Clinical trial NCT05098054
Conditions: Hepatic Impairment Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2021-10-29; Completion date: 2022-06-07
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main aim is to check the effect of a single dose of soticlestat in adults with moderate or mild liver failure compared to healthy adults with normal liver function.

Participants will check into the study clinic for 8 days. During the stay, one oral dose of soticlestat will be given and the participant will be monitored. The clinic staff will follow up with the participant about a week after discharge from the clinic.

Detailed description:
The drug being tested in this study is called soticlestat (TAK-935). The study will assess the safety and tolerability of single oral dose of soticlestat in participants with moderate or mild Hepatic Impairment (HI) compared to healthy participants matched by age (mean ±10 years), sex (±2 per sex), and body mass index (BMI, mean ±10 percent \[%\]) with normal hepatic function.

The study will enroll approximately 40 participants. Participants will be assigned to following study arms:

* Arm 1, Moderate HI: Soticlestat 300 milligram (mg) (Child-Pugh Class B)
* Arm 2, Mild HI: Soticlestat 300 mg (Child-Pugh Class A)
* Arm 3, Normal hepatic function: Soticlestat 300 mg

All participants will receive single oral dose of study drug. The data will be collected and stored in electronic case report form (eCRF).

This multi-center trial will be conducted in the United States and Hungary. The overall duration of the study is approximately 42 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 300 mg, tablets, orally, once on Day 1 to participant with moderate HI. arm 2: Soticlestat 300 mg, tablets, orally, once on Day 1 to participant with mild HI. arm 3: Soticlestat 300 mg, tablets, orally, once on Day 1 to healthy participants.
Interventions: intervention 1: Soticlestat
Intervention descriptions: intervention 1: Soticlestat tablets.

Protocol documents:
Prot_000.pdf: 
NCT Number: NCT05098054
Title: Phase 1 Pharmacokinetics and Safety Study of Oral Soticlestat in Participants with Moderate or Mild 
Hepatic Impairment and Normal Hepatic Function
Study Number: TAK-935-1010
Document Version and Date: Amendment 1; 11 April 2022
Certain information within this document has been redacted (ie, specific content is masked irreversibly from view 
with a black bar) to protect either personally identifiable information or company confidential information. 
Clinical Study Protocol 


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
Phase 1 Pharmacokinetics and Safety Study of Oral Soticlestat in Participants with 
Moderate or Mild Hepatic Impairment and Normal Hepatic Function 
Study Identifier:
TAK-935-1010
Compound:
Soticlestat (TAK-935)
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue
Lexington, MA 02421
Email: PVSafetyAmericas@tpna.com
Date:
11 April 2022
Version:
Amendment No. 1
Amendment History: 
Date
Amendment Number
Amendment Type
Region
03 Sep 2021
Initial Version
Not Applicable
Global
11 Apr 2022
01
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
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CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................13
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................14
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.1.1
Soticlestat (TAK-935)......................................................................................17
4.2
Rationale for the Proposed Study.............................................................................19
4.3
Benefit/Risk Profile .................................................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Hypothesis...............................................................................................................20
5.2
Study Objectives......................................................................................................20
5.2.1
Study Primary Objective..................................................................................20
5.2.2
Study Secondary Objective..............................................................................20
5.3
Endpoints.................................................................................................................21
5.3.1
Primary Endpoints ...........................................................................................21
5.3.2
Secondary Endpoints .......................................................................................21
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................21
6.1
Study Design ...........................................................................................................21
6.2
Dose Escalation .......................................................................................................23
6.3
Stopping Rules.........................................................................................................23
6.4
Rationale for Study Design, Dose, and Endpoints ....................................................23
6.4.1
Rationale of Study Design ...............................................................................23
6.4.2
Rationale for Dose...........................................................................................24
6.4.3
Rationale for Endpoints ...................................................................................25
6.4.4
Future Biomedical Research ............................................................................25
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures ............25
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................25
6.6
Study Beginning and End/Completion .....................................................................26
6.6.1
Definition of Beginning of the Study ...............................................................26
6.6.2
Definition of End of the Study.........................................................................26
6.6.3
Definition of Study Completion.......................................................................26
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Soticlestat (TAK-935)
Study ID TAK-935-1010
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CONFIDENTIAL
6.6.4
Definition of Study Discontinuation.................................................................26
6.6.5
Criteria for Premature Termination or Suspension of the Study........................26
6.6.6
Criteria for Premature Termination or Suspension of a Site..............................27
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .....27
7.1
Inclusion Criteria .....................................................................................................27
7.1.1
Inclusion for Participants with Hepatic Impairment..........................................27
7.1.2
Inclusion for Healthy Participants....................................................................28
7.1.3
Inclusion for Participants with Hepatic Impairment and Healthy Participants...28
7.2
Exclusion Criteria ....................................................................................................29
7.2.1
Exclusion for Participants with Hepatic Impairment.........................................29
7.2.2
Exclusion for Healthy Participants...................................................................29
7.2.3
Exclusion for Participants with Hepatic Impairment and Healthy Participants..29
7.3
Excluded Medications, Supplements, Dietary Products............................................30
7.4
Diet, Fluid, Activity.................................................................................................31
7.4.1
Diet and Fluid..................................................................................................31
7.4.2
Activity ...........................................................................................................32
7.5
Criteria for Discontinuation or Withdrawal of a Participant......................................32
7.6
Procedures for Discontinuation or Withdrawal of a Participant ................................33
7.7
Participant Replacement ..........................................................................................33
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................34
8.1
Clinical Study Drug .................................................................................................34
8.1.1
Clinical Study Drug Labeling ..........................................................................34
8.1.2
Clinical Study Drug Inventory and Storage......................................................34
8.1.3
Clinical Study Drug Blinding...........................................................................34
8.1.4
Randomization Code Creation and Storage......................................................34
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................34
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................34
9.0
STUDY PROCEDURES...............................................................................................35
9.1
Administrative Procedures.......................................................................................35
9.1.1
Informed Consent Procedure............................................................................35
9.1.2
Inclusion and Exclusion...................................................................................35
9.1.3
Medical History/Demography..........................................................................35
9.1.4
Concomitant Medications ................................................................................35
9.2
Clinical Procedures and Assessments.......................................................................35
9.2.1
Full Physical Examination ...............................................................................36
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 4 of 74
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CONFIDENTIAL
9.2.2
Height and Weight...........................................................................................36
9.2.3
BMI.................................................................................................................36
9.2.4
Vital Signs.......................................................................................................36
9.2.5
12-Lead ECG...................................................................................................36
9.2.6
Study Drug Administration..............................................................................37
9.2.7
C-SSRS ...........................................................................................................37
9.2.8
AE Monitoring ................................................................................................37
9.2.9
Laboratory Procedures and Assessments..........................................................37
9.3
PK Samples .............................................................................................................39
9.3.1
PK Measurements............................................................................................39
9.3.2
Biomarker Measurements ................................................................................40
9.3.3
PGx Measurements..........................................................................................41
9.3.4
Confinement....................................................................................................41
10.0
ADVERSE EVENTS ....................................................................................................41
10.1
Definitions and Elements of AEs .............................................................................41
10.1.1
SAEs ...............................................................................................................43
10.1.2
Special Interest AEs.........................................................................................44
10.2
AE Procedures.........................................................................................................44
10.2.1
Assigning Severity/Intensity of AEs ................................................................44
10.2.2
Assigning Causality of AEs .............................................................................45
10.2.3
Start Date.........................................................................................................45
10.2.4
End Date..........................................................................................................45
10.2.5
Pattern of Adverse Event (Frequency)..............................................................45
10.2.6
Action Taken With Study Treatment................................................................45
10.2.7
Outcome..........................................................................................................46
10.2.8
Collection and Reporting of AEs, SAEs, and Abnormal LFTs .........................46
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...48
11.0
STATISTICAL METHODS..........................................................................................49
11.1
Statistical and Analytical Plans ................................................................................49
11.1.1
Analysis Sets ...................................................................................................49
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................49
11.1.3
PK Analysis.....................................................................................................49
11.1.4
PD Analysis.....................................................................................................50
11.1.5
Safety Analysis................................................................................................50
11.2
Interim Analysis and Criteria for Early Termination ................................................51
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 5 of 74
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CONFIDENTIAL
11.3
Determination of Sample Size..................................................................................51
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................51
12.1
Study-Site Monitoring Visits ...................................................................................51
12.2
Protocol Deviations..................................................................................................51
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................52
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................52
13.1
IRB and/or IEC Approval ........................................................................................52
13.2
Participant Information, Informed Consent, and Participant Authorization...............53
13.3
Participant Confidentiality .......................................................................................54
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................55
13.4.1
Publication and Disclosure...............................................................................55
13.4.2
Clinical Study Registration ..............................................................................55
13.4.3
Clinical Study Results Disclosure ....................................................................55
13.5
Insurance and Compensation for Injury....................................................................56
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................56
14.1
Administrative Information......................................................................................56
14.1.1
Study Contact Information...............................................................................56
14.1.2
INVESTIGATOR AGREEMENT ...................................................................57
14.1.3
Study-Related Responsibilities.........................................................................58
14.1.4
List of Abbreviations .......................................................................................58
15.0
DATA HANDLING AND RECORDKEEPING............................................................61
15.1
CRFs (Electronic and Paper)....................................................................................61
15.2
Record Retention .....................................................................................................61
16.0
REFERENCES..............................................................................................................62
17.0
APPENDICES...............................................................................................................63
LIST OF IN-TEXT TABLES
Table 2.a
Study Design for Arms 1, 2, and 3......................................................................13
Table 6.a
Derivation of Child-Pugh Classification Score 1.................................................24
Table 6.b
Determination of Encephalopathy Grade 1..........................................................24
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................31
Table 9.a
Primary Specimen Collections ...........................................................................39
Table 10.a
Takeda Medically Significant AE List................................................................44
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 6 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................63
Appendix B
Elements of the Participant Informed Consent....................................................65
Appendix C
Investigator Consent to the Use of Personal Information ....................................68
Appendix D
Pregnancy and Contraception.............................................................................69
Appendix E
Summary of Changes from Previous Version.....................................................73
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 7 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, MA 02421
Telephone: +1 (617) 679-7000
Compound:
Soticlestat (TAK-935)
Study Identifier: TAK-935-1010
Phase: 1
Protocol Title: Phase 1 Pharmacokinetics and Safety Study of Oral Soticlestat in Participants with Moderate or Mild 
Hepatic Impairment and Normal Hepatic Function
Study Design:
This is a phase 1, open-label, study of oral soticlestat designed to assess the pharmacokinetics (PK) of single dose 
soticlestat 
 in participants with moderate or mild hepatic impairment (HI) 
compared to matched healthy participants with normal hepatic function. At least 12 healthy participants (up to 24 
participants) with normal hepatic function will be recruited to match the group mean of moderate and mild HI arms by 
age (mean ± 10 years), sex (± 2 per sex), and body mass index (BMI, mean ± 10%). Eight (8) participants will also be 
enrolled in each HI arm of the study according to the following criteria: 

Arm 1: (N = 8): Moderate HI (Child-Pugh Class B [Score: ≥ 7 and ≤ 9]), 300 mg single dose

Arm 2: (N = 8): Mild HI (Child-Pugh Class A [Score: ≥ 5 and ≤ 6]), 300 mg single dose 

Arm 3: (N = 12-24): Normal hepatic function, 300 mg single dose 
The study will consist of a 28-day screening period (prior to dosing) and a 7-day confinement period (Day -1 to Day
7).
Two hepatic function assessments are required prior to Day 1 dosing for participants with HI. These 2 assessments 
should be obtained during the screening period and at least 48 hours apart. In the case where a participant has an 
available historical Child-Pugh assessment score within 3 months prior to screening, 1 assessment can be conducted 
during the screening period. If the Child-Pugh scores from these 2 assessments indicate the same liver function 
category for the participant (ie, normal hepatic function, moderate HI, or mild HI), soticlestat can be administered as 
scheduled. If the results of the 2 assessments indicate different liver function categories, a third assessment must be 
conducted at least 24 hours after the second assessment. If the results of the 2 most recent assessments (the second and 
third) are in agreement with regard to the participant’s liver function category, the participant may be enrolled and 
should receive the Day 1 dose within 48 hours of the third assessment. If the second and third measurements differ, the 
participant will not be eligible for the study.
The moderate HI arm (ie, Arm 1) will be conducted first, followed by 12 participants in the matched normal hepatic 
function arm (Arm 3). After all participants in the moderate HI arm and the matching 12 participants in the matched 
normal hepatic function arm have completed the treatment period, an informal interim PK data analysis is planned and 
may additionally leverage historical control PK data in healthy participants to gain an initial estimate of the effect of 
moderate HI on the PK of soticlestat 
. 
Following completion of enrolment of the mild HI arm, and in the instance any of the previously enrolled healthy
participants cannot be used for matching purposes, up to an additional 12 participants may be enrolled for the matched 
normal hepatic function group (Arm 3) to ensure a minimum of 12 participants with normal hepatic function and 
matching the mean of the mild HI arm by age (mean ± 10 years), sex (± 2 per sex), and body mass index (BMI, 
mean ± 10%) are enrolled. 
Participants will receive a single oral dose of 300 mg soticlestat as three 100 mg T4 tablets on Day 1 with 
approximately 240 mL water under fasting conditions. PK samples will be collected from Days 1 to 7, at 
predetermined time points (Section 3.0), to characterize the PK of soticlestat 
in participants with moderate or mild HI compared to matched healthy participants with normal hepatic 
function (Section 3.0).
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 8 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
Participants will remain in the clinic throughout the study. Participants will be discharged from the clinic on Day 7 
after the last PK sample collection and study procedures are completed. A safety follow-up contact for all participants 
(including those who terminate the study early) will occur 14 ± 2 days after the soticlestat dose to determine if any AEs 
have occurred since clinical research unit (CRU) discharge.
Study Primary Objective:

To characterize the plasma PK of soticlestat following a single oral dose in participants with moderate or mild HI
compared to matched healthy participants with normal hepatic function.
Study Secondary Objective:

To evaluate the safety and tolerability of soticlestat following a single oral dose in participants with moderate or 
mild HI as well as matched healthy participants with normal hepatic function.
Study Participant Population: Healthy male and female participants and participants with moderate and mild HI 
aged ≥ 18 to < 75 years and with a BMI ≥18.0 and ≤40.0 kg/m2 at screening (at least 50% of the participants will be 
required to be of BMI ≥18.0 and ≤35.0 kg/m2). Healthy participants will be matched to hepatic impaired participants 
in this study by age (mean ± 10 years), sex (± 2 per sex), and BMI (mean ± 10%). 
Planned Number of Participants:
Up to 40 participants will be enrolled:
8 participants with moderate HI
8 participants with mild HI
12 to 24 participants with normal hepatic function
Planned Number of Sites:
Up to 7 clinical sites
Dose Level:
300 mg soticlestat (3 x 100 mg T4 tablets).
Route of Administration:
Oral
Duration of Treatment:
Single-dose on Day 1
Planned Study Duration:
Approximately 42 days including screening period and 
follow-up.
Criteria for Inclusion:
Inclusion for Participants with Hepatic Impairment
Participants must fulfill the following inclusion criteria to be eligible for participation in the study (participants who do
not qualify based on a reversible condition or mild intercurrent illness may be re-screened after the condition is 
resolved. Screening tests may be repeated if in the Investigator’s opinion the test needs to be repeated): 
1.
Is an adult male or female participant aged ≥ 18 to < 75 years, at screening.
2.
Has a BMI ≥18.0 and ≤40.0 kg/m2, at screening. At least 50% of the participants will be required to be of BMI 
≥18.0 and ≤35.0 kg/m2, at screening. 
3.
Aside from HI, be sufficiently healthy for study participation based upon medical history, physical examination, 
vital signs, ECGs, and screening clinical laboratory profiles, as deemed by the Investigator or designee.

