Clinical trial NCT05098041
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2021-11-22; Completion date: 2022-03-03
Enrollment: 15 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The main aim of this study is to check how rifampin affects the way soticlestat is processed by the body.

Participants will be required to stay at the study clinic for 18 consecutive days. On the first full day and 15th day, participants will take a single dose of soticlestat. Rifampin will be taken each day starting on the 5th day for 13 consecutive days.

Clinic staff will follow up with each participant about 15 days after the last soticlestat dose to check for any side effects.

Detailed description:
The drug being tested in this study is called soticlestat (TAK-935). The study will evaluate the safety and tolerability of soticlestat when co-administered with rifampin in healthy participants.

The study will enroll 14 participants. The participants will be assigned to treatment group to receive following therapies:

• Soticlestat 300 milligram (mg) + Rifampin 600 mg

The study will have two periods: Period 1 and Period 2. In Period 1, participants will receive soticlestat in fasted condition while in Period 2 participants will receive soticlestat along with rifampin. The data will be collected and stored in electronic case report form (eCRF).

This single-center trial will be conducted in the United Kingdom. The overall study duration of the study will be approximately 58 days including 28 days screening and follow up duration. There will be a follow up contact required for all participants approximately 15 days after the last dose of soticlestat.

Arms: arm 1: Soticlestat 3\*100 mg tablets, orally, administered once on Day 1 in fasted state in Period 1, followed by a washout period of 4 days, further followed by Rifampin 600 mg, administered as 2\*300mg capsules, orally, once daily for 13 consecutive days, from Day 1 to Day 13 in fasted state in Period 2. Soticlestat 3\*100 mg tablets, will be administered orally along with rifampin 600 mg (2\*300mg) capsules, orally in the morning of Day 11 in Period 2.
Interventions: intervention 1: Soticlestat intervention 2: Rifampin
Intervention descriptions: intervention 1: Soticlestat tablets. intervention 2: Rifampin capsules.

Protocol documents:
Prot_000.pdf: 
NCT Number: NCT05098041
Title:  Phase 1 Open-Label Study to Evaluate the Drug-Drug Interaction of Rifampin 
as a Strong CYP3A Inducer on Soticlestat Pharmacokinetics in Healthy Adult 
Participants
Study Number: TAK-935-1009
Document Version and Date: Final / 20 August 2021
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. 
Protocol


