = Screening.
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Table 2.b
Study Treatments for Part A
Treatments
Study Drug
Dose
Dose Regimen
Number of Days on Study Drug
Treatment A 
(Reference)
Soticlestat T4 tablets
300 mg (3 x 100 mg strength)
Single dose, oral, 
fast
Day 1 of each period
Treatment B 
(Test)
Soticlestat T3 mini-tablets
300 mg (15 x 20 mg strength)
Single dose, oral, 
fast
Day 1 of each period
Treatment C 
(Test)
Soticlestat commercial tablets
300 mg (1 x 300 mg strength)
Single dose, oral, 
fast
Day 1 of each period
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Table 2.c
Study Design for Part B
S
Period 1
Period 2
Period 3
FU
C-I and 
Predose 
Assessment
Soticlestat 
Dosing, PK 
Sampling and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Soticlestat
Dosing, PK 
Sampling and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Study Exit a
(PK Sampling 
and Study 
Assessments)
Within 
28 days 
prior to 
first 
dosing
Day -1
Day 1
Day 2 – 5 b
Day 1 b
Day 2 – 5 b
Day 1 b
Day 2 – 4
Day 5
14 (±3) 
days 
following 
last 
soticlestat 
dose
--------------------------------- Confinement c---------------------------------
a Study Exit is defined as the end of last treatment period.
b Day 5 of Period 1 and Period 2 will also be considered Day 1 of Period 2 and Period 3, respectively. Procedures scheduled on both days will only be performed 
once.
c Participants will start the confinement on Day -1 of Period 1 and will remain confined until Day 5 of Period 3. Participants may be admitted earlier than Day -1 
for COVID-19 testing not related to study protocol, as per CRU requirements.
Abbreviations: C-I = Check-in, FU = Follow-up, PK = Pharmacokinetics, S = Screening
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Table 2.d
Study Treatments for Part B
Treatments
Study Drug
Dose
Dose Regimen
Number of Days on Study 
Drug
Treatment D 
(Reference)
Soticlestat T4 tablets
300 mg (3 x 100 mg 
strength)
Single dose, oral, fast
Day 1 of each period
Treatment E (Test)
Soticlestat T4 tablets
300 mg (3 x 100 mg 
strength)
Single dose, oral, fed
Day 1 of each period
Treatment F (Test)
Soticlestat T4 tablets
300 mg (3 x 100 mg 
strength)
Single dose, oral, crushed and mixed 
with applesauce, fast
Day 1 of each period
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b
Within 28 days prior to the first dosing.
c
There will be a washout period of exactly 4 days between each soticlestat dose.
d
Day 5 of Periods 1 and 2 will be the same as Day 1 of Periods 2 and 3, respectively. Procedures scheduled on both days will only be performed once.
e
To be performed at time of early termination from the study.
f
After discharge, the CRU will contact all participants (including participants who terminate the study early) 14 (±3) days after the last soticlestat administration by telephone 
or other methods per CRU standards to determine if any AEs have occurred and/or any concomitant medications were taken since the last study visit. If clinically significant 
findings are observed upon discharge, participants may return to the CRU for re-evaluation per Investigator’s discretion.
g
Participants will be admitted to the CRU on Day -1 of Period 1 and be confined up to Day 5 of Period 3. Participants may be admitted earlier than Day -1 for COVID-19 
testing not related to study protocol, as per CRU requirements.
h
To be performed at the end of Period 3 only.
i
To be performed within 24 hours prior to dosing in Period 1 and 2 hours prior to dosing in Periods 2 and 3.
j
Samples for serum chemistry will be obtained after a fast of at least 8 hours, however, in case of dropouts or rechecks, participants may not have fasted for 8 hours prior to 
when the serum chemistry sample is taken.
k
At screening, the C-SSRS Baseline/Screening version will be administered; at all other time points, the Since Last Visit version will be administered.
l
In each period, soticlestat will be administered as per Treatments A, B, or C, as per the randomization sequence. Soticlestat will be administered following an overnight fast of 
at least 10 hours. Fasting will continue for at least 4 hours postdose. 
m
To be performed prior to dosing.
n
The 96-hour PK sample of Periods 1 and 2 will serve as the predose PK sample of Periods 2 and 3, respectively.
Abbreviations: AE = Adverse event(s), BP = Blood pressure, C-I = Check-in, C-SSRS = Columbia-suicide severity rating scale, Chem = Chemistry, Coag = Coagulation, 
COVID-19 = Coronavirus disease 2019, CRU = Clinical research unit, ECG = Electrocardiogram, ET = Early termination, FSH = Follicle-stimulating hormone, FU = Follow-up, 
Hem = Hematology, HIV = Human immunodeficiency virus, PK = Pharmacokinetics, PMP = Postmenopausal, PR = Pulse rate, RR = Respiratory rate, S = Screening, 
T = Temperature, UA = Urinalysis.
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b
Within 28 days prior to the first dosing.
c
There will be a washout period of exactly 4 days between each soticlestat dose.
d
Day 5 of Periods 1 and 2 will be the same as Day 1 of Periods 2 and 3, respectively. Procedures scheduled on both days will only be performed once.
e
To be performed at time of early termination from the study.
f
After discharge, the CRU will contact all participants (including participants who terminate the study early) 14 (±3) days after the last soticlestat administration by telephone 
or other methods per CRU standards to determine if any AEs have occurred and/or any concomitant medications were taken since the last study visit. If clinically significant 
findings are observed upon discharge, participants may return to the CRU for re-evaluation per Investigator’s discretion.
g
Participants will be admitted to the CRU on Day -1 of Period 1 and be confined up to Day 5 of Period 3. Participants may be admitted earlier than Day -1 for COVID-19 
testing not related to study protocol, as per CRU requirements.
h
To be performed at the end of Period 3 only.
i
To be performed within 24 hours prior to dosing in Period 1 and 2 hours prior to dosing in Periods 2 and 3.
j
Samples for serum chemistry will be obtained after a fast of at least 8 hours, however, in case of dropouts or rechecks, participants may not have fasted for 8 hours prior to 
when the serum chemistry sample is taken. 
k
At screening, the C-SSRS Baseline/Screening version will be administered; at all other time points, the Since Last Visit version will be administered.
l
In each period, soticlestat will be administered as per Treatments D, E, and or F, as per the randomization sequence. In Treatment D and F, soticlestat will be administered 
following an overnight fast of at least 10 hours. In Treatment E, soticlestat will be administered following an overnight fast of at least 10 hours until 30 minutes prior to their 
scheduled morning dose, when they will be given a high-fat breakfast. Fasting will continue for at least 4 hours postdose in Treatments D, E, and F.
m
To be performed prior to dosing.
n
The 96-hour PK sample of Periods 1 and 2 will serve as the predose PK sample in Periods 2 and 3, respectively.
Abbreviations: AE = Adverse event(s), BP = Blood pressure, C-I = Check-in, C-SSRS = Columbia-suicide severity rating scale, Chem = Chemistry, Coag = Coagulation, 
COVID-19 = Coronavirus disease 2019, CRU = Clinical research unit, ECG = Electrocardiogram, ET = Early termination, FSH = Follicle-stimulating hormone, FU = Follow-up, 
Hem = Hematology, HIV = Human immunodeficiency virus, PK = Pharmacokinetics, PMP = Postmenopausal, PR = Pulse rate, RR = Respiratory rate, S = Screening, 
T = Temperature, UA = Urinalysis.
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4.0
INTRODUCTION
4.1
Background
Soticlestat is a potent and selective cholesterol 24S hydroxylase (CH24H) inhibitor currently in 
development as an oral adjunct to standard of care therapy for the treatment of rare pediatric 
epilepsies referred to as Developmental and Epileptic Encephalopathies (DEE) which is a cluster 
of pediatric epilepsy syndromes and includes Dravet Syndrome (DS) and Lennox Gastaut 
Syndrome (LGS).
Nonclinical Background
Soticlestat was evaluated in a series of nonclinical pharmacology, toxicology, and drug 
metabolism and PK studies in accordance with relevant Food and Drug Administration (FDA) 
guidance documents. The results supported investigational new drug (IND) opening study. The 
complete results from nonclinical studies demonstrated a favorable benefit over the risk potential 
of soticlestat for further clinical evaluation through Phase 3 studies and registration. Nonclinical 
study results can be found in the Investigator’s Brochure (IB) [1].
Clinical Background
The PK, safety, tolerability, and/or efficacy of soticlestat have been evaluated in 6 Phase 1 
clinical studies in healthy participants (completed), a Phase 1b/2a study in participants with 
DEEs (completed), and 3 Phase 2 studies in participants with DS, LGS, 15q11-q13 duplication 
syndrome (Dup15q), cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), or 
complex regional pain syndrome (completed). One (1) Phase 2 open-label, long-term study in 
participants with various DEEs, including DS, LGS, Dup15q, or CDD, 2 Phase 1 drug-drug 
interaction studies in healthy subjects, 1 Phase 1 study in subjects with moderate to severe 
hepatic impairment and healthy subjects, and 3 Phase 3 studies in DS and LGS patients are 
ongoing.
Overall, 382 subjects have been enrolled in the clinical trials with soticlestat, of which 341 have 
received active treatment based on actual exposure and enrollment data from completed and 
ongoing clinical trials as of the safety data cut-off date (19 November 2021).
In the 6 completed Phase 1 clinical studies, a total of 116 healthy participants received at least 
1 dose of soticlestat. In these studies, soticlestat when administered as a single-dose up to 
1350 mg was safe and well tolerated. In the 14-day multiple rising dose study, soticlestat was 
safe and well tolerated in most healthy participants up to 600 mg daily (either as 600 mg once 
daily [QD] or 300 mg twice daily [BID], without up-titration). Two participants discontinued 
study drug due to a TEAE: one with acute psychosis (Cohort 4: soticlestat 600 mg QD) that was 
reported as severe intensity, and one with mild confusional state (Cohort 3: soticlestat 300 mg 
BID) occurring on study Day 10. There was no additional treatment required beyond cessation of 
study drug for these events. No safety issues of concern were identified based on assessments of 
physical examinations, vital sign measurements, clinical laboratory values, or 12-lead ECG 
findings. No significant safety issues have been identified in the completed patient studies 
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a 2-part, open-label study conducted in healthy adult participants. Part A will evaluate the 
BE of 3 different soticlestat oral tablet formulations. Part B will evaluate the effect of food and 
tablet crushing on soticlestat PK. 
Each part will be conducted independently as a randomized, 3-period, crossover design. Study 
schematics of the study design are shown in Table 2.a, Table 2.b, Table 2.c, and Table 2.d. A 
schedule of assessments is shown in Schedule of Study Procedures (Section 3.0). 
The two study parts may be conducted concurrently. Participants can only participate in one 
study part.
Part A:
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first 
dosing on Day 1 of Period 1). Upon completion of screening, qualified participants will be 
admitted to the study site Day -1 of Period 1 and will remain confined until completion of study 
procedures on Day 5 of Period 3. Participants may be admitted earlier than Day -1 for 
COVID-19 testing not related to study protocol, as per CRU requirements.
In each period, on Day 1, participants will receive a single oral dose of 300 mg soticlestat 
administered as T4 tablets (Treatment A), T3 mini-tablets (Treatment B), or commercial tablets 
(Treatment C), in a 3-way crossover fashion. Blood samples for the PK of soticlestat
 