Supine blood pressure (BP) is ≥ 80/40 mmHg (asymptomatic) and ≤ 150/95 mmHg, at screening;

Supine pulse rate (PR) is ≥ 40 bpm and ≤ 99 bpm, at screening;

QT interval corrected for PR using Friderica’s formula (QTcF) is ≤ 500 msec and electrocardiogram (ECG) 
findings considered normal or not clinically significant by the Investigator or designee, at screening.
4.
The participant must have had chronic HI for at least 3 months before screening, and the HI must be stable, ie, no 
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 9 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
significant changes in hepatic function in the 30 days preceding screening (or since the last visit if within 6 
months before screening) and treatment with stable doses of medication. Has a score on the Child-Pugh Class at 
screening as follows: 

(Arm 1) Moderate HI, Child-Pugh Class B: ≥ 7 and ≤ 9

(Arm 2) Mild HI, Child-Pugh Class A: ≥ 5 and ≤ 6
5.
Participants should not have renal dysfunction as demonstrated by a relatively adequate renal function (creatinine 
clearance ≥ 50 mL/min), at screening.
Inclusion for Healthy Participants
Participants must fulfill the following inclusion criteria to be eligible for participation in the study:
1.
Is an adult male or female participant aged ≥ 18 to < 75 years, at screening. Healthy participants will be matched 
to hepatic impaired participants in this study by sex (± 2 per sex) and by age (mean ± 10 years). 
2.
Has a BMI ≥18.0 and ≤40.0 kg/m2, at screening. At least 50% of the participants will be required to be of BMI 
≥18.0 and ≤35.0 kg/m2, at screening. Healthy participants will be matched to hepatic impaired participants in 
this study by BMI (mean ± 10%).
3.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs or ECGs, as deemed by the Investigator or designee. 

Supine BP is ≥ 90/40 mmHg and ≤ 150/95 mmHg, at screening;

Supine PR is ≥ 40 bpm and ≤ 99 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;

Liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP) and total bilirubin ≤the upper limit of normal (ULN) at screening and check-in.
4.
Participants should not have renal dysfunction as demonstrated by a relatively adequate renal function (creatinine 
clearance ≥60 mL/min), at screening.
Inclusion for Participants with Hepatic Impairment and Healthy Participants
Participants must fulfill the following inclusion criteria to be eligible for participation in the study:
1.
Understands the study procedures in the informed consent form (ICF), provides a signature/date in the ICF, and is 
willing and able to comply with the protocol.
2.
Continuous non-smoker or moderate smoker (≤10 cigarettes/day or the equivalent) before screening. Participant 
must agree to consume no more than 5 cigarettes or equivalent/day from the 7 days prior check-in and until 
discharge from the CRU.
3.
Female participants of childbearing potential and male participants agree to comply with any applicable 
contraceptive requirements of the protocol as detailed in Appendix D.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 10 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Criteria for Exclusion:
Exclusion for Participants with Hepatic Impairment:
The participant must be excluded from participating in the study if the participant:
1.
Has history or presence of clinically significant medical or psychiatric condition or disease (aside from HI) or 
presence of psychotic disorders such as psychosis, delusions, or schizophrenia in the opinion of the Investigator or 
designee.
2.
Has a history of liver or other solid organ transplant.
3.
Has history or presence of alcoholism and drug abuse within the past 6 months prior to dosing.
4.
Positive result at screening for human immunodeficiency virus (HIV). Hepatitis B surface antigen (HBsAg) 
positive participants are allowed to be enrolled if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is below 
1000 copies/mL in the plasma. Participants with moderate or mild HI who are positive for anti-HCV antibody 
(HCVAb) can be enrolled but must not have detectable HCV ribonucleic acid (RNA) in the plasma.
Exclusion for Healthy Participants
The participant must be excluded from participating in the study if the participant:
1.
Has history or presence of clinically significant medical or psychiatric condition or disease or presence of 
psychotic disorders such as psychosis, delusions, or schizophrenia in the opinion of the Investigator or designee.
2.
Has history or presence of alcoholism and drug abuse within the past 2 years prior to dosing.
3.
Positive results at screening for HIV, HBsAg, or hepatitis C virus (HCV).
Exclusion for Participants with Hepatic Impairment and Healthy Participants
The participant must be excluded from participating in the study if the participant:
1.
Has 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.
2.
Has history or presence of clinically significant hypersensitivity or idiosyncratic reaction to the study drug or 
related compounds.
3.
Has positive results for the urine or saliva drug screen at screening or check-in, unless the positive drug screen is 
due to prescription drug use that is approved by the Investigator (cannabinoids can be used for medicinal use at 
the discretion of the Investigator).
4.
Is a female with a positive pregnancy test or who is lactating.
5.
Has positive results for urine or breath alcohol screen at screening or check-in.
6.
Is unable to refrain from or anticipates the use of any medication or substance (including prescription or 
over-the-counter, vitamin supplements, natural or herbal supplements) as indicated in Section 7.3 (Excluded 
Medications, Supplements, Dietary Products) for the prohibited time period.
7.
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 dosing.
8.
Has made a donation of blood or had significant blood loss within 56 days prior to dosing. 
9.
Has made a plasma donation within 7 days prior to dosing.
10. Participated in another clinical study within 30 days prior to dosing. The 30-day window will be derived from the 
date of the last dosing in the previous study to Day 1 of the current study.
11. Any positive responses on the Columbia-Suicide Severity Rating Scale (C-SSRS) or has a risk of suicide 
according to the Investigator’s judgment based on the assessment of the C-SSRS at screening or check-in or has 
made a suicide attempt in the previous 12 months prior to dosing.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 11 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Main Criteria for Evaluation and Analyses:
Primary endpoints:
The following PK parameters in plasma will be analyzed for soticlestat:

Maximum observed concentration (Cmax)

Area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the 
last quantifiable concentration (AUC∞)

Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration 
(AUClast)
Secondary endpoints:

Incidence of treatment-emergent adverse events (TEAEs)

Incidence of clinically significant abnormal values for laboratory evaluations, vital signs, ECG parameters, 
and C-SSRS
Statistical Considerations:
Pharmacokinetics:
Descriptive statistics will be used to summarize concentrations of soticlestat and PK parameters according to hepatic 
function group (normal hepatic function and moderate and mild HI). An analysis of variance (ANOVA) will be 
performed on the natural log (ln)-transformed Cmax, AUClast, and AUC∞for soticlestat to compare each HI group with 
the normal hepatic function group, and 90% confidence intervals (CI) for the ratio of geometric means from each HI 
group versus normal function group will be provided. The addition of other factors and covariates such as age, sex, and 
BMI on the relationship between soticlestat PK parameters and level of HI may also be investigated. 
Descriptive statistics will be used to summarize concentrations of 
 PK 
parameters according to hepatic function group (normal hepatic function and moderate and mild HI).
The fraction of unbound soticlestat will be determined.
Safety:
TEAEs will be tabulated. Summary statistics for vital signs, safety 12-lead ECGs, C-SSRS, and safety laboratory 
assessments will be computed and provided according to hepatic function group (normal hepatic function and 
moderate and mild HI). Markedly abnormal values (MAV) criteria for vital signs, 12-lead ECGs, and safety laboratory 
assessments will be defined in the statistical analysis plan (SAP).
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 12 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Sample Size Justification:
The planned sample size of 8 participants in each HI arm is not based on power calculations and is considered 
adequate to provide a descriptive characterization of the PK of soticlestat 
 in participants with 
moderate or mild HI compared to healthy participants with normal hepatic function.
Any participant who is not PK evaluable including those experiencing emesis within 8 hours post dose may be 
replaced at the discretion of the Investigators in consultation with the Sponsor to ensure 8 PK-evaluable participants in 
each arm of participants with HI and 12-24 PK-evaluable participants in matched participants with normal hepatic 
function complete.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 13 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
2.0
STUDY SCHEMATIC
Table 2.a
Study Design for Arms 1, 2, and 3
Screening
Check-in and 
Predose 
Assessments a
Soticlestat Dosing, 
PK Sampling and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
PK Sampling, Study 
Assessments and Study 
Dischargeb
Follow-up
Within 
28 days prior 
to soticlestat 
dosing
Day -1
Day 1
Days 2-6
Day 7
14 ± 2 days following 
the soticlestat dose 
Outpatient 
Visit
-----------------------------Confinementa-----------------------------------
(Phone Contact)
a Participants will start the confinement on Day -1 and remain confined in the clinic throughout the study until Day 7. Participants 
may be admitted to the clinic earlier for Coronavirus Disease-19 (COVID-19) procedures not related to the study protocol. 
Participants will be discharged from the clinic on Day 7 after the last PK sample collection and study procedures are completed.
b Study Discharge is defined as end of treatment and study procedures.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ow
T
ow-
Te
-up
Te
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ms
14 ± 2 d
lica
14 ± 2 d
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A
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ures not re
ct to
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llection a
ject
llection a
t


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 14 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
Study Procedures a
Study Days in Arms 1, 2, and 3
Days in Period →
S b
-1
1
2
3
4
5
6
7 (EOS)/ET
FU c
Hours →
C-I d
0
0.133
0.25
0.5 0.75
1
1.5
2
4
6
8
10
14
24
36
48
72
96
120
144
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations
Full Physical Examination e
X
X f
X g
Height
X
Weight
X
Child-Pugh Assessment h
X
12-Lead Safety ECG j
X
X i
X
X
X g
Vital Signs (PR and BP) j
X
X i
X
X
X g
Vital Signs (RR and T) j
X
X i
X
X g
Hem, Coag, Serum Chem k, and UA
X
X
X
X g
Serum Pregnancy Test (♀only)
X
X
Serum FSH (♀only)
X
Urine/Saliva Drug Screen
X
X
Urine/Breath Alcohol Screen
X
X
HIV/Hepatitis B and C Screen
X
C-SSRS l
X
X
X g
AE Monitoring
X
X
ConMeds Monitoring
X
Study Drug Administration / PK
Soticlestat Administration
X m
Blood for Soticlestat
X n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X g
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 15 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Study Procedures a
Study Days in Arms 1, 2, and 3
Days in Period →
S b
-1
1
2
3
4
5
6
7 (EOS)/ET
FU c
Hours →
C-I d
0
0.133
0.25
0.5 0.75
1
1.5
2
4
6
8
10
14
24
36
48
72
96
120
144
Other Procedures
Confinement in the CRU o
X
Visit
X
a
For details on Procedures, refer to Section 9.0.
b
Within 28 days prior to the study drug administration.
c
The clinic will contact all participants (including participants who terminate the study early) by phone 14 ± 2 days after the soticlestat administration to 
determine if any AEs have occurred since CRU discharge.
d
Participants will be admitted to the CRU on Day -1 at the time indicated by the CRU. Participants may be admitted to the CRU earlier for COVID-19 
procedures not related to the study protocol.
e
Symptom-driven physical examinations may be performed during the study, at the Investigator’s or designee’s discretion.
f
If the screening assessment was conducted within 4-7 days prior to dosing (Day 1), assessment will be conducted at check-in only if, in the opinion of the 
Investigator or designee, there is reason to believe they have substantially changed. 
g
To be performed at Day 7 (EOS) or prior to ET from the study.
h
Two hepatic function assessments are required prior to Day 1 for participants with HI. These 2 assessments should be obtained during screening and at least 48 
hours apart. In the case where a participant has an available historical Child-Pugh assessment score within 3 months prior to screening, 1 assessment can be 
conducted during the screening period. If the Child-Pugh scores from these 2 assessments indicate the same liver function category for the participant (ie, 
normal function, moderate impairment, or mild impairment), soticlestat can be administered as scheduled. If the results of the 2 assessments indicate different 
liver function categories, a third assessment must be conducted at least 24 hours after the second assessment. If the results of the 2 most recent assessments (the 
second and third) are in agreement with regard to the participant’s liver function category, the participant may be enrolled and should receive the Day 1 dose 
within 48 hours of the third assessment. If the second and third measurements differ, the participant will not be eligible for the study.
i
To be performed within 24 hours prior to dosing.
j
All assessments will be performed (supine position) after participants have rested for at least 5 minutes. 
k
Samples for serum chemistry will be obtained in the fasted state following 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.
l
At screening, the C-SSRS Baseline/Screening version will be administered; at all other time points, the Since Last Visit version will be administered. When
possible, it is highly recommended that assessments are conducted by the same rater to ensure consistency.
m
After an overnight fast of at least 10 hours, soticlestat will be administered. During the first 4 hours after drug administration, no food is allowed.
n
Prior to soticlestat administration.
ject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 16 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
o
Participants will start the confinement on Day -1 and remain confined in the clinic throughout the study until Day 7. Participants will be discharged from the
CRU on Day 7 after the last PK sample collection and study procedures are completed.
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, Coag = Coagulation, ConMeds = Concomitant medication, 
COVID-19 = Coronavirus disease 2019, CRU = Clinical research unit, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = Electrocardiogram, EOS/ET = End-of-Study or 
early termination, FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, PK = Pharmacokinetics, PR = Pulse rate, 
RR = Respiratory rate, S = Screening, T = Temperature, UA = Urinalysis.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
Participan
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Participan
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App
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ECG
Ap
ECG =
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 17 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
4.1.1
Soticlestat (TAK-935)
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 are a cluster 
of pediatric epilepsy syndromes and includes Dravet Syndrome (DS) and Lennox Gastaut 
Syndrome (LGS). Epilepsy is linked to a dysregulation in glutamatergic signaling brought upon by 
an over-activation of CH24H. This enzyme is predominantly expressed in neurons and involved in
the homeostasis of brain cholesterol by converting it to 24S-hydroxycholesterol (24HC), a polar 
metabolite capable of passing the brain barrier via lipoproteins. 
Soticlestat is a first-in-class therapeutic candidate that has the potential to control seizures in 
treatment-resistant patients with epilepsy by reducing over-activated glutamate signaling by 
modulating reactive astrocytes and reducing over-activated glutamate signaling in neurons. This 
mechanism of action is thought to clinically manage seizures by reducing seizure frequency and 
severity as well as brain damage and cognitive deficits that are pathological sequelae of the 
epileptogenic process but also other conditions where excessive glutamatergic signaling activity 
drives the pathology.
nly and Subject to the Applicable Terms of Use
urrently 
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urrently 
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which ar
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Property of Takeda: For Non-Commercial Use On
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 18 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
4.1.1.2
Clinical Safety and Pharmacokinetics
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 participants with mild to moderate HI and healthy 
participants, and 3 phase 3 studies in DS and LGS patients are ongoing.
Overall, 382 participants 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).
Soticlestat was rapidly absorbed with a median time of tmax of 0.25 to 0.52 hours following 
single-dose administration (15 to 1350 mg; Study TAK-935-101) and a median tmax of 0.33 to 0.5 
hours following multipledose administration (100 to 600 mg) under fasting conditions in healthy 
participants (Study TAK-935-1002). When administered under fed conditions, soticlestat tmax was 
delayed by about 1.5 hours and Cmax was decreased by 60%; however, food had little impact on the 
total exposure of the drug as AUC decreased by only 11% using the tablet formulation (Study
TAK935-1005). Soticlestat was shown to cross the blood brain barrier and was able to block 
and Subject to the Applicable Terms of Use
ted in 6
App
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 19 of 74
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11 April 2022
CONFIDENTIAL
tracer binding to the enzyme target demonstrating a sigmoidal maximum observed effect (Study 
TAK935-1003). Mean soticlestat t1/2z ranged from 4.39 to 7.16 hours from 200 to 1350 mg 
following a single-dose administration, and 3.49 to 4.83 hours across the 100 to 600 mg dose range 
after administration of multiple doses and similar between Days 1 and 14. 
.
The PK profile following single-dose and multiple-dose administration were further characterized 
in healthy Japanese participants (Study TAK-935-1004). Soticlestat was rapidly absorbed after 
administration, with tmax of 0.5 to 0.75 hours. Soticlestat t1/2z values ranged from 5.075 to 8.695 
hours after a single-dose and from 2.620 to 3.630 hours after multiple doses with uptitration. PK 
exposure to soticlestat increased in a greater than dose-proportional manner in the dose ranges 
from 200 to 1200 mg single dose and 100 to 300 mg BID. Accumulation of 100 BID dosing was 
minimal for Cmax and AUC of soticlestat with accumulation ratios less than 1.06 at steady state.
 