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1 Open-Label Study to Evaluate the Drug-Drug Interaction of Rifampin as a 
Strong CYP3A Inducer on Soticlestat Pharmacokinetics in Healthy Adult Participants
Study Identifier:
TAK-935-1009
Compound:
Soticlestat (TAK-935)
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
Date:
20 August 2021
Version/Amendment 
Number:
Final Protocol
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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-935
Study ID TAK-935-1009
Page 2 of 67
Protocol 
20 August 2021
CONFIDENTIAL
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.1.1
Soticlestat (TAK-935)........................................................................................15
4.1.2
Rifampin............................................................................................................16
4.2
Rationale for the Proposed Study.............................................................................17
4.3
Benefit/Risk Profile .................................................................................................18
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................18
5.1
Hypothesis...............................................................................................................18
5.2
Study Objectives......................................................................................................19
5.2.1
Study Primary Objective ....................................................................................19
5.2.2
Study Secondary Objective ................................................................................19
5.2.3
Study Exploratory Objectives.............................................................................19
5.3
Endpoints.................................................................................................................19
5.3.1
Primary Endpoint...............................................................................................19
5.3.2
Secondary Endpoints..........................................................................................19
5.3.3
Exploratory Endpoints .......................................................................................19
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................20
6.1
Study Design ...........................................................................................................20
6.2
Dose Escalation .......................................................................................................21
6.3
Stopping Rules.........................................................................................................21
6.4
Rationale for Study Design, Dose, and Endpoints ....................................................21
6.4.1
Rationale of Study Design..................................................................................21
6.4.2
Rationale for Dose .............................................................................................21
6.4.3
Rationale for Endpoints......................................................................................21
6.4.4
Future Biomedical Research...............................................................................22
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures...............22
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................22
6.6
Study Beginning and End/Completion .....................................................................22
6.6.1
Definition of Beginning of the Study..................................................................22
6.6.2
Definition of End of the Study ...........................................................................22
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Study ID TAK-935-1009
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6.6.3
Definition of Study Completion .........................................................................22
6.6.4
Definition of Study Discontinuation...................................................................23
6.6.5
Criteria for Premature Termination or Suspension of the Study..........................23
6.6.6
Criteria for Premature Termination or Suspension of a Site................................23
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .....23
7.1
Inclusion Criteria .....................................................................................................23
7.2
Exclusion Criteria ....................................................................................................24
7.3
Excluded Medications, Supplements, Dietary Products............................................25
7.4
Diet, Fluid, Activity.................................................................................................27
7.4.1
Diet and Fluid ....................................................................................................27
7.4.2
Activity..............................................................................................................28
7.5
Criteria for Discontinuation or Withdrawal of a Participant......................................28
7.6
Procedures for Discontinuation or Withdrawal of a Participant ................................29
7.7
Participant Replacement ..........................................................................................29
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................30
8.1
Clinical Study Drug .................................................................................................30
8.1.1
Clinical Study Drug Labeling.............................................................................30
8.1.2
Clinical Study Drug Inventory and Storage ........................................................30
8.1.3
Clinical Study Drug Blinding.............................................................................30
8.1.4
Randomization Code Creation and Storage ........................................................31
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure...................................31
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................31
9.0
STUDY PROCEDURES...............................................................................................31
9.1
Administrative Procedures.......................................................................................31
9.1.1
Informed Consent Procedure..............................................................................31
9.1.2
Inclusion and Exclusion .....................................................................................31
9.1.3
Medical History/Demography ............................................................................32
9.1.4
Concomitant Medications...................................................................................32
9.2
Clinical Procedures and Assessments.......................................................................32
9.2.1
Physical Exam ...................................................................................................32
9.2.2
Height and Weight .............................................................................................32
9.2.3
BMI ...................................................................................................................32
9.2.4
Vital Signs .........................................................................................................33
9.2.5
12-Lead ECG.....................................................................................................33
9.2.6
Study Drug Administration ................................................................................33
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Study ID TAK-935-1009
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CONFIDENTIAL
9.2.7
C-SSRS..............................................................................................................34
9.2.8
AE Monitoring...................................................................................................34
9.2.9
Laboratory Procedures and Assessments ............................................................34
9.3
Pharmacokinetic Samples ........................................................................................36
9.3.1
Pharmacokinetic Measurements.........................................................................36
9.3.2
Biomarker Measurements...................................................................................37
9.3.3
PGx Measurements ............................................................................................38
9.3.4
Confinement ......................................................................................................38
10.0
ADVERSE EVENTS ....................................................................................................38
10.1
Definitions and Elements of AEs .............................................................................38
10.1.1 SAEs..................................................................................................................40
10.1.2 Special Interest AEs...........................................................................................41
10.2
AE Procedures.........................................................................................................41
10.2.1 Assigning Severity/Intensity of AEs...................................................................41
10.2.2 Assigning Causality of AEs................................................................................42
10.2.3 Start Date...........................................................................................................42
10.2.4 End Date............................................................................................................42
10.2.5 Pattern of Adverse Event (Frequency)................................................................43
10.2.6 Action Taken With Study Treatment..................................................................43
10.2.7 Outcome ............................................................................................................43
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................43
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....46
11.0
STATISTICAL METHODS..........................................................................................46
11.1
Statistical and Analytical Plans ................................................................................46
11.1.1 Analysis Sets......................................................................................................46
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................46
11.1.3 PK Analysis .......................................................................................................46
11.1.4 PD Analysis .......................................................................................................47
11.1.5 Safety Analysis ..................................................................................................47
11.2
Interim Analysis and Criteria for Early Termination ................................................48
11.3
Determination of Sample Size..................................................................................48
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................49
12.1
Study-Site Monitoring Visits ...................................................................................49
12.2
Protocol Deviations..................................................................................................49
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................49
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TAK-935
Study ID TAK-935-1009
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CONFIDENTIAL
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................50
13.1
IRB and/or IEC Approval ........................................................................................50
13.2
Participant Information, Informed Consent, and Participant Authorization...............51
13.3
Participant Confidentiality .......................................................................................52
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................52
13.4.1 Publication and Disclosure.................................................................................52
13.4.2 Clinical Study Registration.................................................................................53
13.4.3 Clinical Study Results Disclosure.......................................................................53
13.5
Insurance and Compensation for Injury....................................................................53
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................53
14.1
Administrative Information......................................................................................53
14.1.1 Study Contact Information .................................................................................54
14.1.2 INVESTIGATOR AGREEMENT......................................................................55
14.1.3 Study-Related Responsibilities...........................................................................56
14.1.4 List of Abbreviations .........................................................................................56
15.0
DATA HANDLING AND RECORD KEEPING...........................................................57
15.1
CRFs (Electronic and Paper)....................................................................................57
15.2
Record Retention .....................................................................................................58
16.0
REFERENCES..............................................................................................................59
17.0
APPENDICES...............................................................................................................60
LIST OF IN-TEXT TABLES
Table 2.a
Study Schematic ................................................................................................11
Table 2.b
Dose Regimens for Study Drugs ........................................................................11
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................27
Table 9.a
Primary Specimen Collections ...........................................................................36
Table 10.a
Takeda Medically Significant AE List................................................................41
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................60
Appendix B
Elements of the Participant Informed Consent....................................................62
Appendix C
Investigator Consent to the Use of Personal Information ....................................65
Appendix D
Pregnancy and Contraception.............................................................................66
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Study ID TAK-935-1009
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Protocol 
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CONFIDENTIAL
1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDCA)
95 Hayden Avenue
Lexington, MA 02421
Telephone: +1 (617) 679-7000
Compound:
Soticlestat (TAK-935)
Study Identifier: TAK-935-1009
Phase: 1
Protocol Title: A Phase 1 Open-Label Study to Evaluate the Drug-Drug Interaction of Rifampin as a Strong 
CYP3A Inducer on Soticlestat Pharmacokinetics in Healthy Adult Participants
Study Design:
This is an open-label, 2-period, fixed-sequence drug-drug interaction (DDI) study to evaluate the effect of a strong 
cytochrome P450 (CYP) 3A inducer, rifampin, on the single-dose pharmacokinetics (PK) of soticlestat in healthy 
participants.
Study schematic of the study design and dose regimens are shown in Table 2.a and Table 2.b. A schedule of 
assessments is shown in Schedule of Study Procedures (Section 3.0).
Participants will be screened within 4 weeks (28 days) prior to the first administration of soticlestat (Day -28 to first 
dosing, Day 1). Qualified participants will be admitted to the clinic on Day -1 of Period 1, at the time indicated by 
the Clinical Research Unit (CRU), and will remain confined until after the last blood draw and/or study procedures 
on Day 14 of Period 2.
In Period 1, on Day 1, participants will receive a single oral dose of soticlestat (300 mg; 3 x 100 mg immediate-
release tablets [T4 tablets]) under fasting conditions. Blood samples for the PK of soticlestat 
 will 
be collected at scheduled time points from predose through 96 hours postdose. There will be washout period of 
4 days between the soticlestat dose in Period 1 and the first rifampin dose in Period 2.
In Period 2, from Days 1 to 13, participants will receive a once daily (QD) oral dose of rifampin (600 mg; 
2 x300 mg capsules) under fasting conditions. On the morning of Day 11, participants will receive a single dose of 
soticlestat (300 mg; 3 x 100 mg T4 tablets) co-administered with the rifampin dose under fasting conditions. Blood 
samples for the PK of soticlestat 
 will be collected at scheduled time points from soticlestat 
predose on Day 11 through 72 hours postdose.
Safety and tolerability will be assessed throughout the study by treatment-emergent adverse events (TEAEs), clinical 
laboratory evaluations, physical examinations, 12-lead electrocardiograms (ECGs), vital signs, and
Columbia-Suicide Severity Rating Scale (C-SSRS).
After discharge, the CRU will contact all participants (including participants who terminate the study early) 15 (± 2)
days after the last soticlestat administration by telephone or other methods per CRU standards to determine if any 
adverse event (AE) has occurred or concomitant medications have been taken since the last study visit. If clinically 
significant findings are observed upon discharge, participants may return to the CRU for re-evaluation per 
Investigator’s discretion.
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Protocol 
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CONFIDENTIAL
Study Primary Objective:
To characterize the effect of rifampin, a strong CYP3A inducer, on the single-dose PK of soticlestat.
Study Secondary Objective:
To assess the safety and tolerability of soticlestat following a single oral dose in healthy adult participants 
with/without a strong CYP3A inducer.
Study Participants Population: Healthy male and female participants aged 18 to 55 years inclusive, at screening. 
Body Mass Index (BMI) 18.0-32.0 kg/m2, inclusive, at screening
Planned Number of Participants:
14 participants will be enrolled
Planned Number of Sites:
1
Dose Levels:
Soticlestat
300 mg (3 x 100 mg strength T4 tablets)
Rifampin
600 mg (2 x 300 mg strength capsules)
Route of Administration:
Oral
Duration of Treatment:
Soticlestat: Single dose on Day 1 Period 1 and on Day 
11 Period 2.
Rifampin: QD for 13 consecutive days (Days 1-13)
Period 2.
Planned Study Duration:
Approximately 58 days including screening and follow-up.
Criteria for Inclusion: 
Participants must fulfill the following inclusion criteria before the first dose to be eligible for participation in the 
study:
1.
Healthy, adult, male or female of non-childbearing potential (Appendix D), 18 - 55 years of age, inclusive, at 
screening.
2.
Male participant agrees to comply with any applicable contraceptive requirements of the protocol as detailed in 
Appendix D.
3.
BMI ≥18.0 and ≤32.0 kg/m2 at screening. 
4.
Continuous non-smoker who has not used nicotine-containing products for at least 90 days prior to the first 
dosing.
5.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs, or ECGs, as deemed by the PI or designee.
!
Supine BP is ≥90/40 mmHg and ≤140/90 mmHg at screening;
!
Supine PR is ≥45 bpm and ≤100 bpm at screening;
!
QTcF is ≤450 msec (males) or ≤470 msec (females) and ECG findings considered normal or not clinically 
significant by the Investigator or designee at screening;
!
Estimated creatinine clearance ≥80 mL/min at screening;
!
Liver function tests including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 
X the upper limit of normal (ULN) at screening and check-in.
6.
Able to swallow multiple tablets/capsules.
7.
Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with 
the protocol.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable
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Study ID TAK-935-1009
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Protocol 
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CONFIDENTIAL
Criteria for Exclusion: 
Participants must not be enrolled in the study if they meet any of the following criteria before the first dose of study
drug:
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
Investigator or designee.
3.
History or presence of gastritis, gastrointestinal tract, gastric bypass surgery, or hepatic disorder or other clinical 
condition which, in the opinion of the Investigator or designee, may affect the absorption, distribution, 
metabolism, or elimination of study drugs.
4.
History or presence of cataracts or other clinically significant vision disturbances.
5.
History or presence of epilepsy, seizure, or convulsion, tremor or related symptoms.
6.
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.
7.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
8.
History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.
9.
Any positive responses on the C-SSRS that in the clinical judgment of the Investigator has a risk of suicide or
has made a suicide attempt in the previous 12 months prior to the first dosing.
10. Female participants of childbearing potential.
11. Female participants with a positive pregnancy test at screening or check-in or who is lactating.
12. Positive urine drug or alcohol results at screening or check-in.
13. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or 
hepatitis C virus (HCV).
14. Unable to refrain from or anticipates the use of:
!
Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin 
supplements within 14 days prior to the first dosing. Thyroid hormone replacement medication may be 
permitted if the participant has been on the same stable dose for the immediate 3 months prior to first 
dosing.
15. History of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately 
equivalent to the following: beer [354 mL/12 oz], wine [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per 
day).
16. Consumes excessive amounts, defined as greater than 4 servings (1 serving is approximately equivalent to 120 
mg of caffeine), of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
17. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 
30 days prior to the first dosing and throughout the study.
18. Donation of blood or significant blood loss within 56 days prior to the first dosing.
19. Plasma donation within 7 days prior to the first dosing.
20. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-days 
window or 5 half-lives will be derived from the date of the last blood collection or dosing, whichever is later, in 
the previous study to Day 1 of Period 1 of the current study.
Main Criteria for Evaluation and Analyses:
Primary Endpoints:
The following PK parameters will be analyzed for soticlestat, when administered alone and when co-administered 
with rifampin:
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the 
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TAK-935
Study ID TAK-935-1009
Page 9 of 67
Protocol 
20 August 2021
CONFIDENTIAL
last quantifiable concentration (AUC∞).
!
Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration 
(AUClast).
!
Time of first occurrence of Cmax (tmax).
Secondary Endpoint:
!
Number of participants with at least one TEAE.
!
Incidence of clinically significant abnormal values for laboratory evaluations, vital signs, ECG parameters, 
and C-SSRS.
Statistical Considerations:
Pharmacokinetics:
Natural log (ln)-transformed AUClast, AUC∞, and Cmax data will be analyzed using a linear mixed effects model, 
separately. The model will include treatment (soticlestat with and without rifampin) as a fixed effect and participant 
as a random effect. The point estimate and 90% confidence interval (CI) for the geometric mean ratio (GMR) of 
AUC∞for the soticlestat with versus without rifampin will be calculated. The same approach will be used to 
estimate the GMR of AUClast and Cmax of soticlestat with versus without rifampin.
The same analysis as described above will be conducted for soticlestat metabolites if appropriate.
Safety:
AEs will be tabulated. Summary statistics for vital signs, safety 12-lead ECGs, C-SSRS, and clinical laboratory 
assessments will be computed and provided.
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Sample Size Justification: 
This study is not powered for hypothesis testing and is not based on any specific no-effect boundaries. The sample 
size is based on an estimation approach and is considered sufficient to provide a reliable estimate of the DDI 
magnitude.
A total of 14 participants will be dosed to ensure that 12 evaluable subjects complete the study.
Property of Takeda: For Non-Commercial Use Only and Subject to the
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2.0
STUDY SCHEMATIC
Table 2.a
Study Schematic
Screening
Period 1
Period 2
Follow-up
Check-in and 
Predose 
Assessments
Soticlestat 
Dosing, PK 
Sampling,
and Study 
Assessments
PK Sampling 
and Study 
Assessments
Rifampin 
Dosing and 
Study 
Assessments
Co-administration 
(Rifampin and 
Soticlestat), PK 
Sampling, and 
Study Assessments
Rifampin 
Dosing, PK 
Sampling and 
Study 
Assessments
Within 
28 days 
prior to first 
dosing
Day -1
Day 1
Day 2-5a
Day 1a-10
Day 11
Day 12 -14c
15 (± 2) 
days 
following 
last 
soticlestat 
dose
---------------------------Confinementb-------------------------------------
Contact
a Day 5 Period 1 will also be considered Day 1 Period 2.
b Participants will start the confinement on Day -1 Period 1 and will remain confined until Day 14 Period 2.
c Last dose of rifampin will be administered on Day 13.
Table 2.b
Dose Regimens for Study Drugs
Study Drug
Dose
Dose Regimen
Number of Days on Study Drug
Soticlestat (T4 
tablets)
300 mg
(3 x 100 mg
tablets)
Single dose, oral
Day 1 Period 1 and Day 11 Period 2
Rifampin (capsules)
600 mg 
(2 x 300 mg
capsules)
QD, oral
Days 1 through 13 Period 2
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Study ID TAK-935-1009
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CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
Study Procedures a
Study Days in Period 1 c
Days in Period →S b
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2
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2
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6
8
10
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96 e
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations 
Physical Examination f
X
X
Height
X
Weight
X
12-Lead Safety ECG g
X
X i
Vital Signs (PR, BP, RR, and T) g
X
X i
X
X
X
Hem, Coag, Serum Chem h, and UA 
X
X
X
Serum Pregnancy Test (♀ only)
X
X
Serum FSH (♀only)
X
Urine Drug and Alcohol Screen
X
X
HIV/Hepatitis B and C Screen
X
C-SSRS j
X
X
AE Monitoring
X
ConMeds Monitoring
X
Study Drug Administration / PK
Soticlestat Administration
X k
Blood for Soticlestat
 