 will be collected at schedules time points from predose through 96 hours postdose. 
There will be a washout period of exactly 4 days between each soticlestat doses.
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory 
evaluations, physical examinations, C-SSRS, 12-lead ECG, and vital signs.
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 14 (±3) days after the last soticlestat administration by telephone or other methods 
per CRU standards to determine if any AEs have occurred and/or any concomitant medications 
were taken since the last study visit. If clinically significant findings are observed upon 
discharge, participants may return to the CRU for re-evaluation per Investigator’s discretion.
Part B: 
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first 
dosing on Day 1 of Period 1). Upon completion of screening, qualified participants will be 
admitted to the study site Day -1 of Period 1 and will remain confined until completion of study 
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procedures on Day 5 of Period 3. Participants may be admitted earlier than Day -1 for 
COVID-19 testing not related to study protocol, as per CRU requirements.
In each period, on Day 1, participants will receive a single oral dose of 300 mg soticlestat 
administered as intact T4 tablets under fasting conditions (Treatment D), intact T4 tablets under 
fed condition (Treatment E), or as crushed T4 tablets mixed with applesauce under fasting 
conditions (Treatment F), in a 3-way crossover fashion. Blood samples for the PK of soticlestat 
 will be collected at schedules time points from predose through 96 hours 
postdose. There will be a washout period of exactly 4 days between each soticlestat doses. 
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory 
evaluations, physical examinations, C-SSRS, 12-lead ECG, and vital signs.
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 14 (±3) days after the last soticlestat administration by telephone or other methods 
per CRU standards to determine if any AEs have occurred and/or any concomitant medications 
were taken since the last study visit. If clinically significant findings are observed upon 
discharge, participants may return to the CRU for re-evaluation per Investigator’s discretion.
6.2
Dose Escalation
Not applicable. 
6.3
Stopping Rules
Not applicable.
6.4
Rationale for Study Design, Dose, and Endpoints
6.4.1
Rationale of Study Design 
This is a 2-part study conducted in healthy adult participants. Part A will evaluate the BE of 
3 different soticlestat oral tablet formulations. Part B will evaluate the effect of food and tablet 
crushing on soticlestat PK. Each part will be conducted independently as a randomized, 3-period, 
William Square crossover design. Participants will be randomized to treatment sequences to 
minimize assignment bias. A crossover design is used to reduce the residual variability as every 
participant acts as their own control. There will be a washout period of 4 days between the 
soticlestat doses and is considered sufficient to prevent carryover effects of the preceding 
treatment.
6.4.2
Rationale for Dose 
The dose of soticlestat selected for this 2-part study is 300 mg, the recommended Phase 3 dose. 
In clinical studies, soticlestat when administered as a single-dose up to 1350 mg was safe and 
well tolerated by healthy participants. The increase in soticlestat exposure from 300 mg to 
1350 mg is >4-fold. Taken together the dose is not anticipated to cause any risk or benefit to the 
subjects participating in this study.
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6.4.3
Rationale for Endpoints
6.4.3.1
Pharmacokinetic Endpoints
The PK endpoints are standard for this type of study.
6.4.3.2
Safety Endpoints
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring 
of AEs, vital signs, C-SSRS, 12-lead ECGs, clinical laboratory evaluations, and physical 
examinations.
6.4.4
Future Biomedical Research
Any residual plasma samples will be stored by the Sponsor or Bioanalytical facility for the 
maximal 5 years determined by the Sponsor following the last dosing. Tubes or containers will 
be identified with a barcode using an appropriate label.
No diseases/conditions, deoxyribonucleic acid, or ribonucleic acid will be analyzed in this study. 
The analyses will focus on PK profiling for soticlestat 
. Samples will not 
be submitted to a public database. The Sponsor and contract research organizations involved in 
the clinical conduct, bioanalytical analyses, and PK and statistical analysis of the data will have 
access to the samples and/or the data that resulted from the analysis, if performed. 
By signing the ICF, participants agree to the possible future analysis of these samples. At any 
time, the participants can contact the CRU staff to request destruction of the residual samples 
once PK assessments required to meet the study objective are completed. Any additional 
research on these samples unspecified by this protocol will require approval from the 
participants.
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
soticlestat 
, and is to be collected as close to the scheduled times defined in 
this protocol as possible.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drugs to any participant may not be modified. 
Unscheduled procedures might be performed for safety reasons. If necessary, a participant may 
be discontinued for the reasons described in Section 7.5 and Section 7.6.
6.6
Study Beginning and End/Completion
6.6.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first participant.
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6.6.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0).
6.6.3
Definition of Study Completion
The end of the study is scheduled after completion of the evaluations in the follow-up contact for 
the last participant in the study.
This time period may change in the event that the study is terminated early or the last participant 
is lost to follow-up. 
6.6.4
Definition of Study Discontinuation
Celerion reserves the right to terminate the study in the interest of participant welfare.
The Sponsor reserves the right to suspend or terminate the study at any time for any reason.
6.6.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is 
no longer acceptable for participants participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises participant safety.
6.6.6
Criteria for Premature Termination or Suspension of a Site
6.6.6.1
Criteria for Premature Termination or Suspension
A study site may be terminated prematurely or suspended if the site (including the Investigator) 
is found in significant violation of GCP, the study protocol, or contractual agreement; if the site 
(including the Investigator) is unable to ensure adequate performance of the study; or as 
otherwise permitted by the contractual agreement. 
6.6.6.2
Procedures for Premature Termination or Suspension
In the event that the Sponsor, an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), or a regulatory authority elects to terminate or suspend the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable investigational site(s) 
during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
7.1
Inclusion Criteria 
Participants must fulfill the following inclusion criteria prior to the first dosing to be eligible for 
participation in the study:
1. Healthy, adult, male or female of non-childbearing potential (Appendix D), 18 to 55 years of 
age, inclusive, at screening.
2. Male agrees to comply with any applicable contraceptive requirements of the protocol as 
detailed in Appendix D.
3. BMI ≥18.0 and ≤32.0 kg/m2 at screening. 
4. Continuous non-smoker who has not used nicotine-containing products for at least 90 days 
prior to the first dosing.
5. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs and ECGs, as deemed by the Investigator or designee.

Supine blood pressure is ≥90/40 mmHg and ≤140/90 mmHg at screening;

Supine heart rate is ≥45 bpm and ≤100 bpm at screening;

QTcF is ≤450 msec (males) or ≤470 msec (females) and ECG findings considered 
normal or not clinically significant by the Investigator or designee at screening;

Estimated creatinine clearance ≥80 mL/min at screening.

LFT including ALT or AST ≤1.5 X the ULN at screening and check-in.
6. Able to swallow multiple tablets.
7. Understands the study procedures in the ICF, and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
Participants must not be enrolled in the study if they meet any of the following criteria prior to 
the first dosing:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History or presence of gastritis, GI tract, gastric bypass surgery, or hepatic disorder or other 
clinical condition which, in the opinion of the Investigator or designee, may affect the 
absorption, distribution, metabolism, or elimination of study drug.
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4. History or presence of any of the following, deemed clinically significant by the Investigator
or designee:

GI disorder (eg peptic ulcer disease, gastroesophageal reflux disease, impaction, chronic 
constipation, inflammatory bowel disease, ischemic colitis, vascular intestinal 
atherosclerosis, previous bowel resection, bowel obstruction, bariatric surgery, 
cholecystitis, intestinal ulceration or inflammation);

GI bleeding or perforation;

Recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or 
bleeding).
5. History or presence of cataracts. 
6. History or presence of other clinically significant vision disturbances as judged by the 
Investigator or designee.
7. History or presence of epilepsy, seizure, or convulsion, tremor or related symptoms that are 
deemed clinically significant by the Investigator or designee.
8. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the participant by their participation in the 
study.
9. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
dosing.
10. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related 
compounds.
11. Any positive responses on the C-SSRS that in the clinical judgement of the Investigator has a 
risk of suicide or has made a suicide attempt in the previous 12 months prior to the first 
dosing.
12. Female participant of childbearing potential.
13. Female participant with a positive pregnancy test at screening or check-in or who is lactating.
14. Positive urine drug or alcohol results at screening or check-in.
15. Positive results at screening for HIV, HBsAg or HCV.
16. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications, herbal remedies, or 
vitamin supplements within 14 days prior to the first dosing. Thyroid hormone 
replacement medication may be permitted if the participant has been on the same stable 
dose for the immediate 3 months prior to the first dosing.