4.2
Rationale for the Proposed Study
In this study, the impact of HI on the PK of single dose soticlestat 
. After entering the body, drugs are eliminated by excretion and/or 
metabolism. Although elimination can occur through a variety of routes, most drugs are cleared by 
metabolism in the liver and/or small intestine and/or by elimination of unchanged drug by the 
kidney. Liver disease is associated with several pathophysiologic changes that may alter the PK of 
a drug. These include alterations in hepatic blood flow, changes in liver enzyme activity, decreased 
binding of drug to plasma proteins, and impaired biliary excretion [2, 3]. Accordingly, current 
United States (US) FDA guidance recommends a PK study in patients with impaired hepatic 
function if hepatic metabolism and/or excretion accounts for a substantial portion (≥20 % of the 
absorbed drug) of the elimination of a parent drug or active metabolite [4].
The magnitude of the effect of mild, moderate, or severe HI on the PK of soticlestat was assessed 
based on model-based simulations of HI effect using in vitro enzyme phenotyping data and data 
from the human ADME study. The simulations suggested that in participants with mild, moderate, 
or severe HI, soticlestat AUC∞ is expected to be 1%, 23%, and 33% higher, respectively, than 
healthy participants with normal hepatic function; soticlestat Cmax is expected to be 0%, 6%, and 
7% higher, respectively, compared with healthy participants with normal hepatic function.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 20 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Based on model-based simulations, this study first evaluated the PK in participants with moderate 
HI (n=8) and healthy matched participants with normal hepatic function (n=12) and an interim PK 
analysis was conducted. The interim analysis indicated higher impact of moderate HI on soticlestat 
PK than the model predicted. For participants with moderate HI, soticlestat PK exposure increased 
to 214.93%, 316.47%, and 299.38% for Cmax, AUClast, and AUC∞, respectively, when compared to 
the respective PK exposure in matched participants with normal hepatic function. As a result, this 
study will further evaluate the impact of mild HI on the PK of soticlestat. In addition, the Sponsor 
decides not to dose participants with severe HI. Soticlestat will not be recommended to use in 
subjects with severe HI.
4.3
Benefit/Risk Profile
The single dose of 300 mg soticlestat has been selected for this study as it is the recommended 
phase 3 dose [1]. In addition, doses up to 1350 mg were administered in healthy participants and 
were found to be safe and well tolerated.
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (ie, 12-lead ECG, vital signs, clinical laboratory tests, AE questioning, C-SSRS, and 
physical examinations) are adequate to protect the participant’s safety and should detect all 
TEAEs.
There will be no direct health benefit for study participants from receipt of the study drugs. An 
indirect health benefit to the healthy participants enrolled in this study is the free medical tests 
received at screening and during the study.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
Not applicable.
5.2
Study Objectives
5.2.1
Study Primary Objective

To characterize the plasma PK of soticlestat following a single oral dose in participants with 
moderate or mild HI compared to matched healthy participants with normal hepatic function.
5.2.2
Study Secondary Objective

To evaluate the safety and tolerability of soticlestat following a single oral dose in participants 
with moderate or mild HI as well as matched healthy participants with normal hepatic function.
nly and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 21 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
5.3
Endpoints
5.3.1
Primary Endpoints
The following PK parameters in plasma will be analyzed for soticlestat:

Cmax

AUC∞

AUClast
5.3.2
Secondary Endpoints 

Incidence of TEAEs

Incidence of clinically significant abnormal values for laboratory evaluations, vital signs, 
ECG parameters, and C-SSRS
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a phase 1, open-label, study of oral soticlestat designed to assess the PK of single dose 
soticlestat
 in participants with moderate or mild HI 
compared to matched healthy participants with normal hepatic function. At least 12 healthy 
participants (up to 24 participants) with normal hepatic function will be recruited to match the 
group mean of moderate and mild HI arms by age (mean ± 10 years), sex (± 2 per sex), and BMI 
(mean ± 10%). Eight (8) participants will also be enrolled in each HI arm of the study according to 
the following criteria: 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 22 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL

Arm 1: (N = 8): Moderate HI (Child-Pugh Class B [Score: ≥ 7 and ≤ 9]), 300 mg single 
dose

Arm 2: (N = 8): Mild HI (Child-Pugh Class A [Score: ≥ 5 and ≤ 6]), 300 mg single dose 

Arm 3: (N = 12 - 24): Normal hepatic function, 300 mg single dose 
The study will consist of a 28-day screening period (prior to dosing) and a 7-day confinement 
period (Day -1 to Day 7).
Two hepatic function assessments are required prior to Day 1 dosing for participants with HI. 
These 2 assessments should be obtained during the screening period and at least 48 hours apart. In 
the case, where a participant has an available historical Child-Pugh assessment score within 
3 months prior to screening, 1 assessment can be conducted during the screening period. If the 
Child-Pugh scores from these 2 assessments indicate the same liver function category for the 
participant (ie, normal hepatic function, moderate HI, or mild HI), soticlestat can be administered 
as scheduled. If the results of the 2 assessments indicate different liver function categories, a third 
assessment must be conducted at least 24 hours after the second assessment. If the results of the 2 
most recent assessments (the second and third) are in agreement with regard to the participant’s 
liver function category, the participant may be enrolled and should receive the Day 1 dose within 
48 hours of the third assessment. If the second and third measurements differ, the participant will 
not be eligible for the study.
The moderate HI arm (ie, Arm 1) will be conducted first, followed by 12 participants in the 
matched normal hepatic function arm (Arm 3). After all participants in moderate HI arm and the 
matching 12 participants in the matched normal hepatic function arm have completed the 
treatment period, an informal interim PK data analysis is planned and may additionally leverage 
historical control PK data in healthy participants to gain an initial estimate of the effect of 
moderate HI on the PK of soticlestat 
.
Following completion of enrolment of the mild HI arm, and in the instance any of the previously 
enrolled healthy participants cannot be used for matching purposes, up to an additional 
12 participants may be enrolled for the matched normal hepatic function group (Arm 3) to ensure a 
minimum of 12 participants with normal hepatic function and matching the mean of the mild HI 
arm by age (mean ± 10 years), sex (± 2 per sex), and body mass index (BMI, mean ± 10%) are 
enrolled. 
Participants will receive a single oral dose of 300 mg soticlestat as three 100 mg T4 tablets on Day 
1 with approximately 240 mL water under fasting conditions. PK samples will be collected from 
Days 1 to 7, at predetermined time points (Section 3.0), to characterize the PK of soticlestat 
 
in participants with moderate or mild HI compared to matched 
healthy participants with normal hepatic function (Section 3.0).
Participants will remain in the clinic throughout the study. Participants will be discharged from the 
clinic on Day 7 after the last PK sample collection and study procedures are completed. A safety 
follow-up contact of all participants (including those who terminate the study early) will occur 14 
± 2 days after the soticlestat dose to determine if any AEs have occurred since the CRU discharge.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 23 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 
After entering the body, drugs are eliminated by excretion and/or metabolism. Although 
elimination can occur through a variety of routes, most drugs are cleared by metabolism in the liver 
and/or small intestine and/or by elimination of unchanged drug by the kidneys. Liver disease is 
associated with several pathophysiologic changes that may alter the PK of a drug. These include 
alterations in hepatic blood flow, changes in liver enzyme activity, decreased binding of drug to 
plasma proteins, and impaired biliary excretion [2, 3]. Accordingly the current United States (US) 
Food and Drug Administration (FDA) guidance recommends a PK study in patients with impaired 
hepatic function if hepatic metabolism and/or excretion accounts for a substantial portion 
(ie, ≥20 % of the absorbed drug) of the elimination of a parent drug or active metabolite [4]. 
Urinary excretion is the major route for soticlestat elimination with 95% of the dose excreted in 
urine; however, urinary excretion of the parent drug is low (< 1% of the dose) indicating that 
metabolism is the near exclusive clearance pathway of soticlestat. TAK-935-G excreted in urine 
contributed to 86% of the dose suggesting that soticlestat was predominantly cleared by direct 
glucuronidation, thus the potential implications of HI on soticlestat’s hepatic metabolism, should 
be evaluated.
This study will investigate the impact of impaired hepatic function on the plasma PK of soticlestat 
and safety compared to matched healthy participants with normal
hepatic function in order to provide dosing recommendations to clinicians for future treatments of 
soticlestat to patients with varying degrees of HI. An informal interim PK data analysis was
performed following soticlestat administration in participants with moderate HI (n=8) and healthy 
matched participants with normal hepatic function, which has demonstrated higher than expected 
soticlestat exposure in participants with moderated HI than in healthy matched participants with
normal hepatic function. The Sponsor has decided not to recommend soticlestat dosing in patients
with severe HI, therefore participants with severe HI will not be enrolled in the current study. 
Instead, this study will enroll an arm of participants with mild HI in order to further investigate the 
impact of HI on soticlestat PK. Due to the variability of soticlestat PK and easier accessibility of 
healthy participants in comparison to participants with HI, an increased number of healthy 
participants will be enrolled.
The Child-Pugh classification will be used to categorize HI due to its widespread use and 
acceptance by regulatory agencies (including the FDA). It has been shown to correlate with
hepatic (ie, metabolic) clearance for several compounds [4]. In the current study, participants with 
chronic, stable HI with features of cirrhosis due to any etiology will be enrolled using the 
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 24 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Child-Pugh scale. The scale employs five clinical measures of liver disease listed in Table 6.a.
Each assessment is scored 1 - 3, with 3 indicating most severe derangement. Participants’ scores of 
5 to 6, 7 to 9, and 10 to 15 on this scale are classified as having mild, moderate, and severe HI, 
respectively.
Table 6.a
Derivation of Child-Pugh Classification Score 1
Parameter
1 point
2 points
3 points
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
Total serum bilirubin (mg/dL)
<2.0
2.0 to 3.0
>3.0
Prothrombin time (PT) (second prolonged) or
International normalized ratio (INR) (ratio)
<4
<1.70
4 to 6
1.70 to 2.30
>6
>2.30
Ascites
Absent
Slight
Moderate or participants on medication 
to control ascites
Hepatic encephalopathy grade 
None
Grade 1 or 2
Grade 3 or 4 or
participant receiving medication(s) to 
prevent encephalopathy
1 Adapted from U.S. Department of Health and Human Services. Guidance for Industry. Pharmacokinetics in Patients 
with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling (2003) [4].
Table 6.b
Determination of Encephalopathy Grade 1
Encephalopathy Grade
Definition
0
Normal consciousness, personality, neurological exam
1
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting
2
Lethargic, time-disoriented, inappropriate, asterixis, ataxia
3
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity
4
Unrousable coma, no personality/behavior, decerebrate
1 Adapted from U.S. Department of Health and Human Services. Guidance for Industry. Pharmacokinetics in Patients 
with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling (2003) [4].
6.4.2
Rationale for Dose 
T4 tablets are immediate release tablets of 100 mg strength that will be utilized for phase 3 clinical 
studies and will be used in this study. The model simulation (SimCYP®) predicted increase in 
soticlestat exposure in participants with moderate or mild HI is within two-fold, therefore the dose 
of soticlestat selected for the HI study is 300 mg, the recommended phase 3 dose. The 300 mg dose 
is approximately 22% of the highest single dose of 1350 mg evaluated in healthy participants, and 
soticlestat exposure at 1350 mg was > 4-fold the exposure at 300 mg. In clinical studies, soticlestat 
administered as a single dose of up to 1350 mg was safe and well tolerated. As metabolism is the 
near exclusive clearance pathway of soticlestat in humans, the effect of moderate or mild HI on the 
exposure to soticlestat 
 will be characterized in this study 
on-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 25 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
to establish scientifically guided dosing recommendations in these special patient populations. The 
PK of soticlestat 
 following oral administration of 
soticlestat in participants with moderate or mild HI using Child-Pugh scores will be compared to 
matched healthy participants with normal hepatic function. 
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, ECGs, laboratory assessments, C-SSRS, and physical examinations.
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 within the sampling windows.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of soticlestat for all participants with moderate HI, mild HI, and 
healthy participants with normal hepatic function (ie, Arms 1, 2, and 3) may not be modified.
ct to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 26 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
After all participants in the moderate HI arm and 12 participants in the matched normal hepatic 
function arm have completed the treatment period, an informal interim PK data analysis is planned 
and may additionally leverage historical control PK data in healthy participants to gain an initial 
estimate of the effect of moderate HI on the PK of soticlestat 
. Following 
completion of enrolment of the mild HI arm, and in the instance any of the previously enrolled 
healthy participants cannot be used for matching purposes, up to an additional 12 participants may 
be enrolled for the matched normal hepatic function group (Arm 3) to ensure a minimum of 
12 participants with normal hepatic function and matching the mean of the mild HI arm by age 
(mean ± 10 years), sex (± 2 per sex), and body mass index (BMI, mean ± 10%) are enrolled.
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.
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 visit 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
The clinical site(s) reserve(s) 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.
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.
Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 27 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL

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.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
7.1
Inclusion Criteria 
7.1.1
Inclusion for Participants with Hepatic Impairment
Participants must fulfill the following inclusion criteria to be eligible for participation in the study 
(participants who do not qualify based on a reversible condition or mild intercurrent illness may be 
re-screened after the condition is resolved. Screening tests may be repeated if in the Investigator’s 
opinion the test needs to be repeated):
1. Is an adult male or female participant aged ≥ 18 to < 75 years, at screening.
2. Has a BMI ≥18.0 and ≤40.0 kg/m2, at screening. At least 50% of the participants will be
required to be of BMI ≥18.0 and ≤35.0 kg/m2, at screening. 
3. Aside from HI, be sufficiently healthy for study participation based upon medical history, 
physical examination, vital signs, ECGs, and screening clinical laboratory profiles, as deemed 
by the Investigator or designee.