X l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X l
Other Procedures
Confinement in the CRU d
X
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CONFIDENTIAL
Study Procedures a
Study Days in Period 2 c
Days in Period→1 e 2 - 9
10
11
12
13
14
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24
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Safety Evaluations
12-Lead Safety ECG g
X o
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X o
X
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X l
X
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Hem, Serum Chem h, and UA 
X o
X l
X
C-SSRS j
X
X
AE Monitoring
X
X
ConMeds Monitoring
X
X
Study Drug Administration / 
PK
Rifampin Administration p
X
X
X
X
X
X
Soticlestat Administration
X k
Blood for Soticlestat
 
X l
X
X
X
X
X
X
X
X
X
X
X
X
X l
X
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X
X
Other Procedures
Confinement in the CRU d
X
a.
For details on Procedures, refer to Section 9.0.
b.
Within 28 days prior to the first dosing.
c.
There will be washout period of 4 days between the soticlestat dose in Period 1 and the first rifampin dose in Period 2.
d.
Participants will be admitted to the CRU on Day -1 of Period 1, at the time indicated by the CRU, and be confined throughout the study (Day 14 of 
Period 2). Participants may be asked to check-in to the CRU earlier to undergo additional COVID-19 precaution procedures.
e.
Day 5 of Period 1 will be the same as Day 1 of Period 2, study procedures scheduled for both days will only be performed once.
f.
A full physical examination will be conducted at screening. An abbreviated physical examination will be conducted at check-in. Symptom-driven physical 
examinations may be performed during the study, at the Investigator’s or designee’s discretion.
g.
All assessments will be performed after participants have rested for at least 5 minutes in the supine position.
h.
Samples for serum chemistry will be obtained 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.
i.
To be performed within 24 hours prior to dosing of soticlestat.
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TAK-935
Study ID TAK-935-1009
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CONFIDENTIAL
j.
At screening, the C-SSRS Baseline/Screening version will be administered; at all other time points, the Since Last Visit version will be administered.
k.
Soticlestat will be administered after an overnight fast of at least 10 hours. Fasting will continue for at least 4 hours postdose.
l.
To be performed prior to dosing.
m. To be performed prior to early termination from the study.
n.
The CRU will contact all participants (including participants who terminate the study early) 15 (± 2) days after the last soticlestat administration by 
telephone or other methods per CRU standards to determine if any AE has occurred since the last study visit.
o.
To be performed within 2 hours prior to dosing of soticlestat.
p.
On Day 11 (Period 2), participants will receive soticlestat and rifampin together, after an overnight fast of at least 10 hours. On Days 1 to 10 and Days 12 
and 13 (Period2), rifampin will be administered after an overnight fast of at least 8 hours. No food is allowed during the first 4 hours after drug
administration.
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, C-SSRS = Colombia-Suicide Severity Rating Scale 
Chem = Chemistry, Coag = Coagulation, ConMeds = Concomitant medication, CRU = Clinical research unit, ECG = Electrocardiogram, ET = 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.
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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 is 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, a 
polar metabolite capable of passing the blood-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
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.
Clinical Safety and Pharmacokinetics
The PK, safety, tolerability, and efficacy of soticlestat have been evaluated in 6 phase 1 clinical 
studies in healthy participants (completed), a phase 1b/2a in participants with DEEs (completed), 
and 2 phase 2 studies in participants with DS, LGS, 15q11-q13 duplication syndrome (Dup15q), 
or CDKL5 deficiency disorder (CDD; clinically completed [study completed, clinical study
report (CSR) pending]). One phase 2, open-label, long-term study in participants with various 
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T
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CONFIDENTIAL
DEEs, including DS, LGS, Dup15q, or CDD, is ongoing. In addition, 2 phase 1 studies in 
healthy participants and 1 phase 2 study in participants with complex regional pain syndrome 
(CRPS) are clinically completed with data analysis or CSR pending. Overall, 350 participants
have been enrolled in the clinical trials with soticlestat, of which 310 have received active 
treatment based on actual exposure data from completed clinical trials and enrollment at the time 
of data lock point for ongoing clinical trials.
Soticlestat was rapidly absorbed with an average median tmax of 0.25 to 0.52 hours following 
single-dose (15 to 1350 mg) and an average median tmax of 0.33 to 0.5 hours following 
multiple-dose (100 to 600 mg) under fasting conditions in healthy participants. When 
administered under fed conditions, soticlestat tmax was delayed by about 1.5 hours, 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. Soticlestat was shown to cross the blood 
brain barrier and was able to block tracer binding to the enzyme target, demonstrating a 
sigmoidal maximum observed effect. 
Refer to the Investigator’s Brochure (IB) for detailed background information on soticlestat [2].
4.1.2
Rifampin
Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin inhibits 
deoxyribonucleic acid-dependent ribonucleic acid polymerase activity in susceptible 
Mycobacterium tuberculosis organisms [3].
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After oral administration, rifampin is readily and completely absorbed from the gastrointestinal
tract. Serum Cmax in healthy adults and pediatric populations vary widely from individual to 
individual. After a single 600 mg oral dose of rifampin in healthy adults, Cmax is reached within 
1 - 2 hours and peak serum concentration averages at 7 μg/mL but may vary from 4 - 32 μg/mL. 
Absorption of rifampin is reduced by about 30% when the drug is ingested with food. Thus, daily 
doses of rifampin should be given at least 1 hour before or 2 hours after a meal [3].
After absorption, rifampin is rapidly eliminated in the bile, and an enterohepatic circulation 
ensues. During this process, rifampin undergoes progressive deacetylation to form the 
desacetylrifampin metabolite, and nearly all the drug in the bile is in this form by ~6 hours. 
Following multiple dosing, rifampin is a potent inducer of drug metabolism by inducing a variety 
of hepatic and intestinal CYP enzymes, especially CYP3A4 [3].
Systemic hypersensitivity reactions were reported with rifampin administration. Signs and 
symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, 
hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver 
transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, 
chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, 
palpitations). Isolated reports have associated porphyria exacerbation with rifampin 
administration [3].
4.2
Rationale for the Proposed Study
 Although metabolism via CYP3A4 is not 
the main route of elimination for soticlestat, there is still a potential of decrease in soticlestat 
systemic exposure when it is concomitantly administered with strong CYP3A inducers because 
of the induction of CYP3A-mediated intestinal and/or hepatic metabolism following oral dose 
administration of these inducers. 
The purpose of this study is therefore to assess the effect of co-administration of a strong CYP3A 
inducer on the PK soticlestat to provide information for management of potential DDIs with 
strong CYP3A inducers in future clinical studies of soticlestat. 
Rifampin was chosen as a perpetrator for this study as it is considered a strong index inducer of
CYP3A as per the Food and Drug Administration [4]. In addition, rifampin also induces
UGT1A9 and UGT2B4 [5-7] and direct glucuronidation by UGT1A9 and 2B4 is the
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TAK-935
Study ID TAK-935-1009
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Protocol 
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CONFIDENTIAL
predominant clearance pathway of soticlestat, this study will also inform strategies for 
management of potential DDIs with UGT1A9 and UGT2B4 inducers in future clinical studies of 
soticlestat.
4.3
Benefit/Risk Profile
The dose of 300 mg soticlestat is the recommended phase 3 dose [2] and will be administered as 
a single-dose in this study. In addition, doses up to 1350 mg were administered in healthy 
participants and were found to be safe and well tolerated.
The doses of rifampin are administered for a very short duration in this study, any potential 
risk(s) to participants in this study following cumulative intake will be mitigated according to the 
dosing recommendations presented in the labelling [3].
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 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.
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5.2
Study Objectives
5.2.1
Study Primary Objective
To characterize the effect of rifampin, a strong CYP3A inducer, on the single-dose PK of 
soticlestat.
5.2.2
Study Secondary Objective
To assess the safety and tolerability of soticlestat following a single oral dose in healthy adult 
participants with/without a strong CYP3A inducer.
5.3
Endpoints
5.3.1
Primary Endpoint
The following PK parameters will be analyzed for soticlestat, when administered alone and when 
co-administered with rifampin:
!
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).
!
Time of first occurrence of Cmax (tmax).
5.3.2
Secondary Endpoints 
!
Number of participants with at least one TEAE.
!
Incidence of clinically significant abnormal values for laboratory evaluations, vital signs, 
ECG parameters, and C-SSRS.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is an open-label, 2-period, fixed sequence DDI study to evaluate the effect of a strong 
CYP3A inducer, rifampin, on the single-dose PK of soticlestat in healthy participants.
Study schematic of the study design and dose regimens are shown in Table 2.a and Table 2.b. A 
schedule of assessments is shown in Schedule of Study Procedures (Section 3.0).
Participants will be screened within 4 weeks (28 days) prior to the first administration of 
soticlestat (Day -28 to first dosing, Day 1). Qualified participants will be admitted to the clinic 
on Day -1 of Period 1, at the time indicated by the CRU, and will remain confined until after the 
last blood draw and/or study procedures on Day 14 of Period 2.
In Period 1, on Day 1, participants will receive a single dose of soticlestat (300 mg; 3 x 100 mg 
T4 tablets) under fasting conditions. Blood samples for the PK of soticlestat 
will be collected at scheduled time points from predose through 96 hours postdose. There will be 
washout period of 4 days between the soticlestat dose in Period 1 and the first rifampin dose in 
Period 2.
In Period 2, from Days 1 to 13, participants will receive a QD oral dose of rifampin (600 mg; 
2 x 300 mg capsules) under fasting conditions. On the morning of Day 11, participants will 
receive a single dose of soticlestat (300 mg; 3 x 100 mg T4 tablets) co-administered with the 
rifampin dose under fasting conditions. Blood samples for the PK of soticlestat 
will be collected at scheduled time points from soticlestat predose on Day 11 through 
72 hours postdose.
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory
evaluations, physical examinations, 12-lead ECGs, vital signs, and C-SSRS.
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 15 (± 2) days after the last soticlestat administration by telephone or other methods 
per CRU standards to determine if any AE has occurred or concomitant medications have been 
taken since the last study visit. If clinically significant findings are observed upon discharge, 
participants may return to the CRU for re-evaluation per Investigator’s discretion.
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6.2
Dose Escalation
Not applicable.
6.3
Stopping Rules
Not applicable.
6.4
Rationale for Study Design, Dose, and Endpoints
6.4.1
Rationale of Study Design 
This study will evaluate the effect of rifampin on soticlestat using an open-label, 2-period, fixed 
sequence. A fixed-sequence design has been selected as this will reduce the study duration and 
prevent any carryover effects of the study treatment. Since the absorption of rifampin is reduced 
when it is administered with food [3], it was thus decided to administer all study drugs under 
fasting conditions. The washout period of 4 days between the soticlestat dosing alone (Day 1 of 
Period 1) and the first rifampin dose (Day 1 of Period 2) is considered sufficient to prevent 
carryover effect of the treatment.
6.4.2
Rationale for Dose
The dose of soticlestat selected for this study is 300 mg (3 x 100 mg), the recommended phase 3 
dose. In clinical studies, soticlestat was safe and well tolerated when administered as a single 
dose up to 1350 mg.
The dose of rifampin selected for this study is 600 mg (2 x 300 mg) QD, which is commonly 
used in therapeutic regimens. The t½z of rifampin is ~3 hours following a 600 mg oral dose [3]; 
however, the time required to produce maximum enzyme induction is substantially longer due to 
the need for enzyme production. The timeframe for maximum induction by rifampin has been 
estimated as at least 5 days following administration of 600 mg QD [9-10]. In most in vivo 
interaction studies in healthy adult participants, oral rifampin has typically been administered as 
a 600 mg dose for 4 to 18 days [11]. To maximize induction of CYP3A4, rifampin will be 
administered QD for 10 days prior to co-administration with soticlestat on Day 11 (Period 2). To 
maintain the level of induction, rifampin will be administered throughout PK sampling of 
soticlestat (ie, until Day 13 of Period 2).
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, clinical laboratory assessments, C-SSRS, and physical examinations.
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6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
soticlestat
, and is to be collected as close to the scheduled times defined in 
this protocol as possible.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drugs to any participant may not be modified. 
Unscheduled procedures might be performed for safety reasons. If necessary, a participant may 
be discontinued for the reasons described in Section 7.5 and Section 7.6.
6.6
Study Beginning and End/Completion
6.6.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first participant.
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
Study completion is defined as the date when the last follow-up visit for the last participating 
participant in the study is completed.
Property of Takeda: For Non-Commercial Use Only and
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This time period may change in the event that the study is terminated early or the last participant 
is lost to follow-up. 
6.6.4
Definition of Study Discontinuation
Celerion reserves the right to terminate the study in the interest of participant welfare.
The Sponsor reserves the right to suspend or terminate the study at any time, for any reason.
6.6.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is 
no longer acceptable for participants participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises participant safety.
6.6.6
Criteria for Premature Termination or Suspension of a Site
6.6.6.1
Criteria for Premature Termination or Suspension
A study site may be terminated prematurely or suspended if the site (including the Investigator) 
is found in significant violation of GCP, the study protocol, or contractual agreement; if the site 
(including the Investigator) is unable to ensure adequate performance of the study; or as 
otherwise permitted by the contractual agreement.
6.6.6.2
Procedures for Premature Termination or Suspension
In the event that the sponsor, an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), or a regulatory authority elects to terminate or suspend the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational site(s) 
during the course of termination or study suspension.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
7.1
Inclusion Criteria
Participants must fulfill the following inclusion criteria before the first dose to be eligible for 
participation in the study:
1. Healthy, adult, male or female of non-childbearing potential (Appendix D), 18 - 55 years of 
age, inclusive, at screening.
2. Male participant agrees to comply with any applicable contraceptive requirements of the 
protocol as detailed in Appendix D.
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3. BMI ≥18.0 and ≤32.0 kg/m2 at screening. 
4. Continuous non-smoker who has not used nicotine-containing products for at least 90 days 
prior to the first dosing.
5. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the PI or designee.