Any drugs known to be significant inducers of CYP3A, CYP2C19, UGT1A9 or UGT2B4 
enzymes and/or P-gp, including St. John’s Wort, within 28 days prior to the first dosing. 
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Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack of 
PK/pharmacodynamics interaction with study drug.
17. History of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is 
approximately equivalent to the following: beer [354 mL/12 oz], wine [118 mL/4 oz], or 
distilled spirits [29.5 mL/1 oz] per day).
18. Consumes excessive amounts, defined as greater than 4 servings (1 serving is approximately 
equivalent to 120 mg of caffeine), of coffee, tea, cola, energy drinks, or other caffeinated 
beverages per day.
19. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to the first dosing and throughout the study.
20. Donation of blood or significant blood loss within 56 days prior to the first dosing.
21. Plasma donation within 7 days prior to the first dosing.
22. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. 
The 30-day window or 5 half-lives will be derived from the date of the last blood collection 
or dosing, whichever is later, in the previous study to Day 1 of Period 1 of the current study. 
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2 and 
throughout the study, including the follow-up period. After the first dose, ibuprofen (up to 1.2 g 
per 24 hour period) may be administered at the discretion of the Investigator or designee. 
Thyroid hormone replacement medication may be permitted if the participant has been on the 
same stable dose for the immediate 3 months prior to the first dosing.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the participant may continue participation in the study.
All medications taken by participants during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing (Days -
28 to predose [Day 1])
After First Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from first dosing until 
the end of PK collection
Xanthine and/or caffeine
Prohibited from 72 hours prior to first dosing a
Prohibited from first dosing until 
the end of PK collection a
Medications 
See Sections 7.1 and 7.2
See Sections 7.1 and 7.2
Nicotine- and tobacco-
containing and/or cannabis 
products
Prohibited from 90 days prior to first dosing
Prohibited from first dosing until 
the follow-up visit
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited from first dosing until 
the end of PK collection.
Other Fruit Juice
Prohibited from 12 hours prior to first dosing
Prohibited from first dosing until 
end of PK collection.
Vegetables from the 
mustard green family 
(eg, kale, broccoli, 
watercress, collard greens, 
kohlrabi, Brussels sprouts, 
mustard), and charbroiled 
meats
Prohibited from 7 days prior to first dosing
Prohibited from first dosing until 
end of PK collection.
a small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour after 
each dosing, but will be allowed ad libitum at all other times, when dosing occurs at the CRU. 
Other fluids may be given as part of meals and snacks but will be restricted at all other times 
throughout the confinement period.
Part A: 
On Day 1 of each period, participants will fast overnight for at least 10 hours prior to dosing and 
will continue the fast for at least 4 hours postdose. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from all 
food and drink except water between meals and snacks.
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Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each period.
Part B: 
On Day 1 of Treatment D, participants will fast overnight for at least 10 hours prior to Day 1 
dosing and will continue the fast for at least 4 hours postdose. 
On Day 1 of Treatment E, participants will be required to fast overnight for at least 10 hours 
until 30 minutes prior to their scheduled morning dose, when they will be given a high-fat 
breakfast which will be entirely consumed within 30 minutes. An example of high-fat breakfast 
would be 2 slices of buttered toast, 2 eggs fried in butter, 2 strips of bacon, 4 oz of hash brown 
potatoes, and 240 mL of whole milk [2]. Participants will fast for at least 4 hours postdose.
On Day 1 of Treatment F, participants will fast overnight for at least 10 hours prior to dosing, 
where a single-dose of soticlestat will be administered orally after being crushed and mixed with 
6 teaspoons or 30 mL of applesauce. Participants will fast for at least 4 hours postdose.
The instructions for crushing soticlestat tablets: 

Three 100 mg tablets will be crushed and mixed with 6 teaspoons or 30 mL of applesauce. 

After crushing, it should be dosed within 2 hours after mixing. Storage is allowed under 
room light conditions, without strict shading.

The crushing operation should be done as described in the instruction manual. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from all 
food and drink except water between meals and snacks.
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition (except for the meal served as part of Treatment E and the applesauce 
Treatment F) and will be taken at approximately the same time in each period.
7.4.2
Activity
Participants will remain seated for the first 4 hours postdose, except when they are supine or 
semi-reclined for study procedures. Participants will then resume normal activity.
However, should AEs occur at any time, participants may be placed in an appropriate position or 
will be permitted to lie down on their right side. During the first 4 hours post soticlestat dose, 
participants may be allowed to rise for brief periods under supervision (eg, in order to use the 
toilet facilities).
Participants will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of 
the study. 
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7.5
Criteria for Discontinuation or Withdrawal of a Participant
The primary reason for discontinuation or withdrawal of the participant from the study or study 
drug should be recorded in the case report form (CRF) using the following categories.
1. Pretreatment event (PTE) or AE: The participant has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk 
to the participant’s health or the participant is unwilling to continue because of the PTE 
or AE. 
LFT Abnormalities:
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a participant’s laboratory profile has returned to 
normal/baseline status, see Section 9.2.7, if the following circumstances occur at any time 
during study drug treatment:

ALT or AST >8 x ULN, or

ALT or AST >5 x ULN and persists for more than 2 weeks, or 

ALT or AST >3 x ULN in conjunction with elevated total bilirubin >2 x ULN or 
international normalization ratio (INR) >1.5, or 

ALT or AST >3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
QTcF interval: 
Study drug should be discontinued immediately with appropriate clinical follow-up if a 
QTcF interval >500 msec or if there is an increase of QTcF >60 msec above baseline 
detected by ECG and confirmed with a repeat ECG. Appropriate clinical follow-up 
includes a repeat ECG. 
2. Significant protocol deviation: The discovery post-enrollment that the participants failed 
to meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the participant’s health.
3. Lost to follow-up: Attempt to contact the participants were unsuccessful. Attempts to 
contact the participants must be documented in the participant’s source documents. 
4. Voluntary withdrawal: The participants (or participant’s legally acceptable 
representative) wishes to withdraw from the study. The reason for withdrawal, if 
provided, should be recorded in the CRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal 
due to an AE should not be recorded in the “voluntary withdrawal” category). If a 
participant chooses to withdraw from study participation due to personal concerns related 
to the coronavirus disease 2019 (COVID-19) pandemic (other than a COVID-19-related 
AE), this should be specified as the reason for participant withdrawal in the CRF.
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5. Study termination: The Sponsor, IRB/IEC, or regulatory agency terminates the study. 
6. Pregnancy: as described in Appendix D.
7. Participants may be withdrawn from the study by the Investigator or designee for the
following reasons: 

Difficulties in blood collection.