Supine BP is ≥ 80/40 mmHg (asymptomatic) and ≤ 150/95 mmHg, at screening;

Supine PR is ≥ 40 bpm and ≤ 99 bpm, at screening;

QTcF is ≤ 500 msec and ECG findings considered normal or not clinically significant by 
the Investigator or designee, at screening.
4. The participant must have had chronic HI for at least 3 months before screening, and the HI 
must be stable, ie, no significant changes in hepatic function in the 30 days preceding 
Commercial Use Only and Subject to the Applicable Terms of Use
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


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 28 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
screening (or since the last visit if within 6 months before screening) and treatment with stable 
doses of medication. Has a score on the Child-Pugh Class at screening as follows: 

(Arm 1) Moderate HI, Child-Pugh Class B: ≥ 7 and ≤ 9

(Arm 2) Mild HI, Child-Pugh Class A: ≥ 5 and ≤ 6
5. Participants should not have renal dysfunction as demonstrated by a relatively adequate renal 
function (creatinine clearance ≥ 50 mL/min), at screening.
7.1.2
Inclusion for Healthy Participants
Participants must fulfill the following inclusion criteria to be eligible for participation in the study:
1. Is an adult male or female participant aged ≥ 18 to < 75 years, at screening. Healthy 
participants will be matched to hepatic impaired participants in this study by sex (± 2 per sex) 
and by age (mean ± 10 years). 
2. Has a BMI ≥18.0 and ≤40.0 kg/m2, at screening. At least 50% of the participants will be 
required to be of BMI ≥18.0 and ≤35.0 kg/m2, at screening. Healthy participants will be 
matched to hepatic impaired participants in this study by BMI (mean ± 10%).
3. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee. 

Supine BP is ≥ 90/40 mmHg and ≤ 150/95 mmHg, at screening;

Supine PR is ≥ 40 bpm and ≤ 99 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;

Liver function tests including ALT, AST, ALP and total bilirubin ≤the ULN at screening 
and check-in.
4. Participants should not have renal dysfunction as demonstrated by a relatively adequate renal 
function (creatinine clearance ≥ 60 mL/min), at screening.
7.1.3
Inclusion for Participants with Hepatic Impairment and Healthy Participants
Participants must fulfill the following inclusion criteria to be eligible for participation in the study:
1. Understands the study procedures in the ICF, provides a signature/date in the ICF, and is 
willing and able to comply with the protocol.
2. Continuous non-smoker or moderate smoker (≤10 cigarettes/day or the equivalent) before 
screening. Participant must agree to consume no more than 5 cigarettes or equivalent/day from 
the 7 days prior check-in and until discharge from the CRU.
3. Female participants of childbearing potential and male participants agree to comply with any 
applicable contraceptive requirements of the protocol as detailed in Appendix D.
mmercial Use Only and Subject to the Applicable Terms of Use
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erty
2.


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 29 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
7.2
Exclusion Criteria
7.2.1
Exclusion for Participants with Hepatic Impairment
The participant must be excluded from participating in the study if the participant:
1. Has history or presence of clinically significant medical or psychiatric condition or disease 
(aside from HI) or presence of psychotic disorders such as psychosis, delusions, or 
schizophrenia in the opinion of the Investigator or designee.
2. Has a history of liver or other solid organ transplant.
3. Has history or presence of alcoholism and drug abuse within the past 6 months prior to dosing.
4. Positive result at screening for HIV. HBsAg positive participants are allowed to be enrolled if 
HBV DNA is below 1000 copies/mL in the plasma. Participants with moderate or mild HI who 
are positive for HCVAb can be enrolled but must not have detectable HCV RNA in the plasma.
7.2.2
Exclusion for Healthy Participants
The participant must be excluded from participating in the study if the participant:
1. Has history or presence of clinically significant medical or psychiatric condition or disease or 
presence of psychotic disorders such as psychosis, delusions, or schizophrenia in the opinion 
of the Investigator or designee.
2. Has history or presence of alcoholism and drug abuse within the past 2 years prior to dosing.
3. Positive results at screening for HIV, HBsAg, or HCV.
7.2.3
Exclusion for Participants with Hepatic Impairment and Healthy Participants
The participant must be excluded from participating in the study if the participant:
1. Has 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.
2. Has history or presence of clinically significant hypersensitivity or idiosyncratic reaction to the 
study drug or related compounds.
3. Has positive results for the urine or saliva drug screen at screening or check-in, unless the 
positive drug screen is due to prescription drug use that is approved by the Investigator 
(cannabinoids can be used for medicinal use at the discretion of the Investigator).
4. Is a female with a positive pregnancy test or who is lactating.
5. Has positive results for urine or breath alcohol screen at screening or check-in.
6. Is unable to refrain from or anticipates the use of any medication or substance (including 
prescription or over-the-counter, vitamin supplements, natural or herbal supplements) as 
indicated in Section 7.3 (Excluded Medications, Supplements, Dietary Products) for the 
prohibited time period.
mmercial Use Only and Subject to the Applicable Terms of Use
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4.


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 30 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
7. 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 dosing.
8. Has made a donation of blood or had significant blood loss within 56 days prior to dosing.
9. Has made a plasma donation within 7 days prior to dosing.
10. Participated in another clinical study within 30 days prior to dosing. The 30-day window will 
be derived from the date of the last dosing in the previous study to Day 1 of the current study.
11. Any positive responses on the C-SSRS or has a risk of suicide according to the Investigator’s 
judgment based on the assessment of the C-SSRS at screening or check-in or has made a 
suicide attempt in the previous 12 months prior to dosing.
7.3
Excluded Medications, Supplements, Dietary Products
Healthy participants will be restricted of using any prescription medications/products and any
over-the-counter, nonprescription preparations (including herbal products, natural or herbal 
supplements) from at least 14 days before dosing and throughout the study. However, healthy 
participants that are on stable medication for at least 30 days prior to dosing may be enrolled upon 
approval by the Investigator (or designee) and Sponsor.
Participants with HI who are taking medications to treat manifestations of hepatic disease or 
medications needed to treat for stable diseases (e.g., diuretics, angiotensin converting enzyme 
inhibitors, angiotensin II receptor antagonists, and beta-blockers) will be allowed to participate in 
the study at the discretion of the Investigator and following consultation with the Sponsor. For 
hepatic disease related medical conditions, participants must be on a stable dose (steady dose, 
drug, and regimen) for at least 30 days and/or for non-hepatic disease related medical conditions 
for 14 days before dosing and able to withhold the use for at least 4 hours postdose. Phosphate 
binders containing aluminum, calcium, or lanthanum salts; iron supplements or other metal 
cations; H2-receptor antagonists (except cimetidine); or multivitamins containing iron or zinc 
must be withheld at least 8 hours before dosing and at least 4 hours postdose.
If a participant with HI is prescribed prohibited medication, upon discussion between the sponsor 
and the Investigator, the Investigator may substitute the previously prescribed medication to an 
allowed one for the purpose of this study.
For all participants, any drugs known to be strong inhibitors or inducers of CYP3A, UGT1A9 or 
UGT2B4, including St. John’s Wort, will be restricted for 14 days or 28 days, respectively, before 
dosing and throughout the study. Use of moderate and weak inhibitors or moderate and weak 
inducers may be deemed acceptable following consultation with the sponsor and the Investigator 
or designee. Appropriate sources (e.g., Flockhart TableTM) will be consulted to confirm lack of 
PK/PD interaction with study drug. Cannabinoids can be used for medicinal use at the discretion of 
the Investigator.
For all participants, following dosing, acetaminophen (up to 2 g per 24 hours) may be 
administered at the discretion of the Investigator or designee. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 31 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Any medication (including over-the-counter) that would significantly alter creatinine clearance, 
which, by the determination of the Investigator, might interfere with the study (e.g., cimetidine) 
must be discontinued at least 2 weeks prior to dosing and throughout the study.
All medications taken by participants during the course of the study will be recorded.
Concurrent medication during the course of the study including both prescription and 
non-prescription drugs may be permitted based on the timing of study drug administration and its 
pharmacology, but must first be discussed with the Investigator or designee and sponsor prior to 
dosing, unless appropriate medical care necessitates that therapy should begin before the 
Investigator or designee and sponsor can be consulted. 
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 
based on the time the drugs were administered and their pharmacology.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing 
(Days -28 to Predose [Day 1])
After Dosing (Day 1) to 
Discharge (Day 7)
Alcohol
Prohibited from 48 hours prior to dosing
Prohibited from dosing until 
discharge from CRU completed.
Xanthine and/or caffeine
Prohibited from 24 hours prior to dosing a
Prohibited from dosing until 
discharge from CRU completed.a
Medications 
See Section 7.3
See Sections 7.3
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to dosing
Prohibited from dosing until 
discharge from CRU completed.
Nicotine and analogous 
derivatives
≤5 cigarettes/day 7 days prior to dosing
≤5 cigarettes/day until discharge 
from CRU completed.
(a) small amounts of caffeine derived from normal foodstuffs e.g., 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 dosing) will be restricted 1 hour prior to and 1 hour after 
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.
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
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ble
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W


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 32 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Participants will fast overnight for at least 10 hours prior to dosing. Participants 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.
7.4.2
Activity
All participants will remain seated for the first 4 hours following dosing, 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 postdose, participants may 
be allowed to rise for brief periods under supervision (e.g., 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. 
Participants must not consume more than 5 cigarettes or equivalent/day from the 7 days prior to 
check-in and until discharge from the CRU. Depending on the CRU rules and regulations, 
participants may be prohibited from smoking during their confinement or during portions of their 
confinement. 
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.
Liver Function Test (LFT) Abnormalities
Appropriate clinical follow-up will be conducted (including repeat laboratory tests, until a 
participant’s laboratory profile has returned to normal/baseline status, see Section 9.2.9.1), 
if the following circumstances occur at any time following study drug treatment:
–
ALT or AST >8x ULN, or
–
ALT or AST >5x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
QTcF interval: 
Appropriate clinical follow-up will be conducted if a QTcF interval >500 msec and/or an 
increase from baseline > 60 msec is detected by ECG and confirmed with a repeat ECG at 
any time following study drug treatment. Appropriate clinical follow-up includes a repeat 
ECG.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
om all
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 33 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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: Attempts to contact the participants were unsuccessful. Attempts to contact 
the participant must be documented in the participant’s source documents.
4. Voluntary withdrawal: The participants (or participant’s legally acceptable representative) 
wish 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 
COVID-19 pandemic (other than a COVID-19-related AE), this should be specified as the 
reason for participant withdrawal in the CRF.
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.
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 CRF.
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. Any participant who is not PK evaluable 
including those experiencing emesis within 8 hours post dose may be replaced at the discretion of 
the Investigators in consultation with the sponsor to ensure 8 PK-evaluable participants in each 
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 34 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
arm of participants with HI and 12-24 PK-evaluable participants in matched participants with 
normal hepatic function complete.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Investigational Medicinal Product
Product Name: 
Soticlestat (TAK-935)
Strength: 
100 mg 
Dose: 
300 mg, 3 x 100mg 
Dosage Form/Formulation: 
T4 immediate-release tablet
Dosing regimen: 
Single dose 
Route of Administration: 
Oral
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 same lot number will be used throughout the study. The lot numbers and expiration dates 
(where available) of the study drug 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 Code Creation and Storage 
Not applicable.
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/clinical sites, as applicable, 
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
cal label
ly a
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 35 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 Identification 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 identification number at the time of dosing, different from the screening number.
If replacement participants are used, the replacement participant number will be 100 more than the 
original participant’s identification number (eg, Participant No. 101 will be assigned to the 
replacement of Participant No. 1).
9.1.1.2
Study Drug Assignment
All participants will receive the treatments as detailed in Section 9.2.8.
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, history of
tobacco use, and Child-Pugh classification will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 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 
ercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 36 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 plasma 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
Full Physical Examination
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee.
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.
9.2.4
Vital Signs
Single measurements of temperature, respiratory rate, BP, and PR 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 (after resting in a supine position for at least 5 minutes), except when they are 
semi-reclined because of study procedures and/or AEs (e.g. nausea, dizziness) or if deemed 
necessary by the Investigator or designee.
Vital signs will be measured within 24 hours prior to dosing for the predose time point. 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 (after resting in supine position for 
at least 5 minutes). All ECG tracings will be reviewed by the Investigator or designee.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 37 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
ECGs will be measured within 24 hours prior to dosing for the predose time point. When 
scheduled postdose, ECGs will be performed within approximately 20 minutes of the scheduled 
time point.
9.2.6
Study Drug Administration
Soticlestat will be provided as described in Section 8.1.
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.
Participants will be instructed not to crush, split, or chew the tablets.
The exact clock time of dosing will be recorded.
Treatment will be administered as follows: 
Soticlestat 300 mg (3 x 100 mg T4 tablets) at Hour 0 on Day 1.
9.2.7
C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures (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. 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. When possible, it is highly 
recommended that assessments will be conducted by the same rater for consistency.
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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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 38 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Coagulation
Coagulation test will consist of the following tests:
Activated partial thromboplastin time
PT/ INR
Chemistry 
Serum chemistry tests will be performed in the fasted state 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 taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Amylase
Sodium
Lipase
Potassium
Blood Urea Nitrogen
Chloride
Bilirubin (total and direct)
Glucose
ALP
Creatinine *
AST
Magnesium
ALT
AGP 
Albumin
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault equation.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* 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.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 39 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
9.2.9.1.1
Other 
HIV test
Urine/saliva drug screen
Opiates (includes morphine, heroin (diacetylmorphine), 
codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, 
thebaine, and, hydromorphone)
Amphetamines
Barbiturates
Benzodiazepines
Cocaine
Cannabinoids 
HBsAg (if antibody positive, confirm DNA is below 
1000 copies/mL in participants with HI)
HCV (if antibody positive, confirm RNA negative in 
participants with HI)
Urine/breath alcohol screen
Serum pregnancy test (for females only)
FSH (for females only)
9.3
PK Samples
Samples for assessment of soticlestat
will be collected as delineated in Table 9.a.
Instructions for sample collection, processing, and shipping will be provided in separate 
documents. 
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
(Soticlestat 
)
Blood
Plasma
Plasma sample for PK analysis
Mandatory
Blood
Plasma
Mandatory
9.3.1
PK Measurements 
Samples from all participants will be assayed even if the participants do not complete the study. 
Samples for determination of plasma soticlestat 
will be 
analyzed using validated bioanalytical methods.
Pharmacokinetic parameters of soticlestat 
 will be 
calculated from the individual concentration-time profiles from all evaluable participants using 
noncompartmental analysis methods. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. 
The fraction of unbound soticlestat will be determined.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 40 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
9.3.1.1
Plasma for PK Measurements
The following PK parameters will be calculated from plasma concentrations of sotisclestat 
 unless otherwise specified:
AUClast:
The area under the concentration-time curve, from time 0 to the last 
quantifiable concentration, as calculated by the linear-log trapezoidal 
method.
AUC:
The area under the concentration-time curve, from time 0 extrapolated to 
infinity. AUCis calculated as AUClast plus the ratio of the last measurable 
blood concentration to the elimination rate constant.
Cmax:
Maximum observed concentration.
No value for 
AUC, 
 
will be reported for cases that do not exhibit a terminal 
log-linear phase in the concentration versus time profile.
No PK parameters will be calculated for participants with detectable concentrations at 2 or fewer 
consecutive time points. 
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
Additional PK parameters may be estimated as appropriate.
9.3.2
Biomarker Measurements 
Not applicable.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 41 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
9.3.3
PGx Measurements 
Not applicable.
9.3.4
Confinement
Participants will be restricted and confined to the CRU on Day -1, at the time indicated by the 
CRU, until after the 144-hour blood draw and/or study procedures (Day 7) as outlined in the
Schedule of Study Procedures (Section 3.0). Participants may be admitted to the CRU earlier for 
COVID-19 procedures not related to the study protocol.
At all times, a participant may be required to remain at the CRU for longer for safety reasons at the 
discretion of the Investigator or designee.
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.
A TEAE is defined as any untoward medical occurrence in a clinical investigation participant that 
occurs following administration of the investigational study 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).
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 42 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 
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 administration of 
study medication or 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.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 43 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 
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.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 44 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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).
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
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
COVID-19-related disease
COVID-19 pneumonia
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.
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 45 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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.
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.
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. All other events are continuous or single episodes.
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.
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10.2.
erty
10.2.