Supine BP is ≥90/40 mmHg and ≤140/90 mmHg at screening;

Supine HR is ≥45 bpm and ≤100 bpm at screening;

QTcF is ≤450 msec (males) or ≤470 msec (females) and ECG findings considered normal 
or not clinically significant by the Investigator or designee at screening;

Estimated creatinine clearance ≥80 mL/min at screening.

Liver function tests including ALT and AST ≤1.5 X the ULN at screening and check-in.
6. Able to swallow multiple tablets/capsules.
7. Understands the study procedures in the ICF, and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
Participants must not be enrolled in the study if they meet any of the following criteria before the 
first dose of study drug:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History or presence of gastritis, gastrointestinal tract, gastric bypass surgery, or hepatic
disorder or other clinical condition which, in the opinion of the Investigator or designee, may 
affect the absorption, distribution, metabolism, or elimination of study drugs.
4. History or presence of cataracts or other clinically significant vision disturbances.
5. History or presence of epilepsy, seizure, or convulsion, tremor or related symptoms.
6. 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.
7. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
dosing.
8. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related 
compounds.
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9. Any positive responses on the C-SSRS that in the clinical judgment of the Investigator has a 
risk of suicide or has made a suicide attempt in the previous 12 months prior to the first 
dosing.
10. Female participants of childbearing potential.
11. Female participants with a positive pregnancy test at screening or check-in or who is 
lactating.
12. Positive urine drug or alcohol results at screening or check-in.
13. Positive results at screening for HIV, HBsAg, or HCV.
14. Unable to refrain from or anticipates the use of:
!
Any drug, including prescription and non-prescription medications, herbal remedies, or 
vitamin supplements within 14 days prior to the first dosing. Thyroid hormone 
replacement medication may be permitted if the participant has been on the same stable 
dose for the immediate 3 months prior to first dosing.
15. History of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is 
approximately equivalent to the following: beer [354 mL/12 oz], wine [118 mL/4 oz], or 
distilled spirits [29.5 mL/1 oz] per day).
16. The participant consumes excessive amounts, defined as greater than 4 servings (1 serving is 
approximately equivalent to 120 mg of caffeine), of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
17. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to the first dosing and throughout the study.
18. Donation of blood or significant blood loss within 56 days prior to the first dosing.
19. Plasma donation within 7 days prior to the first dosing.
20. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. 
The 30-days window or 5 half-lives will be derived from the date of the last blood collection 
or dosing, whichever is later, in the previous study to Day 1 of Period 1 of the current study.
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2 and 
throughout the study, including the follow-up period. After the first dose, ibuprofen (up to 1.2 g 
per 24 hour period) may be administered at the discretion of the Investigator or designee. 
Thyroid hormone replacement medication may be permitted if the participant has been on the 
same stable dose for the immediate 3 months prior to the first dosing.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the participant may continue participation in the study.
All medications taken by participants during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing (Days -
28 to predose [Day 1])
After First Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from first dosing until 
the end of PK collection
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing a
Prohibited from first dosing until 
the end of PK collection a
Medications 
See Sections 7.1 and 7.2
See Sections 7.1 and 7.2
Nicotine- and tobacco-
containing and/or cannabis 
products
Prohibited from 90 days prior to first dosing
Prohibited from first dosing until 
the follow-up visit.
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited from first dosing until 
the end of PK collection
Other fruit juice
Prohibited from 12 hours prior to first dosing
Prohibited from first dosing until 
the end of PK collection
Vegetables from the 
mustard green family 
(eg, kale, broccoli, 
watercress, collard greens, 
kohlrabi, Brussels sprouts, 
mustard), and charbroiled 
meats
Prohibited from 7 days prior to first dosing
Prohibited from first dosing until 
the end of PK collection
Processed and grilled meat 
consumption including but 
not limited to sausages, 
salami, pork flank (spiced 
and boiled) and ham
Prohibited from first dosing until 
the end of PK collection
(a) small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz/1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz chocolate bar, per day, would not be 
considered a deviation to this restriction.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Water (except water provided with each dosing) will be restricted 1 hour prior to and 1 hour after 
each dosing, but will be allowed ad libitum at all other times. Other fluids may be given as part 
of meals and snacks but will be restricted at all other times throughout the confinement period.
Participants will fast overnight for at least 10 hours prior to each soticlestat dosing and at least 
8 hours prior to each rifampin dosing. Participants will continue the fast for at least 4 hours on all 
dosing days. For limiting nitrosamine exposure from food, processed and grilled meat 
consumption including but not limited to sausages, salami, pork flank (spiced and boiled) and 
ham will be excluded from first dosing until the end of PK collection.
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When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from all 
food and drink except water between meals and snacks.
Each meal and/or snack served at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each period.
7.4.2
Activity
Participants will remain seated for the first 4 hours post soticlestat dose, 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 (eg, in order to use the toilet 
facilities).
Participants will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of 
the study.
7.5
Criteria for Discontinuation or Withdrawal of a Participant
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:
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a participant’s laboratory profile has returned to 
normal/baseline status, see Section 9.2.9), if the following circumstances occur at any time 
during study drug treatment:

ALT or AST >8 × ULN, or

ALT or AST >5 × ULN and persists for more than 2 weeks, or

ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or

ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
QTcF interval:
Study drug should be discontinued immediately with appropriate clinical follow-up if a QTcF 
interval >500 msec or if there is an increase of QTcF >60 mecs above screening/baseline 
detected by ECG and confirmed with a repeat ECG. Appropriate clinical follow-up includes 
a repeat ECG.
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2. Significant protocol deviation: The discovery post-enrollment that the participant 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 participant (or participant’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the CRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category). If a participant 
chooses to withdraw from study participation due to personal concerns related to the 
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.
8. Other. The specific reasons for discontinuation should be entered into the CRF including 
unavoidable circumstances such as the COVID-19 pandemic. Participants may be withdrawn 
from the study at any time at the discretion of the Investigator or Sponsor for safety reasons 
which should be entered into the CRFs.
7.6
Procedures for Discontinuation or Withdrawal of a Participant
The Investigator may discontinue a participant’s study participation at any time during the study 
when the participant meets the study termination criteria described in Section 7.5. In addition, a 
participant may discontinue his or her participation without giving a reason at any time during 
the study. Should a participant’s participation be discontinued, the primary criterion for 
termination must be recorded by the Investigator. In addition, efforts should be made to perform 
all procedures scheduled for the end-of-study or early termination as described in Section 3.0.
7.7
Participant Replacement
Replacement of discontinued or withdrawn participants due to any reason will be assessed on a 
case by case basis by the Sponsor and Investigator to ensure a minimum of 12 PK-evaluable 
participants complete the study.
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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 100 mg strength)
Dosage Form/Formulation:
T4 immediate release tablet
Dosing regimen:
Single dose 
Route of Administration:
Oral
Interacting Drug
Product Name: 
Rifampin 
Strength: 
300 mg 
Dose: 
600 mg (2 x 300 mg strength)
Dosage Form/Formulation: 
Capsule
Dosing regimen:
Multiple dose (QD)
Route of Administration:
Oral
Preference for generic or brand name: 
Brand name or generic.
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of soticlestat to allow completion of this study.
Celerion will supply sufficient quantities of rifampin to allow completion of this study.
For each study medication (ie, soticlestat and rifampin), the same lot number will be used 
throughout the study. The lot numbers and expiration dates (where available) of the study drugs 
supplied will be recorded in the final report. Study drugs will be stored according to the product 
labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study.
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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, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. Any remaining supplies that were 
purchased by Celerion will be destroyed, if appropriate. 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 participant 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 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 in Period 1, 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 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 9.2.6.
9.1.2
Inclusion and Exclusion 
Please refer to Section 7.1 and Section 7.2.
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9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.3. All medications taken by 
participants during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to participant safety.
For this study, collection of blood for soticlestat
PK is 
the critical parameter and needs to be collected as close to the exact time point as possible. All 
other procedures should be completed as close to the prescribed/scheduled time as possible, but 
can be performed prior to or after the prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Physical Exam
A full and abbreviated physical examination will be performed as outlined in the Schedule of 
Study Procedures (Section 3.0).
An abbreviated physical examination will include at the minimum, examination of respiratory, 
cardiovascular, and gastrointestinal systems, with the option for further examination of 
additional systems as necessary based on reported symptoms/AEs.
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.
Property of Takeda: For Non-Commercial Use Only and Sub
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9.2.4
Vital Signs
Single measurements of temperature, respiratory rate, blood pressure and pulse rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Blood pressure and pulse rate measurements will be performed with participants in a supine 
position (5 minutes).
Vital signs will be measured within 24 hours prior to Day 1 dosing of Period 1 for the predose 
time point. At all other predose time points, vital signs will be measured within 2 hours prior to 
dosing. When scheduled postdose, vital signs will be performed within approximately 
15 minutes of the scheduled time point. 
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
Investigator or designee.
ECGs will be performed with participants in a supine position (5 minutes). All ECG tracings will 
be reviewed by the Investigator or designee.
ECGs will be measured within 24 hours prior to Day 1 dosing of Period 1 for the predose time 
point. At all other predose time points, ECGs will be collected within 2 hours prior to dosing. 
When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point.
9.2.6
Study Drug Administration
Study drugs and study drug formulations will be provided as described in Section 8.1.
Dose regimens for study drugs are described in Table 2.b.
After initial morning dosing on Day 1 of Period 2, each subsequent study drug dose will be 
administered within ± 1 hour of dosing time established on Day 1 of Period 2.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
participant, as appropriate.
Study drugs will be administered with approximately 240 mL of water.
Additional information regarding drug preparation and administration may be provided in a 
separate document.
Participants will be instructed not to crush, split, or chew the tablets and/or capsules.
The exact clock time of dosing will be recorded.
A qualified designee will be responsible for monitoring the administration of the assigned doses. 
A mouth check will be performed by the qualified designee to ensure that the participants have 
swallowed the study drug(s). Once a participant has finished the dosing water, the qualified 
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designee will use a flashlight and a tongue depressor to check the participant’s mouth. 
Participants’ hands will also be verified to ensure that the study drug(s) was ingested.
9.2.7
C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures (Section 3.0) for each study part. Two versions of the C-SSRS will be used in 
this study: the Screening/Baseline C-SSRS Lifetime and the Since-Last-Visit C-SSRS. It is 
recommended that the same staff be used to administer the scale to the participant at all time 
points when C-SSRS is scheduled. Any suicidal ideation or suicidal behavior during the trial 
periods detected by the C-SSRS will be recorded as an AE. The Investigator will ensure that any 
suicidal ideation or behavior is medically addressed, including assessment and treatment by 
qualified medical personnel.
9.2.8
AE Monitoring
Participants will be monitored throughout the study for adverse reactions to the study drugs 
and/or procedures as described in Section 10.0.
9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator or designee.
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Erythrocytes
Mean platelet volume
Total and differential leukocyte count
Immune cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Coagulation
Coagulation test will be conducted as outlined in the Schedule of Study Procedures (Section 3.0).
Coagulation test will consist of the following tests:
Activated partial thromboplastin time
Prothrombin time / International normalized ratio
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Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, participants may not have fasted for 8 hours prior to when the serum 
chemistry sample is taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Blood Urea Nitrogen
Albumin
Bilirubin (total, direct and indirect)
Sodium
Alkaline phosphatase (ALP)
Potassium
Aspartate aminotransferase (AST)
Chloride
Alanine aminotransferase (ALT)
Glucose
Calcium
Creatinine **
Carbon dioxide
Phosphate
Protein (total)
Alpha1-acidic glycoprotein (AGP) (screening only)
Gamma-glutamyl transferase (GGT)
Magnesium
Urea
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
Erythrocytes
Creatinine
Calcium
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
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9.2.9.1.1
Other 
HIV test
Urine drug screen
-
Opiates (includes morphine, heroin (diacetylmorphine), 
codeine, 6-acetylmorphine, dihydrocodeine, 
hydrocodone, thebaine, and, hydromorphone)
-
Amphetamines
-
Barbiturates
-
Benzodiazepines
-
Cocaine
-
Cannabinoids
-
Buprenorphine/metabolite
-
MDMA(3,4-methylenedioxy-methamphetamine)
-
Methadone/metabolite
-
Oxycodone/oxymorphone
-
Phencyclidine
HBsAg
HCV (if antibody positive, confirm RNA negative)
Urine alcohol screen
Serum pregnancy test (for females only)
FSH (for females only)
COVID-19 (SARS-CoV-2 polymerase chain 
reaction test or equivalent) 
9.3
Pharmacokinetic Samples
Samples for assessment of soticlestat
) will be collected 
as delineated in 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 soticlestat
Blood
Plasma
Plasma sample for PK analysis
Mandatory
9.3.1
Pharmacokinetic 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.
PK 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. 
Property of Takeda: For Non-Commercial Use On
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9.3.1.1
Plasma for PK Measurements
The following PK parameters will be calculated from plasma concentrations of soticlestat 
 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.
AUCextrap%:
Percent of AUC∀extrapolated, represented as (1 - AUClast/AUC∀)*100.
CL/F:
Apparent total plasma clearance after oral (extravascular) administration, 
calculated as Dose/AUC∀(soticlestat only).
Cmax:
Maximum observed concentration.
tmax:
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value.
λz
Terminal disposition phase rate constant.
t½z:
Terminal disposition phase half-life will be calculated as 0.693/λz.
Where λz is the apparent first order terminal disposition phase rate constant 
calculated from a semilog plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares- regression 
analysis using the maximum number of points in the terminal log-linear 
phase (eg, three or more non-zero plasma concentrations).
Vz/F:
Apparent volume of distribution during the terminal disposition phase after 
oral (extravascular) administration, calculated as Dose/(AUC∀x λz) 
(soticlestat only).
No value for λz, AUC∀, AUCextrap%, CL/F, Vz/F, λz, or t½z 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.3.3
PGx Measurements 
Not applicable.
9.3.4
Confinement
Participants will be housed on Day -1 of Period 1, at the time indicated by the CRU, until after 
the last blood draw and/or study procedures on Day 14 of Period 2. Participants may be asked to 
check-in to the CRU earlier to undergo additional COVID 19 precaution procedures or testing 
not related to study protocol, as per CRU requirements.
At all times, a participant may be required to remain at the CRU for longer at the discretion of
the Investigator or designee.
The CRU will contact all participants (including participants who terminate the study early) 
15 (± 2) days after the last soticlestat administration to determine if any AEs have occurred since 
the last study visit. If clinically significant findings are observed upon discharge, participants 
may return to the CRU for re-evaluation per Investigator’s discretion.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation participant who 
has signed informed consent to participate in a study; it does not necessarily have to have a 
causal relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
whether or not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).
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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 first 
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.
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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.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
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
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
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
COVID-19 pneumonia
Spontaneous abortion / stillbirth and fetal death
COVID-19-related disease
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 AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
An AE 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.
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Severe:
An AE 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.
In addition, relationship (causality) to COVID-19 should be determined for all PTEs and AEs. 
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to COVID-19. Otherwise, the relationship should be 
assessed as not related.
Similarly, relationship (causality) to COVID-19 vaccines should be determined for all PTEs and 
AEs. The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to COVID-19 vaccines. Otherwise, the relationship 
should be assessed as not related. If the AE has relationship to vaccination, specific verbatim 
term should be used, eg, post-vaccination fever, vaccination site burning.
In addition, if the causality assessment done by the investigator determines that the event or 
events (PTEs or AEs) are related or possible related to COVID-19 or the COVID-19 vaccine, the 
events should be assessed as not related to the investigational product. If the AE is related to 
COVID-19 vaccination, specific verbatim term(s) should be used, eg, post-vaccination fever, 
vaccination site burning.
10.2.3
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the participant 
and/or investigator.
10.2.4
End Date 
The end date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae or the participant died.
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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.
10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been 
taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the participant died, dosing with study medication had not 
yet started or dosing with study medication was already stopped before the onset of the AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7
Outcome 

Recovered/resolved – participant returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the participant died from a cause 
other than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; 
the participant died from another cause with the particular AE state remaining “Not 
recovered/not resolved.”