Positive urine drug or alcohol test.
8. Other: The specific reasons for discontinuation should be entered into the CRF including 
unavoidable circumstances such as the COVID-19 pandemic. Participants may be 
withdrawn from the study at any time at the discretion of the Investigator or Sponsor for 
safety reasons which should be entered into the CRFs.
7.6
Procedures for Discontinuation or Withdrawal of a Participant
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 7.5. In addition, a
participant may discontinue his or her participation without giving a reason at any time during 
the study. Should a participant’s participation be discontinued, the primary criterion for 
termination must be recorded by the Investigator. In addition, efforts should be made to perform 
all procedures scheduled for the end-of-study or early termination as described in Section 3.0.
7.7
Participant Replacement
Replacement of discontinued or withdrawn participants due to any reason will be assessed on a 
case by case basis by the Sponsor and Investigator to ensure a minimum of 66 and 
18PK-evaluable participants complete Part A and Part B of the study, respectively.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Investigational Medicinal Products:
Product Name:
Soticlestat (TAK-935)
Strength:
20 mg, 100 mg, and 300 mg
Dose:
300 mg
Dosage Form/Formulations:
20 mg T3 mini-tablet 
100 mg T4 tablet 
300 mg commercial tablet
Dosing Regimen:
Single-dose 
Route of Administration:
Oral
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8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of soticlestat to allow completion of this study. For 
Part A, sufficient quantities of soticlestat will also be included for the retention of testing 
samples as per FDA 21 CFR 320 and Guidance for Industry: Handling and Retention of BA and 
BE testing Samples [3].
The same lot number will be used throughout the study. The lot numbers and expiration dates 
(where available) of the study drugs supplied will be recorded in the final report. Study drugs 
will be stored according to the product labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study. 
8.1.4
Randomization Sequence
Part A and Part B are each based on a 3 x 6 x 3 Williams square crossover design.
The following randomization sequence (Table 8.a and Table 8.b) will be available to the CRU 
pharmacy staff that is preparing the study drugs.
Table 8.a
Randomization Sequence in Part A
Sequence
N
Period 1
Period 2
Period 3
1
12
B
A
C
2
12
A
C
B
3
12
C
B
A
4
12
B
C
A
5
12
A
B
C
6
12
C
A
B
N: number of participants
Treatment A: 3 x 100 mg T4 tablets, fasted (Reference)
Treatment B: 15 x 20 mg T3 mini-tablets, fasted (Test)
Treatment C: 1 x 300 mg commercial tablet, fasted (Test)
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Table 8.b
Randomization Sequence in Part B
Sequence
N
Period 1
Period 2
Period 3
1
4
E
D
F
2
4
D
F
E
3
4
F
E
D
4
4
E
F
D
5
4
D
E
F
6
4
F
D
E
N: number of participants
Treatment D: 3 x100 mg T4 tablets, fasted (Reference)
Treatment E: 3 x100 mg T4 tablets, fed (Test)
Treatment F: 3 x100 mg T4 tablets crushed and mixed with applesauce, fasted (Test)
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
Records will be made of the receipt and dispensing of the study drugs supplied. At the
conclusion of the study, any unused soticlestat will be retained by Celerion, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies remain, this fact 
will be documented in the pharmacy product accountability records.
9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the participants in non-technical terms. Participants will be required to read, sign, 
and date an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care.
Participants will be given a copy of their signed ICF
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each participant will be assigned a unique identification number upon screening. Participants 
who complete the study screening assessments and meet all the eligibility criteria will be 
assigned a unique randomization identification number at the time of the first dosing, different 
from the screening number and will receive the corresponding product, according to a 
randomization sequence. 
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If replacement participants are used, the replacement participant number will be 100 more than 
the original (eg, Participant No. 101 will replace Participant No. 1).
9.1.1.2
Study Drug Assignment
All participants will receive the treatments as detailed in Section 9.2.6. 
9.1.2
Inclusion and Exclusion 
Please refer to Section 7.1 and Section 7.2.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.2 and 7.3. All medications 
taken by participants during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to participant safety.
For this study, collection of blood for soticlestat 
 PK is the critical 
parameter and needs to be collected as close to the exact time point as possible. All other 
procedures should be completed as close to the prescribed/scheduled time as possible, but can be 
performed prior to or after the prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Physical Exam
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional evaluations/testing may be deemed necessary by the Investigator or 
designee and/or Sponsor for reasons related to participant safety.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study 
Procedures (Section 3.0).
9.2.3
BMI
BMI will be calculated based on the height and weight measured at screening.
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9.2.4
Vital Signs
Single measurements of temperature, respiratory rate, blood pressure and pulse rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Blood pressure and pulse rate measurements will be performed with participants in a supine 
position (5 minutes). 
Vital signs will be measured within 24 hours prior to Day 1 dosing of Period 1 for the predose 
time point. At all other predose time points, vital signs will be measured within 2 hours prior to 
dosing. When scheduled postdose, vital signs will be performed within approximately 
15 minutes of the scheduled time point. 
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
Investigator or designee.
ECGs will be performed with participants in a supine position. All ECG tracings will be 
reviewed by the Investigator or designee.
ECGs will be measured within 24 hours prior to Day 1 dosing of Period 1 for the predose time 
point. At all other predose time points, ECGs will be measured within 2 hours prior to dosing. 
When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point.
9.2.6
Study Drug Administration
Soticlestat formulation will be provided as described in Section 8.1.
Dose regimens for study drugs are described in Table 2.a, Table 2.b, Table 2.c, and Table 2.d.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
participant, as appropriate. 
Study drug will be administered with approximately 240 mL of water. Mini-tablets will be taken 
in multiple at one time. If the study drugs cannot all be swallowed at the same time, up to a 
maximum of 50 mL of additional water may be administered as required by the subject, 
however, dosing should be completed within approximately 3 minutes.
Additional information regarding drug preparation and administration may be provided in a 
separate document. 
Participants will be instructed not to crush, split, or chew the tablets except for Treatment F. 
Tablets in Treatment F will be administered crushed and mixed in applesauce.
The exact clock time of dosing will be recorded.
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A qualified designee will be responsible for monitoring the administration of the assigned doses. 
A mouth check will be performed by the qualified designee to ensure that the participants have 
swallowed the study drug(s). Once a participant has finished the dosing water, the qualified 
designee will use a flashlight and a tongue depressor to check the participant’s mouth. 
Participants’ hands will also be verified to ensure that the study drug(s) was ingested.
9.2.7
C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures for each study part (Section 3.0). Two versions of the C-SSRS will be used in 
this study: the Screening/Baseline C-SSRS Lifetime and the Since-Last-Visit C-SSRS. It is 
recommended that the same rater be used to administer the scale to the participant at all time
points when C-SSRS is scheduled. Any suicidal ideation or suicidal behavior during the trial 
periods detected by the C-SSRS will be recorded as an AE. The Investigator will ensure that any 
suicidal ideation or behavior is medically addressed, including assessment and treatment by 
qualified medical personnel.
9.2.8
AE Monitoring
Participants will be monitored throughout the study for adverse reactions to the study drugs 
and/or procedures as described in Section 10.0.
9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator or designee.
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9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Erythrocytes
Mean platelet volume
Total and differential leukocyte count
Immune cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Coagulation 
Coagulation test will be conducted as outlined in the Schedule of Study Procedures (Section 3.0). 
Coagulation test will consist of the following tests:
Activated partial thromboplastin time (aPPT)
Prothrombin time / INR
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, participants may not have fasted for 8 hours prior to when the serum 
chemistry sample is being taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Blood Urea Nitrogen
Albumin
Bilirubin (total, direct, and indirect)
Sodium
Alkaline phosphatase
Potassium
AST
Chloride
ALT
Glucose 
Calcium
Creatinine *
Carbon dioxide
Phosphate
Protein (total)
Alpha1-acidic glycoprotein (screening only)
Gamma-glutamyl transferase
Magnesium
Urea
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
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Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
Erythrocytes
Creatinine
Calcium
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
9.2.9.1.1
Other 
HIV test
Urine drug screen
Opiates (includes morphine, heroin (diacetylmorphine), 
codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, 
thebaine, and, hydromorphone)
Amphetamines 
Barbiturates
Benzodiazepines
Cocaine
Cannabinoids
Buprenorphine/metabolite
Methadone/metabolite
Oxycodone/oxymorphone
Phencyclidine
HBsAg
HCV (if antibody positive, confirm RNA negative)
Urine alcohol screen
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
COVID-19 (SARS-CoV-2 polymerase chain 
reaction test or equivalent)
9.3
Pharmacokinetic Samples
Samples for assessment of soticlestat 
, will be collected as delineated in 
Section 3.0.
Instructions for sample collection, processing, and shipping will be provided in separate 
documents. 
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation participant who 
has signed informed consent to participate in a study; it does not necessarily have to have a 
causal relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
whether or not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the Investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the Investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory re-
test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

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 only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
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related to a study procedure. However, if the participant experiences a worsening or 
complication of such a concurrent medical history condition, the worsening or complication 
should be recorded appropriately as an AE (worsening or complication occurs after informed 
consent is signed). Investigators should ensure that the event term recorded captures the 
change in the condition (eg, “worsening of…”).

If a participant has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of 
an episode should only be captured as an AE if the episodes become more frequent, serious, 
or severe in nature, that is, Investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a participant has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent 
to that which would be expected. Again, Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the participant experiences a worsening or complication of an AE after the first 
administration of study medication and after any change in study medication, the worsening 
or complication should be recorded as a new AE. Investigators should ensure that the AE 
term recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the participant experiences a change in the severity of an AE that is not associated with a 
change in study medication, the event should be captured once with the maximum severity 
recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as an AE. Complications resulting from 
any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the participant’s medical 
condition should not be recorded as AEs but should be documented in the participant’s 
source documents. Complications resulting from an elective surgery should be reported as 
AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study participant, at a dose above that which is assigned to that individual 
participant according to the study protocol. It is up to the Investigator or the reporting 
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physician to decide whether a dose is to be considered an overdose, in consultation with the 
Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the participant should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the 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.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
COVID-19 pneumonia
Neuroleptic malignant syndrome / malignant hyperthermia
COVID-19-related disease
Spontaneous abortion / stillbirth and fetal death
Abbreviations: COVID-19 = Coronavirus disease-2019.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
Special Interest AEs
There are no AEs of Special Interest for this study.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
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10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant medications 
and concurrent treatments.
In addition, relationship (causality) to COVID-19 should be determined for all PTEs and AEs. 
The relationship should be assessed as related if the Investigator considers that there is 
reasonable possibility that an event is due to COVID-19. Otherwise, the relationship should be 
assessed as not related.
Similarly, relationship (causality) to COVID-19 vaccines should be determined for all PTEs and 
AEs. The relationship should be assessed as related if the Investigator considers that there is 
reasonable possibility that an event is due to COVID-19 vaccines. Otherwise, the relationship 
should be assessed as not related. If the AE has relationship to vaccination, specific verbatim 
term should be used, eg, post-vaccination fever, vaccination site burning.
In addition, if the causality assessment done by the Investigator determines that the event or 
events (PTEs or AEs) are related or possible related to COVID-19 or the COVID-19 vaccine, the 
events should be assessed as not related to the investigational product. If the AE is related to 
COVID-19 vaccination, specific verbatim term(s) should be used, eg, post-vaccination fever, 
vaccination site burning.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the participant 
and/or Investigator.
10.2.4
End Date 
The end date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae or the participant died.
10.2.5
Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days 
are intermittent. 
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10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been 
taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the participant died, dosing with study medication had not 
yet started or dosing with study medication was already stopped before the onset of the AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7
Outcome 

Recovered/resolved – participant returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the participant died from a cause 
other than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; 
the participant died from another cause with the particular AE state remaining “Not 
recovered/not resolved.”

Recovered/ Resolved with sequelae – the participant recovered from an acute AE but was left 
with permanent/significant impairment (eg, recovered from a cardiovascular accident but 
with some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the participant’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the participant signs the informed consent. Routine collection of AEs will continue until 
the follow-up phone call 14 (± 3) days after the last dose of soticlestat. For participants who 
discontinue prior to the administration of study medication, AEs will be followed until the 
participant discontinues study participation. 
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10.2.8.2
Reporting AEs
At each study visit, the Investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Participants may report AEs occurring at any other time during the study. Participants 
experiencing an SAE prior to the first exposure to investigational product must be monitored 
until the symptoms subside and any clinically relevant changes in laboratory values have 
returned to Baseline or there is a satisfactory explanation for the change. Nonserious AEs that 
begin prior to the first exposure to investigational product, related or unrelated to the study 
procedure, need not be followed-up for the purposes of the protocol.
All participants experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All AEs will be documented in the AE page of the CRF, whether or 
not the Investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Relationship to COVID-19.

Relationship to COVID-19 vaccine.