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 46 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL

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.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular 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, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, 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 
on Day 14 ± 2 days after the soticlestat dose. For participants who discontinue prior to the 
administration of study medication, AEs will be followed until the participant discontinues study 
participation. 
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 
l Use Only and Subject to the Applicable Terms of Use
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part
erty
part


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 47 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
experiencing an SAE prior to the 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 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]).

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.

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 
Appendix 14.1.1.
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
o o 
be 
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Inv

e



Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 48 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 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 
Not Applicable. 
10.2.8.5
Reporting of Abnormal LFTs
Healthy Participants Only
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 10.0 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 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
Commercial Use Only and Subject to the Applicable Terms of Use
me 
o
me 
later da
able
later da
ocument
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er
IEC


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 49 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will
be documented in a SAP. The SAP will be prepared by Celerion and agreed upon with the 
Sponsor. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoints definition and/or its analysis will also be reflected in a 
protocol amendment. Additional statistical analyses other than those described in this section may 
be performed if deemed appropriate.
11.1.1
Analysis Sets
11.1.1.1
PK Set
All participants who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) will 
be included in the statistical analyses.
11.1.1.2
Safety Set
All participants who received the dose of soticlestat will be included in the safety evaluations.
11.1.1.3
PD Set
Not applicable.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, sex, race, and ethnicity)
will also be listed and tabulated.
11.1.3
PK Analysis
Statistical analysis of PK data will be based on the PK analysis set. 
Descriptive statistics will be used to summarize concentrations of soticlestat and PK parameters 
according to hepatic function group (normal hepatic function, moderate and mild HI). An ANOVA 
will be performed on the ln-transformed Cmax, AUClast, and AUC∞for soticlestat to compare each 
HI group with the normal hepatic function group, and 90% CIs for the ratio of geometric means 
from each HI group versus normal function group will be provided. The addition of other factors 
and covariates such as age, sex, and BMI on the relationship between soticlestat PK parameters 
and level of HI may also be investigated. 
y of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
in this s
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in this s
pon with
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App
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Descr
acc
er
acc


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 50 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Descriptive statistics will be used to summarize concentrations 
and PK parameters according to hepatic function group (normal hepatic function and 
moderate and mild HI).
The fraction of unbound soticlestat will be determined.
11.1.4
PD Analysis 
Not applicable.
11.1.5
Safety Analysis
All safety data will be populated in the individual CRFs.
Dosing dates and times will be listed by participant.
TEAEs will be tabulated. The remaining quantitative safety data as well as the difference to 
baseline, when appropriate, will be summarized using the appropriate descriptive statistics.
11.1.5.1
AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by group for the number of participants 
reporting the TEAE and the number of TEAEs reported. A by-participant AE data listing including 
verbatim term, coded term, treatment, severity, and relationship to treatment will be provided. AEs 
that occur before administration of study drug will be included in listings but will not be 
summarized.
11.1.5.2
Clinical Laboratory
Clinical laboratory results will be summarized by group and point of time of collection and a shift
table describing out of normal range shifts will be provided. 
MAV criteria for safety laboratory assessments will be defined in the SAP.
11.1.5.3
Vital Signs
Vital signs assessments will be summarized by group and point of time of collection and a shift 
table describing out of normal range shifts will be provided. 
MAV criteria for vital signs will be defined in the SAP.
11.1.5.4
Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs and C-SSRS results will be summarized by group and point of time of collection and a shift
table describing out of normal range shifts will be provided. 
MAV criteria for ECGs will be defined in the SAP.
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
as well
ct to
as well
ropriate
bjec
ropriate
Medica
and
Medica
ed by gr
nly a
ed by gr
reported
Only
reported
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and 
drug w
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ill be su
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Co
rmal ran
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Property of Takeda: Fo
labo
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labo
al Signs
For 
al Signs
as
d
assessm
da: F
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cribing 
keda
cribing 
V cri
Tak
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11.1.5.
ty o
11.1.5.
Ph
er
Ph


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 51 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
Medical history and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization (WHO) drug dictionary and will 
be listed by participant.
11.2
Interim Analysis and Criteria for Early Termination
After all participants in the moderate HI arm and 12 participants in the matched normal hepatic 
function arm are enrolled, an informal interim PK data analysis is planned and may additionally
leverage historical control PK data in healthy participants to gain an initial estimate of the effect of 
moderate HI on the PK of soticlestat 
.
11.3
Determination of Sample Size
The planned sample size of 8 participants in each HI arm is not based on power calculations and is 
considered adequate to provide a descriptive characterization of the PK of soticlestat 
 
 in participants with moderate or mild HI compared to healthy participants with normal 
hepatic function.
Any participant who is not PK evaluable including those experiencing emesis within 8 hours post 
dose may be replaced at the discretion of the Investigators in consultation with the sponsor to 
ensure 8 PK-evaluable participants in each arm of participants with HI and 12-24 PK-evaluable 
participants in matched participants with normal hepatic function complete.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study sites will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Detailed information for monitoring visits to be conducted in 
this study will be documented in a Clinical Research Associate Monitoring Plan and followed 
during the study. Source documents will be reviewed for verification of data recorded on the 
CRFs. Source documents are defined as original documents, data, and records. The Investigator
and study site guarantee access to source documents by the Sponsor or its designee contract 
research organization and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee, including but not limited to the Investigator’s Binder, study drug, participant 
medical records, informed consent documentation, and review of CRFs and associated source 
documents. It is important that the Investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
12.2
Protocol Deviations
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the Investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
al hepat
Te
al hepati
addi
ble
additi
e 
ti
iti
e
iti o
te of the
cab
te of the
d on pow
o th
d on pow
he PK o
t to
he PK o
to healt
ject 
to healt
e exper
d Su
e exper
gators in
and
gators in
f particip
ly a
f particip
al
O
al hepat
Only
hepat
l
O
l
UALIT
Use
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sits
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tes will 
mer
tes will 
llowed. 
mm
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Com
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ments ar
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ments ar
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or
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nit
1
e
1


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 52 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
There will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria.
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. 
Detailed information for medical and safety monitoring to be conducted in this study will be 
documented in a Medical Monitoring Plan and followed during the study.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be participant to quality assurance audits by the Sponsor or designees. In 
this circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the 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.
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
conduct,
le T
conduct,
udy asse
able
udy asse
s study
plic
s study
ctions
the
ctions
by the S
t to
by the S
the site
ject 
the site
ere labo
ubje
ere labo
her facili
d Su
her facili
inspect
nd S
inspect
ited Kin
y an
ited Kin
als and M
Only 
als and M
regul
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On
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access f
Use O
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F T
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m
with
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For 
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ty
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an
e
an


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 53 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, participant recruitment materials and/or advertisements and other documents required 
by all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and participant informed consent 
must be obtained and submitted to the Sponsor or designee before commencement of the study (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 participant 
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 ICF 
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 
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
d
o
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onsent 
erms
onsent 
e study (
Ter
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he IRB
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date; ide
able
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App
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ent auth
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ect 
ive IRB
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Sub
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nt
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e
a


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 54 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
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 
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 ICF 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 ICF 
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 ICF, 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 ICF, the signed participant authorization form (if applicable), and participant 
information sheet (if applicable) shall be given to the participant.
All revised ICFs 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 ICF.
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
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 55 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
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 Americas 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.
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.
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 56 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
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.
ubject to the Applicable Terms of Use
ant
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policy, h
e Te
policy, h
t t
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Sub
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je
Property of Takeda: For Non-Commercial Use Only and Su


Soticlestat
Study ID
Page 57 of 74
Protacol Incorporating Amendment
01
2022
INVESTIGATOR AGREEMENT
confirm that
have read and that I understand this protocol, the Investigator’s Brochure, packa
insert and any other product information provided by the Sponsor.
agree to conduct this stu
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
on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.
All applicable laws and regulations,
without limitation, dat privacy laws and
regulations.
Regulatory requirements for reporting serious adverse events defined in
10.2.9 ofthis
protocol.
Terms outlined in the study site agreement.
Responsibilities ofthe
ftf
Investigator (Appendix B).
that my
information m
be processed and transferred in accordance
CONFIDENTIAL
ly and Subject to the Applicable Terms of Use
ckage
of U
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study
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study in
o
in
privacy
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define
).
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).
may
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may be
n
be
Property of Ta
Takeda: For Non-Commercial Use Only


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 57 of 74
Protocol Incerporating Amendment No. 01
April 2022
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. J 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:
e
The ethical principles that have their origin in the Declaration of Helsinki.
e
Council on Harmonisation,
Good Clinical Practice: Consolidated Guideline.
e
All applicable laws and regulations, including, without limitation, da
privacy laws and
regulations.
Regulatory requirements for reporting serious adverse events
fined in Section 10.2.9 ofthis:
protocol.
e
Terms outlined in the study site agreement.
e
Responsibilities ofthe Investigator (Appendix B).
I further authorize tha
pergonal information may be processed and transferred in accordance
with the uses
D ofth
protocol.
CONFIDENTIAL
Only and Subject to the Applicable Terms of Use
ackage
ms
ackage
study
Term
study in
m
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,
e
, privacy
e Te
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B).
may
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may be
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f
O
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this pr
nly
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Property of
of Takeda: For Non-Commercial Use On


The ethical principles that have their origin in the Declaration ofHelsinki.
International Council on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.
Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 ofthis
protocol.
Terms outlined in the study site agreement.
Responsibilities ofthe
ftf
Investigator (Appendix B).
CONFIDENTIAL
nly and Subject to the Applicable Terms of Use
olidated
ppli
olidated
a
e
a privac
he Ap
privac
defined
t to
defined
Property of Ta
Takeda: For Non-Commercial Use Only


The ethical principles that have their origin in the Declaration of Helsinki.
International Council on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.
Regulatory requirements for reporting serious adverse events defin
in Section 10.2.9 ofthis
ftf
protocol.
Terms outlined in the study site agreement.
Responsibilities ofthe Investigator (Appendix B).
CONFIDENTIAL
ms of Use
y and 
d Subject to the Applicable Term
ly a
dated
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dated G
privacy
App
privacy
fined
to t
fined in
t
in
Propertyty o
y of Takeda: For Non-Commercial Use Only


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 58 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
14.1.3
Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4
List of Abbreviations
µg
Microgram
24HC
24S-hydroxycholesterol
ADME
Absorption, distribution, metabolism, excretion
AE
Adverse event
AGP
Alpha-1-acid glycoprotein
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC
The area under the concentration-time curve, from time 0 to infinity
AUClast
The area under the concentration-time curve, from time 0 to the last quantifiable 
concentration, as calculated by the linear-log trapezoidal method.
BID
Twice daily
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
CDD
CDKL5 deficiency disorder
C-SSRS
Columbia-Suicide Severity Rating Scale
CFR
Code of Federal Regulations
CH24H
cholesterol 24S hydroxylase
CI
Confidence interval
Cm
Centimeter
Cmax
Maximum observed concentration 
COVID-19
Coronavirus Disease-2019
CRF
Case report form
CRU
Clinical Research Unit
CSR
Clinical study report
CYP
Cytochrome P450
DEE
Developmental and Epileptic Encephalopathies
dL
Deciliter
DNA
Deoxyribonucleic acid
mmercial Use Only and Subject to the Applicable Terms of Use
e curv
an
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n
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ion
nl
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nly
-time
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time
tration
On
tration-t
n
t
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se 
lated by 
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e
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mme
r minute
For Non-Co
KL5 defic
Com
KL5 defic
olumbia
Co
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Code o
Non
Code o
ch
No
ch
Property of Takeda
VID
f T
VID-
f T
-19
Ta
19
CRF
y o
CRF
CRU
erty
CRU
C
e
C
da: F


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 59 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
DS
Dravet Syndrome 
Dup15q
15q11-q13 duplication syndrome
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
h
Hour(s)
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus 
HCVAb
Hepatitis C virus antibodies
HI
hepatic impairment
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
IUD
Intrauterine device
kg
Kilogram
L
Liter
LFT
Liver function test
LGS
Lennox Gastaut Syndrome
ln
Natural log
m2
Meters squared
MAV
Markedly abnormal values
μg
Microgram
μmol
Micromole
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
N
Number
OATP
organic-anion-transporting polypeptide
PD
Pharmacodynamic(s)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
nisation
y an
nisation
ee
O
ee
ratio
O
ratio
Board
Use
Board
unction t
mm
unction t
nox Gas
Com
nox Gas
Natural l
n-C
Natural l
Mete
Non
Mete
M
N
M
n
o
n
mL
ty
mL
mmH
erty
mmH
pe


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 60 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
PK
Pharmacokinetic(s)
PR
Pulse rate
PT
Prothrombin time
PTE
Pretreatment event
QD
Daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
t½z
Terminal disposition phase half-life
TEAE
Treatment-emergent adverse event
tmax
Time of first occurrence of Cmax
UGT
Uridine 5' diphospho-glucuronosyltransferase
ULN
Upper limit of normal
US
United States
USA
United States of America
WHO
World Health Organization
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
n
nly an


Soticlestat (TAK-935)
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Protocol Incorporating Amendment No. 01
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA®. Drugs will be 
coded using the WHO Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed CRFs are required for each participant who signs an informed consent.
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the CRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory
authorities. CRFs must be completed in English. Data are transcribed directly onto CRFs.
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 ICFs, participant authorization forms regarding 
the use of personal health information (if separate from the ICFs), electronic copy of CRFs, 
including the audit trail, and detailed records of drug disposition to enable evaluations or audits 
from regulatory authorities, the Sponsor or its designees. Any source documentation printed on 
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
an. 
o
an. 
ill be
ms o
ill be
nt.
ic
nt.
RFs. The
Appli
RFs. The
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e Ap
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to th
ed direc
ill be ru
ect t
ill be ru
ueries m
bje
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s the old
and 
s the old
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y an
he date 
sh
On
shoul
Only
ould a
y
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CRFs for
se O
CRFs for
Furtherm
Use
Furtherm
he
al
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nticit
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Non
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. The Sp
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Property of Taked
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 62 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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. Edition 7, 
31 January 2022; plus Addendum 1, 03 February 2022, for Edition 7, 31 January 2022.
2. Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet 
1999;37(5):399-431.
3. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. 
European Journal of Clinical Pharmacology 2008;64(12):1147-61.
4. U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function 
— Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003.
y and Subject to the Applicable Terms of Use
rs
o
rs
gated 
ms o
gated 
ued and
rms
ued and
dy
T
dy record
Ter
record
y
T
y
ments or
ble T
ments or
Sponso
able
Sponso
record 
plic
record 
written 
App
written 
nvest
ject
nvestiga
ct
iga
f
Su
for Edi
ubje
or Edi
fo
f
u
fo
f
rcial Use On
kinet
d S
kinetics
S
ics
 adjustm
Only 
 adjustm
gy
O
gy 2008
On
2008
y
O
y
an Servi
Use
an Servi
DER), C
al U
DER), C
. Pharm
rcia
. Pharm
Property of Takeda: For Non-Comme
ysis, and
merc
ysis, and