Recovered/ Resolved with sequelae – the participant recovered from an acute AE but was left 
with permanent/significant impairment (eg, recovered from a cardiovascular accident but 
with some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the participant’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at
the time the participant signs the informed consent. Routine collection of AEs will continue until 
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the follow-up contact 15 (± 2) days after last dose of soticlestat. For participants who discontinue 
prior to the administration of study medication, AEs will be followed until the participant
discontinues study participation. 
10.2.8.2
Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Participants may report AEs occurring at any other time during the study. Participants
experiencing an SAE prior to the first exposure to investigational product must be monitored 
until the symptoms subside and any clinically relevant changes in laboratory values have 
returned to Baseline or there is a satisfactory explanation for the change. Nonserious AEs that 
begin prior to the first exposure to investigational product, related or unrelated to the study 
procedure, need not be followed-up for the purposes of the protocol.
All participants experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All AEs will be documented in the AE page of the CRF, whether or 
not the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Relationship to COVID-19.

Relationship to COVID-19 vaccine.

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:
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
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.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Reporting Special Interest AEs 
There are no AEs of Special Interest for soticlestat.
10.2.8.5
Reporting of Abnormal LFTs
If a participant is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a participant is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the Medical Monitor for discussion of the 
relevant participant details and possible alternative etiologies, such as acute viral hepatitis A or B 
or other acute liver disease. Follow-up laboratory tests as described in Section 9.2.8 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).
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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 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 statistical analysis plan (SAP). 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 PK set. More details will be provided in SAP.
11.1.1.2
Safety Set
All participants who received at least one dose of the study drug(s) will be included in the safety 
set.
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, gender, 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 data set. 
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Values will be reported for the plasma soticlestat 
concentrations for each participant. PK parameters for plasma concentrations of soticlestat
will be calculated as described in Section 9.3.1.1, and 
outlined in the SAP.
11.1.3.1
Linear Mixed Effects Models
Ln-transformed AUClast, AUC∞, and Cmax data will be analyzed using a linear mixed effects 
model, separately. The model will include treatment (soticlestat with and without rifampin) as a 
fixed-effect and participant as a random effect. The point estimates and 90% CIs for the GMRs 
of AUC∞, AUClast, and Cmax for soticlestat with versus without rifampin will be calculated using 
the exponentiation of the point estimates of the difference between treatment regimen and the 
corresponding 90% CIs from the analyses on the ln-transformed AUClast, AUC∞, and Cmax.
11.1.3.2
Non-Parametric Analysis
!
tmax will be analyzed using nonparametric analysis for paired samples (the Wilcoxon Signed 
Rank Test statistic). The difference of medians (treatment effect) and the corresponding 90% 
CI will be estimated using the Hodges-Lehmann method and Walsh Averages. tmax will not 
be ln-transformed. The comparisons of interest is the same as the analysis described in 
Section 11.1.3.1.
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 treatment days (soticlestat alone 
[Period 1 Days 1 - predose Day 5]; rifampin alone [Period 2 Day 1 postdose – Day 11 predose]; 
and soticlestat+rifampin [Day 11 postdose to end of study]) 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.
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11.1.5.2
Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by baseline and treatment days (soticlestat alone 
[Period 1 Days 1 - predose Day 5]; rifampin alone [Period 2 Day 1 postdose – Day 11 predose]; 
and soticlestat+rifampin [Day 11 postdose to end of study]). Point of time of collection and a 
shift table describing out of normal range shifts will be provided.
11.1.5.3
Vital Signs
Vital signs assessments will be summarized by baseline and treatment days (soticlestat alone 
[Period 1 Days 1 - predose Day 5]; rifampin alone [Period 2 Day 1 postdose – Day 11 predose]; 
and soticlestat+rifampin [Day 11 postdose to end of study]) and point of time of collection.
11.1.5.4
Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs baseline and treatment days (soticlestat alone [Period 1 Days 1 - predose Day 5]; rifampin 
alone [Period 2 Day 1 postdose – Day 11 predose]; and soticlestat+rifampin [Day 11 postdose to 
end of study]) and point of time of collection.
C-SSRS results will be summarized by point of time of collection.
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
Not applicable.
11.3
Determination of Sample Size
This study is not powered for hypothesis testing and is not based on any specific no-effect 
boundaries. The sample size is based on an estimation approach and is considered sufficient to 
provide a reliable estimate of the DDI magnitude.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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A total of 14 participants will be dosed to ensure that 12 evaluable subjects complete the study.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Due to COVID-19, monitoring visits may also be conducted 
remotely. 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 
organisation) 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 (as long as blinding is not jeopardized), 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. 
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.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In 
this circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the Sponsor should 
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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 Conference on Harmonisation (ICH) Harmonised 
Tripartite Guideline for GCP. Each investigator will conduct the study according to applicable 
local or regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki 
are addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The Sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those Americas sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, 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, informed 
consent form) 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 informed consent 
form, 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.
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Participant incentives should not exert undue influence for participation. Payments to 
participants must be approved by the IRB or IEC and Sponsor.
13.2
Participant Information, Informed Consent, and Participant Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, 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 informed consent form 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 informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the participant authorization form. The informed 
consent form, 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 informed consent form, 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 informed consent form, participant authorization form (if applicable), and participant
information sheet (if applicable) to the participant. Information should be given in both oral and 
written form whenever possible and in the manner deemed appropriate by the IRB or IEC. In the 
event the participant is not capable of rendering adequate written informed consent, then the 
participant’s legally acceptable representative may provide such consent for the participant in 
accordance with applicable laws and regulations.
The participant, or the participant’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the study, and (2) decide whether or not to participate 
in the study. If the participant, or the participant‘s legally acceptable representative, determines 
he or she will participate in the study, then the informed consent form and participant
authorization form (if applicable) must be signed and dated by the participant, or the 
participant’s legally acceptable representative, at the time of consent and prior to the participant
entering into the study. The participant or the participant’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the informed consent form and participant
authorization (if applicable) at the time of consent and prior to participant entering into the study; 
however, the Sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original informed consent form, participant authorization form (if applicable), 
and participant information sheet (if applicable) will be stored in the investigator’s site file. The 
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investigator must document the date the participant signs the informed consent in the 
participant’s medical record. Copies of the signed informed consent form, the signed participant
authorization form (if applicable), and participant information sheet (if applicable) shall be given 
to the participant.
All revised informed consent forms must be reviewed and signed by relevant participants or the 
relevant participant’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
participant’s medical record, and the participant should receive a copy of the revised informed 
consent form.
13.3
Participant Confidentiality
The Sponsor and designees affirm and uphold the principle of the participant’s right to protection 
against invasion of privacy. Throughout this study, a participant’s source data will only be linked 
to the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited participant attributes, such as sex, age, 
or date of birth, and participant initials may be used to verify the participant and accuracy of the 
participant’s unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the participant’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a participant’s study 
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.
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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.
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
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14.1.1
Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
E-mail: eupv@tgrd.com
Fax: +1-202-315-3560
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14.1.2
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the Sponsor. I agree to conduct 
this study in accordance with the requirements of this protocol and also to protect the rights, 
safety, privacy, and well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 [R2] Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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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
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC∞
Area under the concentration-time curve from time 0 to infinity
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
BID
Twice daily
BMI
Body mass index
bpm
Beats per minute
C-SSRS
Columbia-Suicide Severity Rating Scale
CFR
Code of Federal Regulations
CH24H
Cholesterol 24S-hydroxylase
CI
Confidence interval
CL/F
Apparent clearance after extravascular administration
Cmax
Maximum observed concentration 
COVID-19
Coronavirus disease 2019
CRF
Case report form
CRU
Clinical Research Unit
CSR
Clinical study report
CYP
Cytochrome P450
DDI
Drug-drug interaction
DEE
Developmental and Epileptic Encephalopathies
DS
Dravet Syndrome
ECG
Electrocardiogram
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GMR
Geometric mean ratio
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
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ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
LFT
Liver function test
ln
Natural log
LGS
Lennox Gastaut Syndrome
MedDRA®
Medical Dictionary for Regulatory Activities®
OATP
organic-anion-transporting polypeptide
P-gp
P-glycoprotein
PBPK
Physiologically-based PK
PK
Pharmacokinetic(s)
PTE
Pretreatment event
QD
Once 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 reactions
t1/2z
Terminal disposition phase half-life
T4
Immediate release tablets
TEAE
Treatment-emergent adverse event
tmax
Time of first occurrence of Cmax
ULN
Upper limit of normal
US
United States
USA
United States of America
15.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the 
Investigator. The final signed CRFs are provided to the Sponsor in the format as decided upon 
between Celerion and the Sponsor (e.g., CD, flashdrive, SFTP). This will be documented in the 
Data Management Plan (if applicable).
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After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the CRFs for completeness and accuracy and must sign 
and date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the CRFs should be made by the investigator with use of change and modification 
records of the CRFs. The principal investigator must review the data change for completeness 
and accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the participant’s
medical and hospital records pertinent to the study to ensure accuracy of the CRFs. The 
completed CRFs are the sole property of the Sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, medical records, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated informed consent forms, participant
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of CRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the Sponsor or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the participant’s chart to ensure long-term 
legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain essential 
documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the Clinical Study Site Agreement between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.0
REFERENCES
1. Kupper, L. L. and Hafner, K.B., How appropriate are popular sample size formulas? Am 
Stat, 1989. 43(2): 101-105
2. TAK-935. Takeda Pharmaceutical Company Ltd. Global Investigator’s Brochure. Edition 6, 
15 January 2021.
3. Rifadin® (Rifampin) capsules, Sanofi-Aventis U.S. LLC, full prescribing information 
(electronic monograph; document revised: 12/2020). Available at 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=036ab68e-5085-4edc-bd83-
784b43d64eab.
4. Food and Drug Administration: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors, and Inducers. Available at: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteracti
onslabeling/ucm093664.htm. (26 September 2016).
5. Pang, X., et al., Effects of rifampin and ketoconazole on pharmacokinetics of morinidazole in 
healthy chinese subjects. Antimicrob Agents Chemother, 2014. 58(10):5987-93.
6. Damayanthi, D., et al., Effects of rifampin, cyclosporine A, and probenecid on the 
pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in 
healthy participants. Int J Clin Pharmacol Ther, 2015. 53(2):115-28.
7. Kasichayanula, S., et al., Effects of rifampin and mefenamic acid on the pharmacokinetics 
and pharmacodynamics of dapagliflozin. Diabetes Obes Metab, 2013. 15(3):280-3.
8. EMA/425645/2020. European Medicines Regulatory Network approach for the 
implementation of the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) No 
726/2004 for nitrosamine impurities in human medicines; Feb 2021. Available at: 
https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-
assessment-report_en.pdf
9. Kapetas AJ, Sorich MJ, Rodrigues AD, Rowland A. Guidance for rifampin and midazolam 
dosing protocols to study intestinal and hepatic cytochrome P450 (CYP) 3A4 induction and 
de-induction. AAPS J. 2019 Jun 19;21(5):78. doi: 10.1208/s12248-019-0341-y. PMID: 
31218462.
10. Tran JQ, Kovacs SJ, McIntosh TS, Davis HM, and Martin DE. Morning spot and 24-Hour 
urinary 6β-hydroxycortisol to cortisol ratios: intraindividual variability and correlation under
basal conditions and conditions of CYP 3A4 induction. J Clin Pharmacol. 1999;39:487–94.
11. Tortorici MA, Matschke K, Korth-Bradley JM, DiLea C, Lasseter KC. The effect of rifampin 
on the pharmacokinetics of sirolimus in healthy volunteers. Clin Pharmacol Drug Dev, 
2014;3(1):51-56.
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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 participant who participates in the study, and 
document the date of consent in the participant‘s medical chart. Valid informed consent is the 
most current version approved by the IRB/IEC. Each informed consent form should contain a 
participant authorization section that describes the uses and disclosures of a participant’s 
personal information (including personal health information) that will take place in 
connection with the study. If an informed consent form does not include such a participant
authorization, then the investigator must obtain a separate participant authorization form 
from each participant or the participant’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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2 years following notification by the Sponsor that all investigations have been discontinued 
or that the regulatory authority has approved the marketing application. The investigator 
should contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor
within 24 hours.
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Appendix B
Elements of the Participant Informed Consent
In seeking informed consent, the following information shall be provided to each participant:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the participant’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of participants involved in the study.
7. A description of the participant’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the participant may receive.
11. A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the participant or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the participant, the participant
should be made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the participant and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the 
participant will be maintained, and a note of the possibility that regulatory agencies, 
auditor(s), IRB/IEC, and the monitor may inspect the records. By signing a written informed 
consent form, the participant or the participant’s legally acceptable representative is 
authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the participant for participating in the study.
17. The anticipated expenses, if any, to the participant for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the participant.
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the participant otherwise is entitled, and that the participant or the 
participant’s legally acceptable representative may discontinue participation at any time 
without penalty or loss of benefits to which the participant is otherwise entitled.
20. The consequences of a participant’s decision to withdraw from the research and procedures 
for orderly termination of participation by the participant.
21. A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.
23. A written participant authorization (either contained within the informed consent form or 
provided as a separate document) describing to the participant the contemplated and 
permissible uses and disclosures of the participant’s personal information (including personal 
health information) for purposes of conducting the study. The participant authorization must 
contain the following statements regarding the uses and disclosures of the participant’s
personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
participants the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that participants agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the participant’s identity will remain confidential in the event that study results are 
published.
24. Regular pregnancy tests will be performed throughout the study for all female participants.
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Protocol 
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CONFIDENTIAL
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 the 
last dose of study drug.
26. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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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.
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Study ID TAK-935-1009
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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 last 
dose of study drug, nonsterilized* male participants who are sexually active with a female 
partner of childbearing potential** must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Total abstinence (no sexual intercourse) may be considered an acceptable method of birth 
control if it agrees with his preferred and usual lifestyle.
Female Participants and Their Male Partners
Only women of non-childbearing potential will be included in this study. A female of 
non-childbearing potential, must have undergone one of the following sterilization procedures at 
least 6 months prior to the first dosing:
–
hysteroscopic sterilization;
–
bilateral tubal ligation or bilateral salpingectomy;
–
hysterectomy;
–
bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and FSH serum 
levels consistent with postmenopausal status**. 
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
**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 follicle 
stimulating hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to 
confirm a post-menopausal state in younger women (eg, those <45 year old) or women who are 
not using hormonal contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