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the Investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Participant identification number.
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
Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the Investigator following the AE collection period should 
be reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
Investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Reporting Special Interest AEs 
There are no AEs of Special Interest for soticlestat.
10.2.8.5
Reporting of Abnormal LFTs
If a participant is noted to have ALT or AST elevated >3 × ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
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, the event should be recorded as an SAE and 
reported as per Section 10.2.8.3. The Investigator must contact the Medical Monitor for 
discussion of the relevant participant details and possible alternative etiologies, such as acute 
viral hepatitis A or B or other acute liver disease. Follow-up laboratory tests as described in 
Section 9.2.9 must also be performed. In addition, an LFT Increases CRF must be completed and 
transmitted with the Takeda SAE form (as per Section 10.2.9). 
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, Investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
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For COVID-19-related protocol deviations, the specific protocol deviation, the reason for the 
deviation, and the relationship to COVID-19 should be documented using CRU standard 
processes.
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. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In 
this circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the Sponsor should 
be notified immediately. The Investigator guarantees access for quality assurance auditors to all 
study documents as described in Section 12.1.
13.0
ETHICAL ASPECTS OF THE STUDY
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 on Harmonisation (ICH) Harmonised 
Tripartite Guideline for GCP. Each Investigator will conduct the study according to applicable 
local or regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki 
are addressed through the protocol and through appendices containing requirements for informed 
consent and Investigator responsibilities.
13.1
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 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 Investigator’s Brochure, a copy of 
the ICF, and, if applicable, participant recruitment materials and/or advertisements and other 
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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 (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). 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. The Sponsor will ship drug/notify site once the Sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the Sponsor has received 
permission from competent authority to begin the study. Until the site receives drug/notification 
no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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 IRB or 
IEC, and submission of the Investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the Sponsor or its 
designee.
Participant incentives should not exert undue influence for participation. Payments to 
participants must be approved by the IRB or IEC and Sponsor.
13.2
Participant Information, Informed Consent, and Participant Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, participant authorization form (if applicable), and 
participant information sheet (if applicable) describe the planned and permitted uses, transfers, 
and disclosures of the participant’s personal and personal health information for purposes of 
conducting the study. The ICF and the participant information sheet (if applicable) further 
explain the nature of the study, its objectives, and potential risks and benefits, as well as the date 
informed consent is given. The ICF will detail the requirements of the participant and the fact 
that he or she is free to withdraw at any time without giving a reason and without prejudice to his 
or her further medical care.
The Investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the participant authorization form. The ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) must be 
approved by both the IRB or IEC and the Sponsor prior to use.
The ICF, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective participant. It 
is the responsibility of the Investigator to explain the detailed elements of the ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) to the 
participant. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB or IEC. In the event the participant is not capable of 
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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.
The participant, or the participant’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the study, and (2) decide whether or not to participate 
in the study. If the participant, or the participant’s legally acceptable representative, determines 
he or she will participate in the study, then the informed consent form and participant 
authorization form (if applicable) must be signed and dated by the participant, or the 
participant’s legally acceptable representative, at the time of consent and prior to the participant 
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 blue or black ballpoint 
ink. The Investigator must also sign and date the informed consent form and participant 
authorization (if applicable) at the time of consent and prior to participant entering into the study; 
however, the Sponsor may allow a designee of the Investigator to sign to the extent permitted by 
applicable law.
Once signed, the original informed consent form, participant authorization form (if applicable), 
and participant information sheet (if applicable) will be stored in the Investigator’s site file. The 
Investigator must document the date the participant signs the informed consent in the 
participant’s medical record. Copies of the signed informed consent form, the signed participant 
authorization form (if applicable), and participant information sheet (if applicable) shall be given 
to the participant.
All revised informed consent forms must be reviewed and signed by relevant participants or the 
relevant participant’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
participant’s medical record, and the participant should receive a copy of the revised informed 
consent form.
13.3
Participant Confidentiality
The Sponsor and designees affirm and uphold the principle of the participant’s right to protection 
against invasion of privacy. Throughout this study, a participant’s source data will only be linked 
to the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited participant attributes, such as sex, age, 
or date of birth, and participant initials may be used to verify the participant and accuracy of the 
participant’s unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the participant’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a participant’s study 
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participation, and autopsy reports. Access to a participant’s original medical records requires the 
specific authorization of the participant as part of the informed consent process (see 
Section 13.2).
Copies of any participant source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, participant name, address, and other identifier 
fields not collected on the participant’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and 
information generated by the Investigator) without the consent of the Investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail.
13.4.2
Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with Investigator’s city, state (for America’s Investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting trial 
information. Once participants receive Investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established participant screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide 
the Sponsor with a written notice requesting that their information not be listed on the registry 
site.
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13.4.3
Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
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.
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Email: PVSafetyAmericas@tpna.com
Fax: 224-554-1052
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14.1.2
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the Sponsor. I agree to conduct 
this study in accordance with the requirements of this protocol and also to protect the rights, 
safety, privacy, and well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation, E6 [R2] Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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15.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the 
Investigator. The final signed CRFs are provided to the Sponsor in the format as decided upon 
between Celerion and the Sponsor (eg, electronically, CD, flashdrive, SFTP). This will be 
documented in the Data Management Plan (if applicable).
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. 
Corrections 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 additionally be included. 
The principal Investigator must review the CRFs for completeness and accuracy and must sign 
and date the appropriate CRFs as indicated. Furthermore, the Investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the CRFs should be made by the Investigator with use of change and modification 
records of the CRFs. The principal Investigator must review the data change for completeness 
and accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the participant’s 
medical and hospital records pertinent to the study to ensure accuracy of the CRFs. The 
completed CRFs 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.
15.2
Record Retention
The Investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, medical records, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated informed consent forms, participant 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of CRFs, including the audit trail, and detailed records 
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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 Section 4.9.5 requires the Investigator to retain essential
documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the Clinical Study Site Agreement between the Investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The Investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
16.0
REFERENCES
1. TAK-935. Takeda Pharmaceutical Company Ltd. Global Investigator’s Brochure. 
Addendum 1, 03 February 2022, for Edition 7, 31 January 2022.
2. Food and Drug Administration: Center for Drug Evaluation and Research (CDER). Guidance 
for Industry: Assessing the Effects of Food on Drugs in INDs and NDAs — Clinical 
Pharmacology Considerations (Draft Feb 2019). Available at: 
https://www.fda.gov/media/121313/download
3. Food and Drug Administration. Guidance for Industry: Handling and Retention of 
Bioavailability BA and Bioequivalence BE Testing Samples (May 2004). Available at: 
https://www.fda.gov/media/71393/download.
4. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance 
for Industry: Bioanalytical Method Validation (May 2018). Available at: 
https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-
Industry.pdf
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are participant to ICH GCP and all the 
applicable local laws and regulations. The responsibilities imposed on Investigators by the FDA 
are summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed 
and signed before the Investigator may participate in this study.
The Investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the Investigator/institution retains the services of any individual or party to perform trial-
related duties and functions, the Investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential participants, prior to the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 Code of Federal Regulation (CFR) Part 56, ICH, and local regulatory requirements.
7. 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.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each participant who participates in the study, and 
document the date of consent in the participant’s medical chart. Valid informed consent is the 
most current version approved by the IRB/IEC. Each informed consent form 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 informed consent form 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.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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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.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Participant Informed Consent
In seeking informed consent, the following information shall be provided to each participant:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the participant’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of participants involved in the study.
7. A description of the participant’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the participant may receive.
11. A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant.
12. 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.
13. 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.
14. 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 a written informed 
consent form, the participant or the participant’s legally acceptable representative is 
authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the participant for participating in the study.
17. The anticipated expenses, if any, to the participant for participating in the study.
18. 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.
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19. 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, and 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.
20. The consequences of a participant’s decision to withdraw from the research and procedures 
for orderly termination of participation by the participant.
21. 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.
22. The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.
23. A written participant authorization (either contained within the informed consent form or 
provided as a separate document) describing to the participant the contemplated and 
permissible uses and 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:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
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;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) 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
e) that the participant’s identity will remain confidential in the event that study results are 
published.
24. Regular pregnancy tests will be performed throughout the study for all female participants. 
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25. Male participants are not required to use barrier contraception (as defined in the informed 
consent) from signing the informed consent throughout the duration of the study and for 
90 days after the last dose of study drug. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of Investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting Investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Participants 
Male subjects who participate in the study are not required to use barrier contraception. 
Separately, donation of sperm is not allowed during the study and within 90 days following the 
last administration of the study drug.
Female Participants and Their Male Partners
Only women of non-childbearing potential will be included in this study. A female of 
non-childbearing potential, must have undergone one of the following sterilization procedures at 
least 6 months prior to the first dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and FSH serum 
levels consistent with postmenopausal status*. Definitions and Procedures for Contraception 
and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a post-menopausal state in 
younger women (eg, those <45 year old) or women who are not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Assessment of participant compliance through questions such as:

Have you used the contraception consistently and correctly since the last visit?