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 63 of 74
Protocol Incorporating Amendment No. 01
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CONFIDENTIAL
17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff 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 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 particiant 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 ICF should contain a participant 
authorization section that describes the uses and disclosures of a participant’s personal 
information (including personal health information) that will take place in connection with the 
study. If an ICF does not include such a participant authorization, then the investigator must 
obtain a separate participant authorization form from each participant or the participant’s 
legally acceptable representative.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
icable
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icable
mpleted 
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orm FD
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ocol.
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should
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study
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Use 
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aut


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 64 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 
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.
he Applicable Terms of Use
or 
o
or 
ould 
ms
ould 
cified es
ble 
cified es
f Spons
Appli
f Spons
Property of Takeda: For Non-Commercial Use Only and Subject to t
f an SAE
the
f an SAE


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 65 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 ICF, 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.
n-Commercial Use Only and Subject to the Applicable Terms of Use
es.
ic
es.
lit
ub
lity 
ubj
y fo
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for r
je
r r
reatmen
and
reatmen
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n
risks or 
nly 
sks or 
g infant.
On
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artici
Use
articipan
se
pan
ipi
se
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alternat
mer
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r
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cipant a
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ng the e
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Property of Takeda: For No
mainta
Non
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ant’s leg
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ant’s leg
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keda
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Take
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e
1


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 66 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 ICF 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. Female participants of childbearing potential (eg, nonsterilized, premenopausal female 
participants) who are sexually active must use highly effective/effective contraception (as 
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dures fo
Term
dures fo
ntative w
able
ntative w
relevant
lica
relevant
nt’s part
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nt’s part
he ICF o
ct to
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nd
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nd perm
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perm
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Subje
sonal he
n m
S
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ust c
Su
ust c
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ant’s per
nd 
ant’s per
onal hea
ly a
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ntries fo
Only
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and ef
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keda
evelopin
Property of Tak
clinica
ake
clinica
d)
of T
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T
th


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 67 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
defined in the informed consent) from signing the informed consent, throughout the duration 
of the study, and 30 days after dosing of study drug. Regular pregnancy tests will be performed 
throughout the study for all female participants. 
25. Male participants must use effective contraception (as defined in the informed consent) from 
signing the informed consent, throughout the duration of the study and for 90 days after dosing 
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.
ble Terms of Use
from
ms
from
er dosin
Term
er dosin
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicab
sed in a 
able
sed in a 


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 68 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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.
on-Commercial Use Only and Subject to the Applicable Terms of Use
eg, the 
rms
eg, the 
d transf
to t
d transf
g:
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g:
dy
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and/o
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For
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 69 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Participants
From signing of informed consent, throughout the duration of the study, and for 90 days after 
dosing of study drug, nonsterilized* male participants who are sexually active with a female 
partner of childbearing potential** must agree to use a condom with spermicide. In addition, they 
must be advised not to donate sperm during this period.
Female Participants and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 30 days after 
dosing of study drug, female participants of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective/effective method of contraception (from 
the list below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* No restrictions are required for a vasectomized male provided his vasectomy has been performed 
4 months or more prior to dosing. A male who has been vasectomized less than 4 months prior to 
study dosing must follow the same restrictions as a non-vasectomized male).
** A woman is considered a woman of childbearing potential (WOCBP), 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.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, 
acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
IUD
–
Bilateral tubal occlusion;
–
bilateral salpingectomy;
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
after 
Term
after 
female
e Te
female
addi
ble
additi
e
ti
iti
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iti
, and fo
he A
, and fo
who are 
o the
who are 
method
t to 
method
this peri
Subj
this peri
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and preg
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and preg
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ed male 
Only
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who has 
se O
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SH >40
Co
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hose <4
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Property of T
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y o
acc


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 70 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
–
hysterectomy;
–
bilateral oophorectomy;
–
Vasectomised partner (provided that partner is the sole sexual partner of the study
participant and that the vasectomised partner has received medical assessment of the 
surgical success).

Hormonal Methods: 
Combined (estrogen and progestogen) hormonal contraception associated with inhibition of 
ovulation initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if for shorter duration until she 
has been on contraceptive for 3 months;

oral.

Intravaginal (eg, ring).

transdermal.
Progestogen-only hormonal contraception associated with inhibition of ovulation initiated at least
6 months prior to the dose of study drug OR combined with a barrier method (male condom with or 
without spermicide) if shorter till she has been on contraceptive for 6 months;

oral.

Injectable.

Implantable.
2.
Effective methods of contraception (there may be a higher than 1% failure rate). In this 
study, where medications and devices containing hormones are included, acceptable 
methods of contraception are:
– Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom)
3.
Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
Commercial Use Only and Subject to the Applicable Terms of Use
of the 
rms
of the 
with in
plic
with in
g OR com
App
g OR com
shorter d
he A
shorter d
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and
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bined wi
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n on con
Only
n on con
ontracep
mm
ontracep
t
C
tio
Co
ions an
Com
ns an
Property of Takeda: For Non
aception
n-C
aception
arrier m
or N
arrier m
creams
For
creams
cceptabl
da:
cceptabl

a

Pe
ke
Pe

T



Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 71 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
4. Participants will be provided with information on highly effective/effective methods of 
contraception as part of the participant informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
5. During the course of the study, regular human chorionic gonadotropin (hCG) pregnancy tests 
will be performed only for all females and all participants (male and female) will receive 
continued guidance with respect to the avoidance of pregnancy, ova donation, and sperm 
donation as part of the study procedures. Such guidance should include a reminder of the 
following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) assessment of participant compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
6.
In addition to a negative serum hCG pregnancy test at Screening, female participants of 
childbearing potential must also have confirmed menses in the month before dosing (no 
delayed menses; with the exception of female participants using a protocol acceptable 
contraception method that has a known side effect of delayed or irregular menses). In addition,
participants must also have a negative serum hCG pregnancy test prior to receiving the dose of 
investigational drug as close as possible and prior to the dose of investigational drug, 
preferably on the same day.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.

reasons for use of barrier methods (ie, condom) in males with pregnant partners.

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? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ncy tests
Term
ncy tests
receive
e Te
receive
and sper
ble 
and sper
minder o
icab
minder o
pregna
the
pregna
uch as
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and
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ly a
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On
egnant?
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Use 
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rcial
n of f
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merc
s a know
e a nega
mme
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close as
Com
close as
me
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day
With Res
Non
With Res
should in
For 
should in
eptive re
da: 
eptive re
Property of Tak
sons for
aked
sons for
assessm
f T
assessm
–
y
–


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 72 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
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 dosing, 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 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.
plicable Terms of Use
orded 
ms
orded 
mary car
ble T
mary car
n that
able
n that th
le
th
y at the 
lica
at the 
y
bject to the App
ed (blin
Appli
ed (blin
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final out
t to t
final out
eam
ect
eam
Property of Takeda: For Non-Commercial Use Only and Subj
. Th
ct t
. Th
evaluat
bjec
evaluatio
c
io


Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 73 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
Appendix E
Summary of Changes from Previous Version 
The protocol is amended following informal interim PK analysis in participants with moderate HI
and matching healthy subjects with normal hepatic function. The interim analysis indicated higher 
impact of moderate HI on soticlestat PK than predicted based on model-based stimulations. The 
Sponsor decided to remove the participants with severe HI from the study because soticlestat will 
not be recommended to use in subjects with severe HI. The study protocol is amended to evaluate 
the impact of mild HI on the PK of soticlestat.
A summary of changes incorporated into Amendment 1 is provided in the table below. 
Summary of Changes(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
The protocol is update to replace 
participants with severe HI in Arm 2 with
participants with mild HI. 
Title Page
Section 1.0 (Study Summary)
Section 3.0 (Schedule of Study Procedures)
Section 4.2 (Rationale for the Proposed Study)
Section 5.2.1 (Study Primary Objective)
Section 5.2.2 (Study Secondary Objective)
Section 5.2.3 (Study Exploratory Objective)
Section 6.1 (Study Design)
Section 6.4.1 (Rational of Study Design)
Section 6.4.2 (Rationale for Dose)
Section 6.5 (Study Design/Dosing/Procedures 
Modifications Permitted Within Protocol Parameters)
Section 7.1.1 (Inclusion for Participants with Hepatic 
Impairment)
Section 7.2.1 (Exclusion for Participants with Hepatic 
Impairment)
Section 11.1.3 (PK Analysis)
Section 11.3 (Determination of Sample Size)
Participants with mild HI enrolled in 
Arm 2 of the study will receive a single 
300 mg dose of soticlestat. The protocol is 
updated to the remove the allowance to 
modify the dose of soticlestat for 
Section 1.0 (Study Summary)
Section 6.1 (Study Design)
Section 6.5 (Study Design/Dosing/Procedures 
Modifications Permitted Within Protocol Parameters)
to the Applicable Terms of Use
HI
o
HI
igher 
ms o
igher 
s.
e
s. The 
erm
The 
clestat w
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clestat w
ed to ev
ble T
ed to ev
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d Proto
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d Proto
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ffected b
o th
ffected b
he
ly and Subject to
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Soticlestat (TAK-935)
Study ID TAK-935-1010
Page 74 of 74
Protocol Incorporating Amendment No. 01
11 April 2022
CONFIDENTIAL
participants in Arm 2 following interim 
PK analysis. 
Section 8.1 (Clinical Study Drug)
Section 9.2.6 (Study Drug Administration)
Section 11.2 (Interim Analysis and Criteria for Early
Termination)
Rationale for the amendment and change 
in HI population was added.
Section 4.2 (Rationale for the Proposed Study)
Section 6.4.1 (Rational of Study Design)
The protocol is updated to include data 
from the most current IB version: 
“TAK-935. Takeda Pharmaceutical 
Company Ltd. Global Investigator’s 
Brochure. Addendum 1, 03 February
2022, for Edition 7, 31 January 2022”
Section 4.1.1 (Soticlestat (TAK-035))
Section 16.0 (References)
The protocol is updated to correct units
used for creatinine clearance listed in the 
inclusion criteria section as indicated in 
protocol clarification letter dated 
03 November 2021. Creatinine clearance 
units were incorrectly presented as 
mL/min/1.73m2 and are changed to 
mL/min since Cockcroft-Gault equation
will be used for creatinine clearance 
calculation.
Section 1 (Study Summary)
Section 7.1.1 (Inclusion for Participants with Hepatic 
Impairment)
Section 7.1.2 (Inclusion for Healthy Participants)
The protocol is updated to increase the 
number of planned clinical sites from up 
to 3 sites to up to 7 sites. 
Section 1 (Study Summary)
The protocol is updated to include new 
details for future biomedical research on
residual plasma PK samples.
Section 6.4.4 (Future Biomedical Research)
The protocol is updated to clarify that 
HBV DNA will be measured in 
participants with HI with positive HBsAg 
results. HCV RNA will be measured in 
participants with HI with positive HCV 
antibody results
Section 9.2.9.1.1 (Other)
Typographical and grammatical corrections, as well as formatting changes, were made throughout 
the protocol.
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ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
090101d6813057b6
Phase 1 Pharmacokinetics and Safety Study of Oral Soticlestat in Participants with Moderate or Mild Hepatic
Impairment and Normal Hepatic Function
Clinical Pharmacology Approval
11-Apr-2022 20:35 UTC
Clinical Approval
11-Apr-2022 21:56 UTC
Biostatistics Approval
11-Apr-2022 23:36 UTC
ble Terms of Use
e Te
ate 
T
ate 
ble T
HH:mm ‘U
ble 
HH:mm ‘U
Ter
Applicable
ble
:35 UTC
able
:35 UTC
022 21:56
ppli
022 21:56
Property of Takeda: For Non-Commercial Use Only and Subject to the
-Apr-2022
he A
-Apr-2022

SAP_001.pdf: 
NCT Number: NCT05098054
Title: Phase 1 Pharmacokinetics and Safety Study of Oral Soticlestat in Participants with Moderate or Mild 
Hepatic Impairment and Normal Hepatic Function
Study Number: TAK-935-1010
Document Version and Date: Amendment 1; 12-Jul-2022
Certain information within this document has been redacted (ie, specific content is masked irreversibly from view 
with a black bar) to protect either personally identifiable information or company confidential information. 
Statistical Analysis Plan 


STATISTICAL ANALYSIS PLAN
Study Number: TAK-935-1010
Study Title: Phase 1 Pharmacokinetics and Safety Study of Oral Soticlestat in Participants with
Moderate or Mild Hepatic Impairment and Normal Hepatic Function
Phase: 1
Version: Amendment 1
Date: 12-Jul-2022
Prepared by: 
Based on:
Protocol Version: Amendment 1
Protocol Date: 11-Apr-2022
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
n Parti
n Part
Funct
unctioio
on:n:
Protoc
Proto
Pr
P
: For Non-Commercial Use