contraceptive requirements of the study.
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Study ID TAK-935-1009
Page 67 of 67
Protocol 
20 August 2021
CONFIDENTIAL

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? 
Pregnancy
Women of childbearing potential will not be included in this study.
If any participant is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male participant during the study or for 90 days after the last dose, should also be 
recorded following authorization from the participant’s partner. 
If the female participant and/or female partner of a male participant agrees to the primary care 
physician being informed, the investigator should notify the primary care physician that the 
female participant and/or 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


  
ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
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SAP_001.pdf: 
NCT Number: NCT05098041
Title:  Phase 1 Open-Label Study to Evaluate the Drug-Drug Interaction of Rifampin 
as a Strong CYP3A Inducer on Soticlestat Pharmacokinetics in Healthy Adult 
Participants
Study Number: TAK-935-1009
Document Version and Date: Final / 16-Nov-2021
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-935-1009
Celerion Study Number: CA34934
A Phase 1 Open-Label Study to Evaluate the Drug-Drug Interaction of Rifampin as a Strong 
CYP3A Inducer on Soticlestat Pharmacokinetics in Healthy Adult Participants
Phase 1
Version: Final
Date: 16-Nov-2021
Prepared by: 
Based on:
Protocol Version: Original
Protocol Date: 20-Aug-2021
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
ion of
on of R
f
altlthy 
hy A
v-2021
202
n:n
Protoco
Protoc
Pro
Pr
da: For Non-Commercial U


TAK-935-1009
Celerion Study Number CA34934
Page 2 of 21
Statistical Analysis Plan Final
16 November 2021
CONFIDENTIAL
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Original version
16-Nov-2021
Not Applicable
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Celerion Study Number CA34934
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Statistical Analysis Plan Final
16 November 2021
CONFIDENTIAL
Approval Signatures
Electronic signature can be found on the last page of this document.
Study Title:
A Phase 1 Open-Label Study to Evaluate the Drug-Drug Interaction of
Rifampin as a Strong CYP3A Inducer on Soticlestat Pharmacokinetics in 
Healthy Adult Participants
Approvals:
Signatur
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
f
tics in
ics i
l Use Only and Subject to th