Have you forgotten to use contraception since the last visit? 
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Pregnancy
If any participant is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male participant during the study or for 90 days after the last dose, should also be 
recorded following authorization from the participant’s partner. 
If the female participant and/or female partner of a male participant agrees to the primary care 
physician being informed, the Investigator should notify the primary care physician that the 
female participant/female partner of the male participant was participating in a clinical study at 
the time she became pregnant and provide details of the study drug the participant received 
(blinded or unblinded, as applicable).
All pregnancies, including female partners of male participants, in participants on active study 
drug (including comparator, if applicable) 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.
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Appendix E
Summary of Changes from Previous Version
A summary of changes incorporated into Amendment 1 is provided in the table below. 
Summary of Changes Since Last Version of Approved Protocol
Description of Change
Sections Affected by Change
The protocol is amended to add C-SSRS 
safety evaluations as requested by the 
Advarra Institutional Review Board 
(IRB) based on the communication dated
01 March 2022.
The protocol is updated to include 
assessment of C-SSRS at screening, 
check-in (Day -1), and at the 
end-of-study or at the time of early 
termination.
Section 1.0 (Study Summary).
Section 3.0 (Schedule of Study Procedures).
Section 4.3 (Benefit/Risk Profile).
Section 6.1 (Study Design).
Section 6.4.3.2 (Safety Endpoints).
Section 7.2 (Exclusion Criteria), exclusion 
criterion #11 is added.
Section 9.2.7 (C-SSRS).
Section 11.1.5.4 (Other Safety Parameters).
Section 14.1.4 (List of Abbreviations).
Details were added for the pooling of 
plasma samples to harmonize with the 
2018 bioanalytical method validation 
guidance.
Section 9.3.1 (Pharmacokinetic Measurements).
The protocol is updated to only conduct 
Day -1 procedures in Period 1, and to 
remove the following Day 4 procedures:
physical examination, weight, and safety 
laboratories (hematology, serum 
chemistry, coagulation, and urinalysis).
Section 3.0 (Schedule of Study Procedures).
The protocol is updated to clarify that 
study drug should be discontinued 
immediately with appropriate clinical 
follow-up if there is an increase of 
QTcF >60 msec above baseline.
Section 7.5 (Criteria for Discontinuation or 
Withdrawal of a Participant)
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Summary of Changes Since Last Version of Approved Protocol
Description of Change
Sections Affected by Change
The protocol is updated to correct
formatting and typos/grammatical errors.
Section 1.0 (Study Summary).
Section 2 (Study Schematic).
Section 3.0 (Schedule of Study Procedures).
Section 4.3 (Benefit/Risk Profile).
Section 6.6.3 (Definition of Study Completion).
Section 6.4.4 (Future Biomedical Research).
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SAP_001.pdf: 
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REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Original version
21-Mar-2022
[Not Applicable]
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TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................8
1.1
Objectives..................................................................................................................8
1.1.1
Primary Objectives ............................................................................................8
1.1.2
Secondary Objective..........................................................................................8
1.1.3
Exploratory Objectives ......................................................................................8
1.2
Endpoints...................................................................................................................8
1.2.1
Primary Endpoints .............................................................................................8
1.2.2
Secondary Endpoint...........................................................................................9
1.2.3
Exploratory Endpoints .......................................................................................9
1.2.4
Additional Endpoints.........................................................................................9
1.3
Estimand(s)..............................................................................................................10
2.0
STUDY DESIGN..........................................................................................................10
3.0
STATISTICAL HYPOTHESES AND DECISION RULES...........................................14
3.1
Statistical Hypotheses..............................................................................................14
3.2
Statistical Decision Rules.........................................................................................15
3.3
Multiplicity Adjustment...........................................................................................15
4.0
SAMPLE-SIZE DETERMINATION.............................................................................15
5.0
ANALYSIS SETS.........................................................................................................16
5.1
Pharmacokinetic Set ................................................................................................16
5.2
Safety Set ................................................................................................................16
6.0
STATISTICAL ANALYSIS..........................................................................................16
6.1
General Considerations............................................................................................16
6.1.1
Handling of Treatment Misallocations .............................................................18
6.2
Study Information....................................................................................................18
6.3
Disposition of Participants .......................................................................................18
6.4
Demographic and Other Baseline Characteristics.....................................................18
6.4.1
Demographics..................................................................................................18
6.4.2
Medical History and Concurrent Medical Conditions.......................................19
6.5
Medication History and Concomitant Medications...................................................19
6.6
Efficacy Analysis.....................................................................................................19
6.7
Safety Analysis........................................................................................................19
6.7.1
Adverse Events................................................................................................20
6.7.2
Adverse Events of Special Interest (if applicable) ............................................21
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6.7.3
Clinical Laboratory Evaluation ........................................................................21
6.7.4
Vital Signs.......................................................................................................21
6.7.5
12-Lead Electrocardiogram..............................................................................22
6.7.6
Physical Examination ......................................................................................22
6.7.7
Columbia-Suicide Severity Rating Scale (C-SSRS) .........................................22
6.7.8
Overdose .........................................................................................................22
6.7.9
Extent of Exposure and Compliance ................................................................22
6.8
Pharmacokinetic Analysis........................................................................................23
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................25
6.10
Preliminary Analyses...............................................................................................25
6.11
Interim Analyses......................................................................................................25
6.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] ............................................................................................................25
7.0
REFERENCES..............................................................................................................25
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................25
9.0
APPENDIX...................................................................................................................26
9.1
Changes From the Previous Version of the SAP.......................................................26
9.2
Analysis Software....................................................................................................26
LIST OF IN-TEXT TABLES
Table 2.a
Study Design for Part A .....................................................................................11
Table 2.b
Study Treatments for Part A...............................................................................11
Table 2.c
Randomization Sequence in Part A ....................................................................12
Table 2.d
Study Design for Part B .....................................................................................13
Table 2.e
Study Treatments for Part B...............................................................................13
Table 2.f
Randomization Sequence in Part B.....................................................................14
Table 6.a
Collection of Blood Samples for Pharmacokinetic Analysis in Part A ................23
Table 6.b
Collection of Blood Samples for Pharmacokinetic Analysis in Part B.................23
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
Apparent clearance after extravascular administration, calculated using the predicted value of 
the last quantifiable concentration (CL/F_pred) for soticlestat only.

Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the predicted value of the last quantifiable concentration 
(Vz/F_pred) for soticlestat only.
.
1.3
Estimand(s)
Not applicable. 
2.0
STUDY DESIGN
This is a 2-part, open-label study conducted in healthy adult participants. Part A will evaluate 
the BE of 3 different soticlestat oral tablet formulations. Part B will evaluate the effect of food 
and tablet crushing on soticlestat PK. 
Each part will be conducted independently as a randomized, 3-period, crossover design. Study 
schematics of the study design are shown in Table 2.a, Table 2.b, Table 2.d, and Table 2.e. The 
two study parts may be conducted concurrently. Participants can only participate in one study 
part.
Note: One (1) study site will be used (Celerion, Phoenix, Arizona), but an additional site 
(Celerion, Lincoln, Nebraska) may be engaged to aid in recruiting, if needed. 
Part A:
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first 
dosing on Day 1 of Period 1). Upon completion of screening, qualified participants will be 
admitted to the study site Day -1 of Period 1 and will remain confined until completion of study 
procedures on Day 5 of Period 3. Participants may be admitted earlier than Day -1 for 
coronavirus disease 2019 (COVID-19) testing not related to study protocol, as per clinical 
research unit (CRU) requirements.
In each period, on Day 1, participants will receive a single oral dose of 300 mg soticlestat
administered as T4 tablets (Treatment A), T3 mini-tablets (Treatment B), or commercial tablets 
(Treatment C), in a 3-way crossover fashion. Blood samples for the PK of soticlestat 
 