TAK-935-1010
Page 2 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Original version
27-Oct-2021
Not Applicable
Amendment 1
12-Jul-2022
The severe hepatic impairment cohort was changed to a mild hepatic 
impairment cohort.  All references to the severe cohort in this SAP 
have been changed to mild. Furthermore, the dose will not be 
adjusted and will stay at 300 mg. Other minor corrections were made 
from the previous version. No changes were made to statistical 
methods.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-1010
Page 3 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................7
1.1
Objectives..................................................................................................................7
1.1.1
Primary Objective..............................................................................................7
1.1.2
Secondary Objective..........................................................................................7
1.1.3
Exploratory Objective(s)....................................................................................7
1.2
Endpoints...................................................................................................................7
1.2.1
Primary Endpoint(s)...........................................................................................7
1.2.2
Secondary Endpoint(s).......................................................................................7
1.2.3
Exploratory Endpoint(s).....................................................................................8
1.3
Estimand(s)................................................................................................................8
2.0
STUDY DESIGN............................................................................................................8
3.0
STATISTICAL HYPOTHESES AND DECISION RULES.............................................9
3.1
Statistical Hypotheses................................................................................................9
3.2
Statistical Decision Rules...........................................................................................9
3.3
Multiplicity Adjustment...........................................................................................10
4.0
SAMPLE-SIZE DETERMINATION.............................................................................10
5.0
ANALYSIS SETS.........................................................................................................10
5.1
Safety Analysis Set..................................................................................................10
5.2
Pharmacokinetic Analysis Set..................................................................................10
6.0
STATISTICAL ANALYSIS..........................................................................................10
6.1
General Considerations............................................................................................10
6.1.1
Handling of Treatment Misallocations .............................................................12
6.2
Study Information....................................................................................................12
6.3
Disposition of Participants .......................................................................................12
6.4
Demographic and Other Baseline Characteristics.....................................................13
6.4.1
Demographics..................................................................................................13
6.4.2
Medical History and Concurrent Medical Conditions.......................................13
6.4.3
Baseline Characteristics...................................................................................13
6.5
Medication History and Concomitant Medications...................................................13
6.6
Efficacy Analysis.....................................................................................................14
6.7
Safety Analysis........................................................................................................14
6.7.1
Adverse Events................................................................................................14
6.7.2
Adverse Events of Special Interest (if applicable) ............................................15
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-1010
Page 4 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
6.7.3
Clinical Laboratory Assessments .....................................................................15
6.7.4
Vital Signs.......................................................................................................16
6.7.5
Electrocardiograms..........................................................................................16
6.7.6
Physical Examination ......................................................................................17
6.7.7
Overdose .........................................................................................................17
6.7.8
Columbia Suicide Severity Rating Scale (C-SSRS)..........................................17
6.7.9
Extent of Exposure and Compliance ................................................................17
6.8
Pharmacokinetic Analysis........................................................................................17
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................20
6.10
Preliminary Analysis................................................................................................20
6.11
Interim Analysis ......................................................................................................20
6.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] ............................................................................................................20
7.0
REFERENCES..............................................................................................................20
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................20
9.0
APPENDIX...................................................................................................................21
9.1
Changes From the Previous Version of the SAP.......................................................21
9.2
Data Handling Conventions .....................................................................................21
9.3
Analysis Software....................................................................................................21
LIST OF IN-TEXT TABLES
Table 6.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................17
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935-1010
Page 5 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
ABBREVIATIONS
ΔQTcF
change-from-baseline QTcF
AE
adverse event
ANOVA
analysis of variance
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
AUCextrap%
area under the curve from the last quantifiable concentration to infinity calculated using the 
observed value of the last quantifiable concentration, expressed as a percentage of AUC∞
BLQ
below the lower limit of quantitation
BMI
body mass index
C-SSRS
Columbia suicide severity rating scale
CI
confidence interval
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019 
CPAP
clinical pharmacology analysis plan
CRF
case report form
CRU
clinical research unit
CSR
clinical study report
CV%
coefficient of variation
ECG
electrocardiogram
ET
early termination
Geom mean
geometric mean
Geom CV%
geometric percent coefficient of variation
GMR
geometric mean ratio
HI
hepatic impairment
ICF
informed consent form
LSMs
least-squares means
MAV
markedly abnormal value
MedDRA®
Medical Dictionary for Regulatory Activities
n
number of observations
PK
pharmacokinetic
PRO
patient-reported outcomes
PT
preferred term
QTcF
QT interval corrected for PR using Friderica’s formula
SAE
serious adverse event
SAP
statistical analysis plan
Property of
n
PK
PK
Takeda: For Non-Commercial Use Only and S
on
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ion
on
mean
mean
etric perc
ric per
ometric m
ometric
hepatic
hepati
info
inf
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RA
RA®
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the obse
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quantif
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ty calc
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a pe
d Sub


TAK-935-1010
Page 6 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
SD
standard deviation
SEM
standard error of the mean
SOC
system organ class
t½z
Terminal disposition phase half-life
TEAE 
treatment-emergent adverse event
TFL
tables, figures, and listings
WHO
World Health Organization
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Applica


TAK-935-1010
Page 7 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
To characterize the plasma pharmacokinetics (PK) of soticlestat following a single oral dose in 
participants with moderate or mild hepatic impairment (HI) compared to matched healthy 
participants with normal hepatic function
1.1.2
Secondary Objective
To evaluate the safety and tolerability of soticlestat following a single oral dose in participants 
with moderate or mild HI as well as matched healthy participants with normal hepatic function
1.2
Endpoints
1.2.1
Primary Endpoint(s)
The following PK parameters in plasma will be analyzed for soticlestat:
!
Maximum observed concentration (Cmax)
!
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞)
!
Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast)
1.2.2
Secondary Endpoint(s) 
!
Incidence of treatment-emergent adverse events (TEAEs)
!
Incidence of clinically significant abnormal values for laboratory evaluations, vital signs, 
ECG parameters, and C-SSRS
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-935-1010
Page 8 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
1.3
Estimand(s)
Not applicable
2.0
STUDY DESIGN
This is a phase 1, open-label, study of oral soticlestat designed to assess the PK of single-dose 
soticlestat 
 in participants with moderate or mild
HI compared to matched healthy participants with normal hepatic function. At least 12 healthy 
participants (up to 24 participants) with normal hepatic function will be recruited to match the 
group mean of moderate and mild HI arms by age (mean ± 10 years), sex (± 2 per sex), and body 
mass index (BMI) (mean ± 10%). Eight (8) participants will also be enrolled in each HI arm of 
the study according to the following criteria: 
!
Arm 1: (N = 8): Moderate HI (Child-Pugh B [Score: ≥ 7 and ≤ 9]), 300 mg single dose
!
Arm 2: (N = 8): Mild HI (Child-Pugh A [Score: ≥ 5 and ≤ 6]), 300 mg single dose 
!
Arm 3: (N = 12 - 24): Normal hepatic function, 300 mg single dose 
The study will consist of a 28-day screening period (prior to dosing) and a 7-day confinement 
period (Day -1 to Day 7).
Two hepatic function assessments are required prior to Day 1 dosing for participants with HI. 
These 2 assessments should be obtained during the screening period and at least 48 hours apart. 
In the case, where a participant has an available historical Child-Pugh assessment score within 
3 months prior to screening, 1 assessment can be conducted during the screening period. If the 
Child-Pugh scores from these 2 assessments indicate the same liver function category for the 
participant (ie, normal hepatic function, moderate HI, or mild HI), soticlestat can be 
administered as scheduled. If the results of the 2 assessments indicate different liver function 
categories, a third assessment must be conducted at least 24 hours after the second assessment. 
Property of Takeda: For Non-Commercial Use
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TAK-935-1010
Page 9 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
If the results of the 2 most recent assessments (the second and third) are in agreement with 
regard to the participant’s liver function category, the participant may be enrolled and should 
receive the Day 1 dose within 48 hours of the third assessment. If the second and third 
measurements differ, the participant will not be eligible for the study.
The moderate HI arm (ie, Arm 1) will be conducted first, followed by 12 participants in the 
matched normal hepatic function arm (Arm 3). After all participants in moderate HI arm and the 
matching 12 participants in the matched normal hepatic function arm have completed the 
treatment period, an informal preliminary PK data analysis will be performed and may 
additionally leverage historical control PK data in healthy participants to gain an initial 
estimate of the effect of moderate HI on the PK of soticlestat 
. 
Following completion of enrollment of the mild HI arm, and in the instance any of the previously 
enrolled healthy volunteer participants cannot be used for matching purposes, up to an 
additional 12 participants may be enrolled for the matched normal hepatic function group (Arm 
3) to ensure a minimum of 12 participants with normal hepatic function and matching the mean 
of the mild HI arm by age (mean ± 10 years), sex (± 2 per sex), and BMI (mean ± 10%) are 
enrolled.
Participants will receive a single oral dose of 300 mg soticlestat as three 100 mg T4 tablets on 
Day 1 with approximately 240 mL water under fasting conditions. PK samples will be collected 
from Days 1 to 7, at predetermined time points (study protocol section 3.0), to characterize the 
PK of soticlestat 
 in participants with moderate 
or mild HI compared to matched healthy participants with normal hepatic function (study 
protocol section 3.0).
Participants will remain in the clinic throughout the study. Participants will be discharged from 
the clinic on Day 7 after the last PK sample collection and study procedures are completed. A 
safety follow-up contact of all participants (including those who terminate the study early) will 
occur 14 ± 2 days after the soticlestat dose to determine if any adverse events (AEs) have 
occurred since the clinical research unit (CRU) discharge.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
Not applicable
3.2
Statistical Decision Rules
Not applicable
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TAK-935-1010
Page 10 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
3.3
Multiplicity Adjustment
Not applicable
4.0
SAMPLE-SIZE DETERMINATION
The planned sample size of 8 participants in each HI arm is not based on power calculations and 
is considered adequate to provide a descriptive characterization of the PK of soticlestat 
 
 in participants with moderate or mild HI compared to healthy participants with 
normal hepatic function.
Any participant who is not PK evaluable including those experiencing emesis within 8 hours post 
dose may be replaced at the discretion of the Investigators in consultation with the sponsor to 
ensure 8 PK-evaluable participants in each arm of participants with HI and 12-24 PK-evaluable 
participants in matched participants with normal hepatic function complete.
5.0
ANALYSIS SETS
5.1
Safety Analysis Set
All participants who received the dose of soticlestat will be included in the safety evaluations.
5.2
Pharmacokinetic Analysis Set 
All participants who comply sufficiently with the protocol and display an evaluable PK profile 
(eg, exposure to treatment, availability of measurements and absence of major protocol 
violations) will be included in the statistical analyses.
6.0
STATISTICAL ANALYSIS
6.1
General Considerations
All PK analyses will be conducted using Phoenix® WinNonlin® Version 8.1, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4. All data recorded on the case 
report form (CRF) will be listed by hepatic function group and participant. All table, figure, and 
listing (TFL) shells and numbering list will be included and specified in the TFL Shells 
document. 
The number of observations (n) will be presented as an integer (no decimal places), arithmetic 
mean (mean), median, and geometric mean (geom mean) values will be presented to 1 more 
level of precision than the individual values. Standard deviation (SD) and standard error of the 
mean (SEM) will be presented to 2 more levels of precision than the individual values. Minimum 
and maximum values will be presented to the same precision as the individual values. Arithmetic 
percent coefficient of variation (CV%) and geometric percent coefficient of variation (geom 
CV%) will be presented to 1 decimal place.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-935-1010
Page 11 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
individual data. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the 
GMRs will be reported using 2 decimal places. 
Noncompartmental analyses will be used in this study. Concentration values below the lower 
limit of quantitation (BLQ) will be presented as ‘BLQ’ in the concentration table listings and 
footnoted accordingly. BLQ values will be treated as zero for the calculation of summary 
statistics, the generation of concentration plots, and the calculation of PK parameters, unless they
are deemed questionable (e.g., BLQ value between measurable values), in which case they will 
be treated as missing and excluded from the concentration summary statistics and the PK 
analysis. Values of 0 are not included in the calculation of geom mean and geom CV%. 
A participant’s PK parameter data will be included in the listings but may be excluded from the 
descriptive and inferential (linear mixed-effects model) statistics if one or more of the following 
criteria are met:
!
A predose (0 hour) concentration is greater than 5% of that participant’s maximum 
concentration value for the given hepatic function group
!
A participant did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Pharmacology Lead and Celerion Pharmacokinetic Scientist)
!
A participant deviates substantially from the protocol defined study procedures including but 
not limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist) 
!
A participant may be excluded due to vomiting
The details on PK parameter calculations and TFLs will be outlined in the clinical pharmacology
and analysis plan (CPAP) and TFL Shells document including specifics on the following:
!
For participants with AUCextrap% greater than 20%, the descriptive and model-based statistics 
for AUC∞will be presented with and without these participants included, if appropriate 
!
PK parameters presented by hepatic function group, including the units, precision, and 
summary statistics that will be presented in in-text and end-of-text tables
!
Concentration data presented by hepatic function group, including the units, precision, and 
summary statistics that will be presented in end-of-text tables
!
Concentration data file used for PK analysis
!
PK parameter Phoenix® WinNonlin® output file used to generate the TFLs
!
ANOVA model results presented in in-text and end-of-text tables
!
Arithmetic mean concentration-time figures presented as in-text and end-of-text figures
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-935-1010
Page 12 of 21
Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL

Individual concentration-time figures presented in Appendix 16.2.6.
Fraction unbound will be calculated based on the ratios of unbound concentration relative to total 
concentration at 0.5 and 10 hours postdose for each subject as follows: 
Fu0.5 hrs = Cu0.5 hrs/C0.5hrs and Fu10hrs = Cu10hrs/C10hrs (where Cut = unbound concentration in 
plasma at time t and Ct = total concentration in plasma at time t).
Continuous demographic and safety data will be summarized descriptively. For 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 participants in the safety set 
for overall summaries, and the number of participants dosed in each hepatic function group in 
hepatic function group summaries. 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. Counts and percentages will be presented to 1 decimal place. 
Baseline is defined as the last observation prior to dosing.
If additional normal hepatic function participants are added to match the mild HI group due to 
differences in matching criteria, then disposition and demographic summaries for the normal 
hepatic function group may be separated based on matching to moderate HI or mild HI.
6.1.1
Handling of Treatment Misallocations
Not applicable
6.2
Study Information
A study information table will be generated including the following items: date of first 
participant’s signed informed consent form, date of dosing, 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) Drug Dictionary, and SAS version used for creating the datasets.
6.3
Disposition of Participants
Disposition of participants (number of participants dosed, completed the study, discontinued 
from the study, discontinued from the study drug, and reason(s) for discontinuation(s)) will be 
summarized by matched hepatic function group (ie, Severe HI, Moderate HI, Mild HI, Normal 
Hepatic Function (Mild), Normal Hepatic Function (Moderate), Normal Hepatic Function
(Overall)) and overall. Study completion status, including reason for discontinuation, will also be 
listed by hepatic function group and participant.  
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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
6.4
Demographic and Other Baseline Characteristics
6.4.1
Demographics
Demographic and baseline characteristics will be summarized descriptively matched hepatic 
function group (ie, Severe HI, Moderate HI, Mild HI, Normal Hepatic Function (Mild), Normal 
Hepatic Function (Moderate), Normal Hepatic Function (Overall)) and overall. Summary 
statistics (n, mean, SD, minimum, median, and maximum) will be generated for continuous 
variables (age as collected on CRF, weight, height, and BMI) and the number and percentage of 
participants within each category will be presented for categorical variables (sex, race, and 
ethnicity). The last height, weight, and BMI recorded prior to dosing will be used in the baseline 
summaries. Demographics data will also be listed as recorded in the case report form (CRF), 
including the date of informed consent.
6.4.2
Medical History and Concurrent Medical Conditions
Medical history will include determining whether the participant has any significant conditions 
or diseases that resolved at or before signing the informed consent form (ICF). 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 started after taking the study drug will be classified as an adverse event. All 
medical history will be coded using the MedDRA® Version 24.1. The medical history listing will 
include the system or organ class (SOC) involved, preferred term (PT), start date (if known) and 
end date (if known) or whether the condition was ongoing, and a description of the condition or 
event. There will be no analysis of medical history.
6.4.3
Baseline Characteristics
Child-Pugh scores will be assessed at screening to classify participants into hepatic function 
groups. Two hepatic function assessments are required prior to Day 1 for participants with HI. 
These 2 assessments should be obtained during screening and at least 48 hours apart. In the case 
where a participant has an available historical Child-Pugh assessment score within 3 months 
prior to screening, 1 assessment can be conducted during the screening period. If the results of 
the 2 assessments indicate different liver function categories, a third assessment must be 
conducted at least 24 hours after the second assessment. The last recorded scores will be 
summarized (n, mean, SD, minimum, median, and maximum) by hepatic function group and 
presented in the demographic summary table. Individual results will be listed by hepatic function 
group and participant. 
6.5
Medication History and Concomitant Medications 
Medication history will include any medication relevant to eligibility criteria and safety 
evaluation 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 visit). All medication history and concomitant medications recorded 
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Celerion Study Number CA33004
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during the study will be coded with the WHO Global Dictionary September 2021 and listed. If
appropriate, the listing will include the medication name, coded term, dosage, route of 
administration, start date and end date, or whether it continued after study completion, and 
indication for use. There will be no statistical analysis of medication history or concomitant 
medications.
6.6
Efficacy Analysis
Not applicable
6.7
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and relationship of TEAEs, 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, ECGs, and 
CSSRS results will be reported as AEs. All safety data will be listed by hepatic function group
(ie, Severe HI, Moderate HI, Mild HI, Normal Hepatic Function), participant, and assessment 
time points, including rechecks, unscheduled assessments, and early termination (ET)
assessments, chronologically. 
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 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators. If additional normal hepatic function participants 
are added to match the mild HI group, then the normal hepatic function group will be separated 
based on matching to moderate HI or mild HI.
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), frequency, and action relative to the study drug as recorded in the CRF. All AEs 
occurring during this study will be coded using the MedDRA® Version 24.1. Only TEAEs will 
be summarized.
A TEAE is defined as an AE that is starting or worsening at the time of or after dosing of study
drug.
If the onset time of an AE is missing and the onset date is the same as the dosing date, then the 
AE will be counted as treatment-emergent. If the onset date of an AE is missing, then the AE 
will be considered treatment-emergent, unless the AE is known to have started prior to dosing. If 
severity is missing, the AE will be counted as severe, and if relationship is missing, the AE will 
be counted as related. 
TEAEs will be tabulated by hepatic function group (ie, Severe HI, Moderate HI, Mild HI, 
Normal Hepatic Function), SOC, and PT. Summary tables will include the number and percent 
of participants reporting the TEAE by hepatic function group. In addition, the number and 
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TAK-935-1010
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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
percent of TEAEs for each hepatic function group will be summarized. Tables for the most 
commonly reported non-serious TEAEs (ie, those events reported by >1 participant in one or 
more hepatic function groups, and TEAEs that are >5% of total TEAEs (or >1 event if fewer 
than 20 TEAEs), excluding serious adverse events (SAEs)) and for SAEs only, will also be 
presented. The denominators for percent calculations will be the number of participants dosed or 
number of events for each hepatic function group.
Additional TEAE summary tables for participants and events will be presented by severity and 
relationship to study drug. If a participant experiences the same TEAE at more than one level of
severity, the participant will be counted in the most severe category only. For relationship to 
study drug, if a participant has both related and unrelated TEAEs with the same term, the 
participant will be counted in the related category.
An overview summary table of TEAEs, including the number of participants with TEAEs, SAEs, 
treatment-related TEAEs, treatment-related SAEs, TEAEs by severity, and AEs leading to study
discontinuation will be provided.
Should any SAEs (including all-cause mortalities) occur, they will be summarized in the same 
way as TEAEs. All AEs will be displayed in the data listings and TEAEs will be discussed in the 
text of the clinical study report (CSR).
6.7.2
Adverse Events of Special Interest (if applicable)
Not applicable
6.7.3
Clinical Laboratory Assessments
Hematology, serum chemistry, coagulation, and urinalysis will be performed at screening, 
Day -1, Day 3, and Day 7 (or at ET if applicable). Urine drug screening will be carried out at 
screening and Day-1 only. For female participants, a pregnancy test will be performed at 
screening and check-in and FSH will be checked at screening. 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 each laboratory test by hepatic function group (ie, Severe 
HI, Moderate HI, Mild HI, Normal Hepatic Function) and time point of collection. Change from 
baseline will be summarized in a similar manner. Baseline is defined as the last assessment,
including recheck and unscheduled assessments, taken prior to dosing. All clinical laboratory 
listings and tables will be presented in international system (SI) units. Postdose unscheduled or 
recheck assessments will not be used in analysis. Similarly, ET results will not be included in 
summaries.
For calculation of summary statistics, lab results below or equal to lower limit of quantification 
(LLOQ) will be set to LLOQ/2 if a LLOQ value has been defined, and otherwise will be set to 
missing; lab results above or equal to upper limit of quantification (ULOQ) will be set to ULOQ 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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CONFIDENTIAL
if a ULOQ value has been defined, and otherwise will be set to missing. Listings will display the 
original result received from the laboratory.
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 consist of temperature, respiratory rate, blood pressure (BP), and heart 
rate (HR). BP and HR will be collected at screening, within 24 hours prior to dosing on Day 1, 
and at 2, 24, and 144 hours postdose (or at ET if applicable). Respiratory rate and temperature 
will be recorded at screening, within 24 hours prior to dosing on Day 1, and at 24 and 144 hours 
postdose (or at ET if applicable). Additional unscheduled vital signs may be recorded at other 
times if deemed necessary by the Investigator.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
signs results by hepatic function group (ie, Severe HI, Moderate HI, Mild HI, Normal Hepatic 
Function) and time point of collection. Change from baseline will be summarized in a similar 
manner. Baseline is defined as the last assessment, including recheck and unscheduled 
assessments, taken prior to dosing. Postdose unscheduled or recheck assessments will not be 
used in analysis. Similarly, ET results will not be included in summaries. Vital sign data will also 
be displayed in a data listing by hepatic function group and participant.
6.7.5
Electrocardiograms
Single 12-lead ECGs will be collected at screening, within 24 hours prior to dosing on Day 1, 
and at 2, 24, and 144 hours postdose (or at ET if applicable). Additional unscheduled ECGs may 
be recorded at other times if deemed necessary by the Investigator. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results by hepatic function group (ie, Severe HI, Moderate HI, Mild HI, Normal Hepatic 
Function) and time point of collection. Change from baseline will be summarized in a similar 
manner. Baseline is defined as the last assessment, including recheck and unscheduled 
assessments, taken prior to dosing. Postdose unscheduled or recheck assessments will not be 
used in analysis. Similarly, ET results will not be included in summaries. ECG data will also be 
displayed in a data listing by hepatic function group and participant.
Shifts from baseline to the worst post baseline QT interval corrected for PR using Friderica’s 
formula (QTcF), and shifts from baseline to the worst change-from-baseline QTcF (ΔQTcF) will 
be presented as cross tabulations (baseline versus post baseline values). Number of subjects and 
corresponding percentages will be presented for each category. For shifts from baseline to the 
worst post baseline QTcF, baseline values will be categorized in the following categories: < 450, 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
450 – < 480, 480 – 500, > 500, and Missing; the worst post-baseline QTcF values will be 
categorized similarly. For shifts from baseline to the worst post baseline ΔQTcF, baseline values 
will be categorized in the following categories: < 450, 450 – < 480, 480 – 500, > 500, and 
Missing; the maximum change from baseline values will be categorized into the following 
categories: < 30, 30 – 60, > 60, and Missing. A subject will be counted only once even if the 
subjects has more than 1 episode of the worst value.
6.7.6
Physical Examination
Full physical examinations will be performed at screening, Day -1, and Day 7 (or ET if 
applicable). If the screening assessment was conducted within 4-7 days prior to dosing (Day 1), 
assessment will be conducted at Day -1 only if, in the opinion of the Investigator or designee, 
there is reason to believe they have substantially changed. Symptom-driven physical exams may 
be performed at other times at the discretion of the Investigator. Physical exam findings will be 
presented in the data listings by hepatic function group and participant.
6.7.7
Overdose
All cases of overdose will be presented in a data listing by participant. 
6.7.8
Columbia Suicide Severity Rating Scale (C-SSRS)
At screening, the C-SSRS Baseline/Screening version will be administered. On Day -1 and Day 
7 (or at ET, if applicable), the ‘Since Last Visit’ version will be administered.
C-SSRS findings will be presented in the data listings by participant.
6.7.9
Extent of Exposure and Compliance
The date, time, and treatment administered will be listed by hepatic function group and 
participant.
6.8
Pharmacokinetic Analysis
Blood samples for assessment of plasma soticlestat (TAK-935), 
concentrations will be collected as outlined in Table 6.a below: 
Table 6.a
Collection of Blood Samples for Pharmacokinetic Analysis
Analytes
Matrix
Day
Scheduled Time (Hours)*
Soticlestat,
Plasma
1 
Predose and 0.133, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 14, 24, 36, 48, 72, 
96, 120, and 144 hours postdose.
Plasma
1
Predose, 0.5, and 10 hours postdose.
*The actual date and time of sample collection will be recorded on the source document in the case report form. 
Note: The collection time points are relative to soticlestat dosing on Day 1. 
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TAK-935-1010
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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
Plasma concentrations of soticlestat (total and unbound), 
will be 
listed and summarized descriptively by PK sampling time according to hepatic function group 
(normal hepatic function and moderate and mild HI) 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 hepatic function group on 
linear and semi-log scales. The mean profiles of the concentration-time data will be plotted by
hepatic function group on linear (with and without SD) and semi-log scales. For summary 
statistics and mean plots by sampling time, the nominal PK sampling time will be used. For 
individual participant plots by time, the actual PK sampling time will be used.
The PK parameters will be calculated from soticlestat (total and unbound), 
concentration-time profiles using non-compartmental analysis methods where all 
calculations will be based on actual sampling times after dosing. The PK parameters will be 
summarized, defined in the CPAP, according to hepatic function group (normal hepatic function 
and moderate and mild HI) using the following descriptive statistics: n, mean, SD, CV%, SEM, 
minimum, median, maximum, geom mean (Cmax, AUC∞, and AUClast only), and geom CV% 
(Cmax, AUC∞, and AUClast only). Excluded parameters will be presented and footnoted as such in 
the PK parameter table listings, and those values will be excluded from descriptive statistics.
Individual plasma soticlestat (total and unbound), 
AUC∞ values for 
participants with moderate and mild hepatic impairment as well as healthy participants will be 
plotted versus serum alpha-1-acid glycoprotein, serum albumin, total serum bilirubin, and INR 
ratio. In addition, individual plasma soticlestat (total and unbound), 
AUC∞ values will be plotted versus Child-Pugh scores in participants with moderate and mild
hepatic impairment. 
Analysis of Variance (ANOVA)
An ANOVA will be performed on the ln-transformed Cmax, AUClast, and AUC∞for total
soticlestat, 
to compare each HI group (moderate HI and mild HI)
with the normal matched hepatic function group, where 90% CIs for the ratio of GMRs from 
each HI group versus normal matched function group will be provided. For total
an ANOVA will also be performed on the ln-transformed PK parameters for 
MRCmax, MRAUClast, and MRAUC∞. The addition of other factors and covariates such as age, 
sex, and BMI on the relationship between soticlestat PK parameters and level of HI may also be
investigated.
The ANOVA model will include hepatic function (Moderate HI, Mild HI, Normal Matched 
Hepatic Function) group as a fixed effect. GMRs and 90% CIs will be calculated from the 
exponentiated difference between group least squares means and corresponding 90% CIs from 
the analyses on the ln-transformed Cmax, AUClast, AUC∞, MRCmax, MRAUClast, and MRAUC∞.
The GMRs and 90% CIs will be expressed as a percentage relative to the Normal Hepatic 
Function group.
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TAK-935-1010
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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
The above statistical analyses will also be performed on the ln-transformed Cmax,u, AUClast,u, and 
AUC∞,u for unbound soticlestat.
If all subjects in the healthy group are matched to both the moderate HI and mild HI groups, the 
ANOVA analysis will be performed using the following SAS® code. Note that due to expected 
differences in the variability of PK parameter values between groups, the residual variance will 
be estimated separately for each group with use of the repeated statement, and variance 
components as the covariance matrix structure:
Where ‘Arm’ is as described in Section 2.0 where 1=Moderate HI, 2=Mild HI, 3=Normal
Function. Appropriate coefficients will be used based on the input variable for arm. 
If 2 healthy groups are needed to match moderate HI and mild HI separately due to differences in 
matching criteria, the analysis will be performed as follows:
Moderate HI versus matched Normal Function
The data will be subset to contain the moderate HI group and the matched normal function
group. The ANOVA analysis will then be performed using the following SAS® code:
Appropriate coefficients will be used based on the input variable for arm. 
Mild HI versus matched Normal Function
The data will be subset to contain the mild HI group and the matched normal function group. The 
ANOVA analysis will then be performed using the following SAS® code:
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TAK-935-1010
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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
12 July 2022
CONFIDENTIAL
Appropriate coefficients will be used based on the input variable for arm.
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
Not applicable
6.10
Preliminary Analysis
After all participants in moderate HI arm and the matching 12 participants in the matched normal 
hepatic function arm have completed the treatment period, an informal preliminary PK data 
analysis is planned and may additionally leverage historical control PK data in healthy 
participants to gain an initial estimate of the effect of moderate HI on the PK of soticlestat 
 
. 
This amendment was written following the preliminary analysis. The preliminary analysis 
indicated higher impact of moderate HI on soticlestat PK than predicted based on model-based 
stimulations. The Sponsor decided to remove the participants with severe HI from the study
because soticlestat will not be recommended to use in subjects with severe HI. The amendment is 
created to evaluate the impact of mild HI on the PK of soticlestat.
6.11
Interim Analysis
No interim analysis is planned for this study. 
6.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
Not applicable
7.0
REFERENCES
Not applicable
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Description as in protocol
Change 
Rationale for Change
Incidence of clinically 
significant abnormal values 
for laboratory evaluations, 
The analysis will not be 
performed.
This endpoint is included as part 
of standard AE reporting and will 
not be analyzed separately.
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TAK-935-1010
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Celerion Study Number CA33004
Statistical Analysis Plan Amendment 1
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CONFIDENTIAL
Description as in protocol
Change 
Rationale for Change
vital signs, ECG parameters, 
and C-SSRS
Vital signs assessments will be 
summarized by group and 
point of time of collection and 
a shift table describing out of 
normal range shifts will be 
provided.
A shift table will not be 
generated for vital signs
The normal criteria are not 
defined, and analysis of out of 
normal range shifts is not 
required.
C-SSRS results will be 
summarized by group and 
point of time of collection and 
a shift table describing out of 
normal range shifts will be 
provided
C-SSRS data will not be 
summarized
Normal criteria are not defined, 
and summary is not required.  
Data will be listed and discussed 
in the CSR.
9.0
APPENDIX 
9.1
Changes From the Previous Version of the SAP
Changes made from the previous version of the SAP that have a material impact to the 
planned statistical analysis methods are described below. In addition, there were textual 
changes purely to improve the flow, organization and clarity. As these represent cosmetic 
changes with no impact to the planned statistical analyses, they are not included in the table 
below.
SAP Section 
Impacted Text 
(shown in bold)
Change 
Rationale for Change
All
All instances of 
severe
Changed to 
mild
Per protocol amendment, the severe hepatic 
impairment cohort was changed to a mild hepatic 
impairment cohort. All references to the severe 
cohort in this SAP have been changed to mild.
9.2
Data Handling Conventions 
Not applicable
9.3
Analysis Software 
SAS® Version 9.4 or higher will be used for all statistical analysis provided in the CSR.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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