 will be collected at schedules time points from predose through 96 hours postdose. 
There will be a washout period of exactly 4 days between each soticlestat doses.
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory 
evaluations, physical examinations, Columbia-Suicide Severity Rating Scale (C-SSRS), 12-lead 
ECGs, and vital signs.
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 14 (±3) days after the last soticlestat administration by telephone or other methods 
per CRU standards to determine if any adverse events (AEs) have occurred and/or any 
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concomitant medications were taken since the last study visit. If clinically significant findings are 
observed upon discharge, participants may return to the CRU for re-evaluation per 
Investigator’s discretion.
The study schematic for Part A is presented in the Table 2.a: 
Table 2.a
Study Design for Part A
S
Period 1
Period 2
Period 3
Follow-up
C-I and 
Predose 
Assessment
Soticlestat 
Dosing, PK 
Sampling, 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling, 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Study Exit a
(PK 
Sampling 
and Study 
Assessments)
Within 
28 days 
prior to 
first 
dosing
Day -1
Day 1
Day 2 – 5 b
Day 1 b
Day 2 – 5 b
Day 1 b
Day 2 – 4
Day 5
14 (±3) 
days 
following 
last 
soticlestat 
dose
--------------------------------- Confinement c---------------------------------
a Study Exit is defined as the end of last treatment period.
b Day 5 of Period 1 and Period 2 will also be considered Day 1 of Period 2 and Period 3, respectively. Procedures scheduled 
on both days will only be performed once.
c Participants will start the confinement on Day -1 of Period 1 and will remain confined until Day 5 of Period 3. Participants 
may be admitted earlier than Day 1 for COVID-19 testing not related to study protocol, as per CRU requirements.
Abbreviations: C-I = Check-in, PK = Pharmacokinetics, S = Screening
The study treatments for Part A are presented in Table 2.b: 
Table 2.b
Study Treatments for Part A
Treatments
Study Drug
Dose
Dose 
Regimen
Number of Days on Study 
Drug
Treatment A 
(Reference)
Soticlestat T4 tablets
300 mg (3 x 100 mg 
strength)
Single 
dose, oral, 
fast
Day 1 of each period
Treatment B 
(Test)
Soticlestat T3 mini-tablets
300 mg (15 x 20 mg 
strength)
Single 
dose, oral, 
fast
Day 1 of each period
Treatment C 
(Test)
Soticlestat 
commercial tablets
300 mg (1 x 300 mg 
strength)
Single 
dose, oral, 
fast
Day 1 of each period
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The randomization sequences for Part A is presented in Table 2.c: 
Table 2.c
Randomization Sequence in Part A
Sequence
N
Period 1
Period 2
Period 3
1
12
B
A
C
2
12
A
C
B
3
12
C
B
A
4
12
B
C
A
5
12
A
B
C
6
12
C
A
B
N: number of participants
Treatment A: 3 x 100 mg T4 tablets, fasted (Reference)
Treatment B: 15 x 20 mg T3 mini-tablets, fasted (Test)
Treatment C: 1 x 300 mg commercial tablet, fasted (Test)
Part B: 
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first 
dosing on Day 1 of Period 1). Upon completion of screening, qualified participants will be 
admitted to the study site Day -1 of Period 1 and will remain confined until completion of study 
procedures on Day 5 of Period 3. Participants may be admitted earlier than Day -1 for 
COVID-19 testing not related to study protocol, as per CRU requirements.
In each period, on Day 1, participants will receive a single oral dose of 300 mg soticlestat 
administered as intact T4 tablets under fasting conditions (Treatment D), intact T4 tablets under 
fed condition (Treatment E), or as crushed T4 tablets mixed with applesauce under fasting 
conditions (Treatment F), in a 3-way crossover fashion. Blood samples for the PK of soticlestat 
 will be collected at schedules time points from predose through 96 hours 
postdose. There will be a washout period of exactly 4 days between each soticlestat doses. 
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory 
evaluations, physical examinations, C-SSRS, 12-lead ECG, and vital signs.
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 14 (±3) days after the last soticlestat administration by telephone or other methods 
per CRU standards to determine if any AEs have occurred and/or any concomitant medications 
were taken since the last study visit. If clinically significant findings are observed upon 
discharge, participants may return to the CRU for re-evaluation per Investigator’s discretion.
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The study schematic for Part B is presented in Table 2.d: 
Table 2.d
Study Design for Part B
S
Period 1
Period 2
Period 3
Follow-up
C-I and 
Predose 
Assessment
Soticlestat 
Dosing, PK 
Sampling 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Soticlestat 
Dosing, PK 
Sampling 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Study Exit a
(PK 
Sampling 
and Study 
Assessments)
Within 
28 days 
prior to 
first 
dosing
Day -1
Day 1
Day 2 – 5 b
Day 1 b
Day 2 – 5 b
Day 1 b
Day 2 – 4
Day 5
14 (±3) 
days 
following 
last 
soticlestat 
dose
--------------------------------- Confinement c---------------------------------
a
Study Exit is defined as the end of last treatment period.
b
Day 5 of Period 1 and Period 2 will also be considered Day 1 of Period 2 and Period 3, respectively. Procedures 
scheduled on both days will only be performed once.
c
Participants will start the confinement on Day -1 of Period 1 and will remain confined until Day 5 of Period 3. 
Participants may be admitted earlier than Day -1 for COVID-19 testing not related to study protocol, as per CRU 
requirements.
Abbreviations: C-I = Check-in, PK = Pharmacokinetics, S = Screening
The study treatments for Part B are presented in Table 2.e: 
Table 2.e
Study Treatments for Part B
Treatments
Study Drug
Dose
Dose Regimen
Number of Days on 
Study Drug
Treatment D 
(Reference)
Soticlestat T4 tablets
300 mg 
(3 x 100 mg 
strength)
Single dose, oral, fast
Day 1 of each period
Treatment E 
(Test)
Soticlestat T4 tablets
300 mg 
(3 x 100 mg 
strength)
Single dose, oral, fed
Day 1 of each period
Treatment F 
(Test)
Soticlestat T4 tablets
300 mg 
(3 x 100 mg 
strength)
Single dose, oral, crushed 
and mixed with applesauce, 
fast
Day 1 of each period
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The randomization sequences for Part B is presented in Table 2.f: 
Table 2.f
Randomization Sequence in Part B
Sequence
N
Period 1
Period 2
Period 3
1
4
E
D
F
2
4
D
F
E
3
4
F
E
D
4
4
E
F
D
5
4
D
E
F
6
4
F
D
E
N: number of participants
Treatment D: 3 x100 mg T4 tablets, fasted (Reference)
Treatment E: 3 x100 mg T4 tablets, fed (Test)
Treatment F: 3 x100 mg T4 tablets crushed and mixed with applesauce, fasted (Test)
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
In Part A, for T3 mini-tablets (Treatment B) and commercial tablets (Treatment C), BE to 
reference formulation T4 tablets (Treatment A) will be for the AUC∞, AUClast, and Cmax and is 
claimed if the 90% CI for the geometric mean ratios (GMRs) for all of these parameters are each 
within 80.00% and 125.00% for soticlestat. Serial gatekeeping will be used to control overall 
type 1 error (alpha = 0.05) such that BE will be tested first between commercial tablets 
(Treatment C) and reference formulation T4 tablets (Treatment A), then followed with T3 
mini-tablets (Treatment B) and reference formulation T4 tablets (Treatment A). In other words, if 
the 90% CI for AUC∞, AUClast, or Cmax GMR for soticlestat between commercial tablets 
(Treatment C) and reference formulation T4 tablets (Treatment A) does not fall within 80.00% 
and 125.00%, BE cannot be claimed for T3 mini-tablets (Treatment B) and reference 
formulation T4 tablets (Treatment A) even if the 90% CI for GMR between B and A falls within 
80.00% and 125.00%.
The hypotheses to be tested to demonstrate BE between test (T) and reference (R) formulations 
for a given PK parameter are:
Null hypothesis:  − < ln (0.8) or  − > ln (1.25)
Alternative hypothesis:  − ≥ln (0.8) and  − ≤ln (1.25)
where  and  are the population means of the natural log (ln)-transformed parameter for the 
test formulation, T, and reference formulation, R, respectively. These hypotheses will be tested 
for the parameters AUC∞, AUClast, and Cmax for the test formulation commercial tablets 
(Treatment C) vs the reference formulation T4 tablets (Treatment A). If the null hypotheses are 
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Continuous demographic and safety data will be summarized descriptively by study part and 
time point, as applicable. For the categorical variables, the count and percentages of each 
possible value will be tabulated, where applicable. The denominator for the percent calculation 
will be the number of non-missing observations in the safety set by study part. Counts will be 
presented as integers. Percentages will be presented to one decimal. For continuous variables, n, 
mean, SD, minimum, median, and maximum values will be tabulated. The level of precision will 
be presented as follows: minimum/maximum in the same precision as in the database, 
mean/median in one more precision level than minimum/maximum, SD in one more precision 
level than mean/median, and n will be presented as an integer.
Baseline, unless specified otherwise, is defined as the last observation prior to dosing in each 
period.
6.1.1
Handling of Treatment Misallocations
Participants who are misallocated treatments will be analyzed per the treatment they received 
rather than per the treatment regimen to which they were randomized.
6.2
Study Information
An overall study information table will be generated including the following items: date of first 
participant’s signed informed consent form (ICF), date of first dose of study drug, date of last 
dose of study drug, date of last participant’s last visit/contact, date of last participant’s last 
procedure for collection of data for primary endpoint, the version of Medical Dictionary for 
Regulatory Activities (MedDRA®), the version of World Health Organization (WHO) 
Dictionary, and SAS version used for creating the datasets. Study drug refers to soticlestat.
6.3
Disposition of Participants
For each study part, disposition of participants (number of participants dosed, completed the 
study, discontinued from the study and/or study drug, and reason(s) for discontinuation(s)) will 
be summarized for each group by randomized treatment sequence and overall. Study completion 
status, including reason for discontinuation, will also be listed by participant.
6.4
Demographic and Other Baseline Characteristics
6.4.1
Demographics
Demographic and baseline characteristics will be summarized descriptively for each part by 
randomized treatment sequence and overall based on the safety set. Summary statistics (n, mean, 
SD, minimum, median, and maximum) will be generated for continuous variables (age, weight, 
height, and body mass index [BMI]) and the number and percentages of participants within each 
category will be presented for categorical variables (sex, race, and ethnicity). Height, weight, and 
BMI measured at screening will be used in the summaries. Demographic data will also be listed 
as recorded on the CRF, including the date of informed consent and protocol version.
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6.4.2
Medical History and Concurrent Medical Conditions
Medical history to be recorded will include determining whether the participant has any 
significant conditions or diseases that resolved at or before signing the ICF. All medical history 
reported by the participant will be recorded regardless of how long ago it may have occurred. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing the ICF. Each participant’s medical history and concurrent medical conditions 
will be listed.
Any medical condition starting or worsening after taking the first dose of study drug will be 
classified as a TEAE. All medical history will be coded using MedDRA® version specified in the 
data management plan (DMP). All medical history and concurrent medical conditions will be 
listed. If available, the medical history and concurrent medical condition listings will include the 
coded term (preferred term [PT] and system organ class [SOC]), start date (if known) and end 
date (if known) or whether the condition was ongoing, and a description of the condition or 
event. No summaries or statistical analysis will be performed for these data.
6.5
Medication History and Concomitant Medications 
Medication history to be obtained includes any medication stopped at or within 28 days prior to 
signing the ICF. Concomitant medication includes any medication other than study drug taken at 
any time between ICF and the end of the study (including follow-up contact). All medication 
history and concomitant medications recorded during the study will be coded with the World 
Health Organization (WHO) Drug Dictionary version specified in the DMP and listed. If 
available, the listings will include the medication name, coded term, dosage, route of 
administration, start date and time (if known), end date and time (if known), or whether it 
continued after study completion, and indication for use. No summaries or statistical analysis 
will be performed for these data.
6.6
Efficacy Analysis
Not applicable. 
6.7
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and relationship of TEAEs, 
C-SSRS, and changes from baseline in the participants’ clinical laboratory results, vital signs, 
and 12-lead ECGs using the safety set. Clinically significant laboratory values, vital signs, and 
ECGs will be reported as AEs. All clinical safety data will be listed by study part, participant, 
and assessment time points, including rechecks, unscheduled assessments, and early termination, 
chronologically. Participants from each part will be included in the same listing but will be 
delineated by study part.
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
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individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
6.7.1
Adverse Events
All AEs captured in the database will be listed in by-participant data listings including verbatim 
term, coded term, severity (mild, moderate, severe), relationship to study drug (related or not 
related), relationship to COVID-19 or COVID-19 vaccine, frequency, and action relative to the 
study drug as recorded in the CRF. Study procedure taken due to AE will also be listed. All AEs 
occurring during this study will be coded using the MedDRA® version specified in the DMP. 
Only TEAEs will be summarized.
A TEAE is defined as an AE that is starting or worsening from the first dose of study drug 
administered in the study. Each TEAE will be attributed to the treatment prior to and the closest 
to the AE based on the AE onset date and time.
If the onset time of an AE is missing and the onset date is the same as a treatment dosing date, 
then the AE will be counted under the treatment given on the same day. If onset time of an AE is 
missing and the onset date does not fall on a dosing date, then the AE will be considered 
treatment emergent for the most recent treatment administered. If the onset date of an AE is 
missing, then the AE will be considered treatment emergent and attributed to the first treatment 
received. If severity is missing, the AE will be counted under the highest severity, and if 
relationship is missing, the AE will be counted as related. Any medical condition starting or 
worsening after the ICF but before the first dose of study drug will be classified as pre-treatment 
event.
Summary of TEAEs will be presented for each study part. TEAEs will be tabulated by treatment 
(including overall), SOC, and PT. Summary tables will include number of participants reporting 
the TEAE and as percent of safety set by treatment and overall. The most commonly reported 
non-serious TEAEs (ie, those events reported by >5% of participants or >2 participants, 
whichever is larger overall, excluding serious adverse events (SAEs)) will also be summarized. 
The denominators for percent calculations will be the number of participants dosed for each 
treatment. In addition, TEAEs will be summarized as number of TEAEs and percentage of 
TEAEs for each treatment and overall. 
Additional TEAE summary tables will be presented by severity and relationship to study drug. If 
a participant has multiple TEAEs with different severity levels within the same PT, the 
participant will be counted in the most severe category only. If a participant has both related and 
unrelated TEAEs with the same term, the participant will be counted as having related TEAEs.
An overview summary of TEAEs table, including number of participants with TEAEs, SAEs, 
treatment-related TEAEs, treatment-related SAEs, TEAEs by severity, and AEs leading to 
discontinuation of study drug will be provided.
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Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAEs. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the CSR.
6.7.2
Adverse Events of Special Interest (if applicable)
Not applicable.
6.7.3
Clinical Laboratory Evaluation
Serum chemistry, hematology, coagulation, and urinalysis will be performed at the following 
time points in both parts: screening, Period 1 Day -1, Period 1 Day 4, Period 2 Day 4, and 
Period 3 Day 5 (or at early termination if applicable).
Urine drug screening will be carried out at screening and Period 1 Day -1 only, in both study 
parts. In addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the Investigator. 
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for laboratory test results and change from baseline by 
treatment and time point of collection for each study part. Baseline is defined as the last 
assessment including rechecks taken prior to dosing in each period. For Periods 2 and 3 baseline, 
the Day 4 result from the previous period will be used. Postdose unscheduled or recheck 
assessments will not be used in analysis. All clinical laboratory data will be listed by study part 
and participant. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. For each laboratory test, a shift table will be 
developed comparing the frequency and percentage of the results at baseline (above normal (H), 
normal (N), or below normal (L)) with the postdose time points. For urinalysis tests, the 
categories are normal (N) and abnormal (A). Out-of-range values and corresponding recheck 
results will be listed. 
6.7.4
Vital Signs
Vital sign measurements of pulse rate, blood pressure, respiration rate, and temperature will be 
obtained at the following time points in both parts: screening, Period 3 Day 5 (or at early 
termination if applicable), and the following time points in all 3 periods, Day 1 predose, Day 1 
Hours 0.5 and 1.5, and Day 2.
Additional unscheduled vital signs measurements may be taken at other times, if deemed 
necessary by the Investigator.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be presented for vital 
sign results and change from baseline by treatment and time point of collection for each study 
part. Baseline is defined as the last assessment including rechecks taken prior to dosing in each 
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period. Postdose unscheduled or recheck assessments will not be used in analysis. Vital sign data 
will be listed by study part and participant.
6.7.5
12-Lead Electrocardiogram
Single 12-lead ECGs will be collected at the following time points in both parts: screening, 
Period 3 Day 5 (or at early termination if applicable), and the following time points in all 
3 periods, Day 1 predose, Day 1 Hours 0.5 and 1.5, and Day 2.
Additional unscheduled ECGs may be taken at other times, if deemed necessary by the 
Investigator.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from study baseline by treatment and time point of collection for each study 
part. Baseline is defined as the last assessment including rechecks taken prior to dosing in each 
period. Postdose unscheduled or recheck assessments will not be used in analysis. ECG data will 
also be listed by study part and participant.
In addition, for each study part, frequency counts of worst post baseline QTcF, and worst 
change-from-baseline QTcF (ΔQTcF) will be presented by treatment. Number of participants 
and corresponding percentages will be presented for each category. Worst post baseline QTcF 
will be categorized in the following categories: <450, 450 – <480, 480 – 500, and >500. Worst
post baseline ΔQTcF (maximum change from baseline) will be categorized in the following 
categories: <30, 30 – 60, and >60. A participant will be counted only once in each treatment 
even if the participant has more than 1 episode of the worst value.
6.7.6
Physical Examination
In both study parts, physical examinations will be performed at screening, Period 1 Day -1, 
Period 1 Day 4, Period 2 Day 4, and Period 3 Day 5 (or at early termination if applicable). 
Physical examination findings will be presented in the data listings by part and participant.
6.7.7
Columbia-Suicide Severity Rating Scale (C-SSRS)
At screening for each study part, the C-SSRS Baseline/Screening version will be administered. 
On Period 1 Day -1 and Period 3 Day 5 (or at early termination, if applicable) of each study part, 
the ‘Since Last Visit’ version will be administered. C-SSRS findings will be presented in the data 
listings by part and participant.
6.7.8
Overdose
All cases of overdose will be presented in a data listing by study part and participant. Any AEs 
associated with overdose will be documented.
6.7.9
Extent of Exposure and Compliance
The date, time, and treatment will be listed by part and participant. 
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6.8
Pharmacokinetic Analysis
Blood samples for assessment of plasma soticlestat 
 concentrations will be collected as 
outlined in Table 6.a for Part A and in Table 6.b for Part B: 
Table 6.a
Collection of Blood Samples for Pharmacokinetic Analysis in Part A
Analytes
Matrix
Periods
Scheduled Time (Hours)#
Soticlestat 
Plasma
1, 2, and 3
Predose and 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 
12, 24, 36, 48, 72, and 96* hours postdose
# The actual date and time of sample collection will be recorded on the source document in the CRF.
* The 96-hour PK sample in Periods 1 and 2 will serve as the predose PK sample of Periods 2 and 3, respectively. 
Table 6.b
Collection of Blood Samples for Pharmacokinetic Analysis in Part B
Analytes
Matrix
Periods
Scheduled Time (Hours)#
Soticlestat 
Plasma
1, 2, and 3
Predose and 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 
6, 8, 10, 12, 24, 36, 48, 72, and 96* hours postdose
# The actual date and time of sample collection will be recorded on the source document in the CRF.
* The 96-hour PK sample in Periods 1 and 2 will serve as the predose PK sample of Periods 2 and 3, respectively. 
Concentrations of plasma soticlestat 
 at each sampling time will be listed and 
summarized descriptively by treatment for each study part using the following descriptive 
statistics: n, mean, SD, CV%, SEM, minimum, median, and maximum. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive statistics. 
Individual participant concentration-time curves will be plotted by treatment for each study part 
on linear and semi-log scales. The arithmetic mean profiles of the concentration-time data will be 
plotted by treatment on linear (with and without SD) and semi-log scales for each study part. For 
arithmetic mean concentration-time plots, the nominal PK sampling times will be used. For 
individual participant concentration-time plots, the actual PK sampling times will be used.
The PK parameters will be calculated from plasma soticlestat 
 concentration-time 
profiles using non-compartmental analysis methods where all calculations will be based on 
actual sampling times after soticlestat dosing. The PK parameters will be summarized by 
treatment for each study part using the following descriptive statistics: n, mean, SD, CV%, SEM, 
minimum, median, maximum, geom mean, and geom CV%. Excluded parameters will be 
presented and footnoted as such in the PK parameter table listings, and those values will be 
excluded from descriptive statistics.
Linear Mixed-Effects Model
For each study part, ln-transformed Cmax, AUClast, AUC∞, and AUC∞_pred data will be analyzed 
using a linear mixed-effects model, separately. The model will include treatment, period, and 
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sequence as fixed effects, and participants nested within sequence as a random effect. The point 
estimates and the 90% CIs for the GMRs of Cmax, AUClast, AUC∞, and AUC∞_pred for the test 
formulation versus the reference formulation will be calculated using the exponentiation of the 
point estimates of the differences between treatments and the corresponding 90% CIs from the 
analyses on the ln-transformed Cmax, AUClast, AUC∞, and AUC∞_pred.
The comparisons of interest are as follows:
BE (Part A):

Treatment C compared with Treatment A

Treatment B compared with Treatment A
In Part A, for T3 mini-tablets (Treatment B) and commercial tablets (Treatment C), BE to 
reference formulation T4 tablets (Treatment A) will be for the Cmax, AUClast, and AUC∞and is 
claimed if the 90% CI for the GMRs for these parameters are each within 80.00% and 125.00% 
for soticlestat. The BE will be tested first between commercial tablets (Treatment C) and 
reference formulation T4 tablets (Treatment A), then followed with T3 mini-tablets (Treatment B) 
and reference formulation T4 tablets (Treatment A). In other words, if the 90% CI for Cmax, 
AUClast, or AUC∞GMRs for soticlestat between commercial tablets (Treatment C) and reference 
formulation T4 tablets (Treatment A) does not fall within 80.00% and 125.00%, BE cannot be 
claimed for T3 mini-tablets (Treatment B) and reference formulation T4 tablets (Treatment A) 
even if the 90% CI for GMR between B and A falls within 80.00% and 125.00%.
Food effect (Part B):

Treatment E compared with Treatment D
Tablet crushing (Part B):

Treatment F compared with Treatment D
The model will be run separately by study part, and using data for each analyte, as appropriate. 
The following SAS® code will be used to perform the analysis:
PROC MIXED DATA=xxx;
CLASS TREAT PERIOD SEQUENCE PARTICIPANT;
MODEL LN_PARAM = TREAT PERIOD SEQUENCE / DDFM=KR;
RANDOM PARTICIPANT(SEQUENCE);
ESTIMATE “Treatment C vs. Treatment A” TREAT -1 0 1 / CL ALPHA=0.1 E;
ESTIMATE “Treatment B vs. Treatment A” TREAT -1 1 0 / CL ALPHA=0.1 E;
LSMEANS TREAT;
RUN;
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9.0
APPENDIX
9.1
Changes From the Previous Version of the SAP
Not applicable. 
9.2
Analysis Software 
SAS® Version 9.4 or higher will be used for all statistical analyses provided in the CSR.
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