TAK-935-1009
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Page 4 of 21
Statistical Analysis Plan Final
16 November 2021
CONFIDENTIAL
TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................8
1.1
Objectives..................................................................................................................8
1.1.1
Primary Objective..............................................................................................8
1.1.2
Secondary Objective..........................................................................................8
1.1.3
Exploratory Objectives ......................................................................................8
1.2
Endpoints...................................................................................................................8
1.2.1
Primary Endpoints .............................................................................................8
1.2.2
Secondary Endpoints .........................................................................................8
1.2.3
Exploratory Endpoints .......................................................................................9
1.2.4
Additional Endpoints.........................................................................................9
1.3
Estimand(s)................................................................................................................9
2.0
STUDY DESIGN............................................................................................................9
3.0
STATISTICAL HYPOTHESES AND DECISION RULES...........................................11
3.1
Statistical Hypotheses..............................................................................................11
3.2
Statistical Decision Rules.........................................................................................11
3.3
Multiplicity Adjustment...........................................................................................11
4.0
SAMPLE-SIZE DETERMINATION.............................................................................11
5.0
ANALYSIS SETS.........................................................................................................12
5.1
PK Set .....................................................................................................................12
5.2
Safety Set ................................................................................................................12
6.0
STATISTICAL ANALYSIS..........................................................................................12
6.1
General Considerations............................................................................................12
6.1.1
Handling of Treatment Misallocations .............................................................13
6.2
Study Information....................................................................................................14
6.3
Disposition of Participants.......................................................................................14
6.4
Demographic and Other Baseline Characteristics.....................................................14
6.4.1
Demographics..................................................................................................14
6.4.2
Medical History and Concurrent Medical Conditions.......................................14
6.5
Medication History and Concomitant Medications...................................................14
6.6
Efficacy Analysis.....................................................................................................15
6.7
Safety Analysis........................................................................................................15
6.7.1
Adverse Events................................................................................................15
6.7.2
Adverse Events of Special Interest (if applicable) ............................................16
6.7.3
Clinical Laboratory Evaluation ........................................................................17
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Statistical Analysis Plan Final
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CONFIDENTIAL
6.7.4
Vital Signs.......................................................................................................17
6.7.5
12-Lead Electrocardiogram..............................................................................17
6.7.6
Physical Examination ......................................................................................18
6.7.7
Columbia Suicide Severity Rating Scale (C-SSRS)..........................................18
6.7.8
Overdose .........................................................................................................18
6.7.9
Extent of Exposure and Compliance ................................................................18
6.8
Pharmacokinetic Analysis........................................................................................18
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................20
6.10
Interim Analyses......................................................................................................20
6.11
Preliminary Analyses...............................................................................................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 ................................................21
9.0
APPENDIX...................................................................................................................21
9.1
Changes From the Previous Version of the SAP.......................................................21
9.2
Analysis Software....................................................................................................21
LIST OF IN-TEXT TABLES
Table 2.a
Study Schematic.................................................................................................10
Table 2.b
Dose Regimens for Study Drugs.........................................................................10
Table 6.a
AE Treatment Assignment Algorithm ................................................................16
Table 6.b
Collection of Blood Samples for Pharmacokinetic Analysis ...............................19
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Celerion Study Number CA34934
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Statistical Analysis Plan Final
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CONFIDENTIAL
LIST OF ABBREVIATIONS
AE
adverse event
AUC
area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value 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.
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration
BLQ
below the lower limit of quantitation
BMI
body mass index
CI
confidence interval
CL/F
apparent clearance after extravascular administration, calculated using the observed value of the 
last quantifiable concentration.
Cmax
maximum observed concentration
COVID-19
coronavirus disease 19
CPAP
clinical pharmacology analysis plan
CRF
case report form
CRU
clinical research unit
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CV%
arithmetic percent coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DMP
data management plan
ECG
electrocardiogram
Geom CV%
geometric percent coefficient of variation
Geom Mean
geometric mean
GMR
geometric least-squares mean ratio
LSM
least-squares mean
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
n
number of observations
PK
pharmacokinetic
PRO
patient-reported outcome
PT
preferred term
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SEM
standard error of the mean
SOC
system organ class
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Statistical Analysis Plan Final
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t1/2z
terminal disposition phase half-life
TAK-935
soticlestat
TEAE 
treatment-emergent adverse event
TFL
table, figure, and listing
tmax
time of first occurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration.
WHO
World Health Organization
λz
terminal disposition phase rate constant
Note: The PK parameters presented in the clinical study report (CSR) and in the in-text tables will be subscripted, whereas the 
PK parameters presented in the end-of-text tables will not be subscripted. In addition, AUC∞and ∀z will be presented as AUCinf 
and Lambdaz in the end-of-text tables, respectively.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
vascular 
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will be
∞and 
and ∀


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Page 8 of 21
Statistical Analysis Plan Final
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1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
To characterize the effect of rifampin, a strong CYP3A inducer, on the single-dose 
pharmacokinetics (PK) of soticlestat.
1.1.2
Secondary Objective
To assess the safety and tolerability of soticlestat following a single oral dose in healthy adult 
participants with/without a strong CYP3A inducer.
1.2
Endpoints
1.2.1
Primary Endpoints
The following PK parameters will be analyzed for soticlestat, when administered alone and when 
co-administered with rifampin:
#
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).
#
Time of first occurrence of Cmax (tmax).
1.2.2
Secondary Endpoints
#
Number of participants with at least one treatment-emergent adverse event (TEAE).
#
Incidence of clinically significant abnormal values for laboratory evaluations, vital signs, 
electrocardiogram (ECG) parameters, and Columbia-Suicide Severity Rating Scale
(C-SSRS).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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dose in
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Page 9 of 21
Statistical Analysis Plan Final
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CONFIDENTIAL
1.3
Estimand(s)
Not applicable.
2.0
STUDY DESIGN
This is an open-label, 2-period, fixed-sequence drug-drug interaction (DDI) study to evaluate the 
effect of a strong CYP3A inducer, rifampin, on the single-dose PK of soticlestat in healthy 
participants.
Study schematics of the study design and dose regimens are shown in Table 2.a and Table 2.b,
respectively.
Property of Takeda: For Non-Commercial U
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Use Only and Subject to the Applicable Terms of Use


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Celerion Study Number CA34934
Page 10 of 21
Statistical Analysis Plan Final
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CONFIDENTIAL
Table 2.a
Study Schematic
Screening
Period 1
Period 2
Follow-up
Check-in and 
Predose 
Assessments
Soticlestat 
Dosing, PK 
Sampling, and 
Study 
Assessments
PK Sampling 
and Study 
Assessments
Rifampin 
Dosing and 
Study 
Assessments
Co-administration 
(Rifampin and 
Soticlestat), PK 
Sampling, and 
Study 
Assessments
Rifampin 
Dosing, PK 
Sampling and 
Study 
Assessments
Within 
28 days 
prior to first 
dosing
Day -1
Day 1
Day 2-5a
Day 1a-10
Day 11
Day 12 -14c
15 (± 2) 
days 
following 
last 
soticlestat 
dose
---------------------------Confinementb-------------------------------------
Contact
a Day 5 Period 1 will also be considered Day 1 Period 2.
b Participants will start the confinement on Day -1 Period 1 and will remain confined until Day 14 Period 2.
c Last dose of rifampin will be administered on Day 13.
Table 2.b
Dose Regimens for Study Drugs
Study Drug
Dose
Dose 
Regimen
Number of Days on Study Drug
Soticlestat (T4 
tablets)
300 mg (3 x 100 mg tablets)
Single dose, 
oral
Day 1 Period 1 and Day 11 
Period 2
Rifampin 
(capsules)
600 mg (2 x 300 mg capsules)
QD, oral
Days 1 through 13 Period 2
Participants will be screened within 4 weeks (28 days) prior to the first administration of 
soticlestat (Day -28 to first dosing, Day 1). Qualified participants will be admitted to the clinic 
on Day -1 of Period 1, at the time indicated by the clinical research unit (CRU), and will remain 
confined until after the last blood draw and/or study procedures on Day 14 of Period 2.
In Period 1, on Day 1, participants will receive a single dose of soticlestat (300 mg; 3 x 100 mg 
T4 tablets) under fasting conditions. Blood samples for the PK of soticlestat
will be collected at scheduled time points from predose through 96 hours postdose. There will be 
a washout period of 4 days between the soticlestat dose in Period 1 and the first rifampin dose in 
Period 2.
In Period 2, from Days 1 to 13, participants will receive a QD oral dose of rifampin (600 mg; 
2 x 300 mg capsules) under fasting conditions. On the morning of Day 11, participants will 
receive a single dose of soticlestat (300 mg; 3 x 100 mg T4 tablets) co-administered with the 
rifampin dose under fasting conditions. Blood samples for the PK of soticlestat 
will be collected at scheduled time points from soticlestat predose on Day 11 
through 72 hours postdose.
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory 
evaluations, physical examinations, 12-lead ECGs, vital signs, and C-SSRS.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Statistical Analysis Plan Final
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After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 15 (± 2) days after the last soticlestat administration by telephone or other methods 
per CRU standards to determine if any AE has occurred or concomitant medications have been 
taken since the last study visit. If clinically significant findings are observed upon discharge, 
participants may return to the CRU for re-evaluation per Investigator’s discretion.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
Not applicable.
3.2
Statistical Decision Rules
Not applicable.
3.3
Multiplicity Adjustment
Not applicable.
4.0
SAMPLE-SIZE DETERMINATION
This study is not powered for hypothesis testing and is not based on any specific no-effect 
boundaries. The sample size is based on an estimation approach and is considered sufficient to 
provide a reliable estimate of the DDI magnitude.
A total of 14 participants will be dosed to ensure that 12 evaluable subjects complete the study.
Property of Take
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Use Only and Subject to the Applicable Terms of Use
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5.0
ANALYSIS SETS
5.1
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 PK set.
5.2
Safety Set
All participants who received at least one dose of the study drug(s) will be included in the safety 
set.
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 or higher. All data recorded on the 
case report form (CRF) will be listed by participant. All tables, figures, and listings (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.
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
individual data. GMRs and 90% CIs around the ratio will be reported to 2 decimal places, and 
intra-participant CV% will be reported to 1 decimal place.
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 in 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.
A participant’s PK parameter data will be included in the listings but may be excluded from the 
descriptive summary and statistical model if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that participant’s maximum 
concentration value in that period.
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#
A participant did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical 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).
The details on PK parameter calculations and TFLs will be outlined in the Clinical 
Pharmacology Analysis Plan (CPAP) and TFL Shells document including specifics on the 
following:
#
PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables.
#
Concentration data presented by treatment, 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 WinNonlin® output file used to generate the TFLs.
#
Linear mixed-effects 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.
#
Individual concentration-time figures presented in Appendix 16.2.6 of the CSR.
Continuous demographic and safety data will be summarized descriptively by time point, as 
applicable. For the categorical variables, the count and percentages of each possible value will be 
tabulated, where applicable. The denominator for the percent calculation will be the number of 
non-missing observations in the safety set. Counts will be presented as integers. Percentages will 
be presented to one decimal. For continuous variables, the number of observations, mean, SD, 
minimum, median, and maximum values will be tabulated. The level of precision will be 
presented as follows: minimum/maximum in the same precision as in the database, mean/median 
in one more precision level than minimum/maximum, SD in one more precision level than 
mean/median, and n will be presented as an integer. 
Baseline, unless specified otherwise, is defined as the last observation prior to the first dose of 
the study.
6.1.1
Handling of Treatment Misallocations
Participants who are misallocated treatments will be analyzed per the treatment they actually
received rather than per the treatment they were supposed to receive.
Property of Takeda: For Non-Commercial Use Only and Subject to the
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6.2
Study Information
An overall study information table will be generated including the following items: date of first 
participant’s signed informed consent form (ICF), date of first dose of study drug, date of last 
dose of study drug, date of last participant’s last visit/contact, date of last participant’s last 
procedure for collection of data for primary endpoint, the version of Medical Dictionary for 
Regulatory Activities (MedDRA®), the version of World Health Organization (WHO) Dictionary, 
and SAS version used for creating the datasets. Study drug refers to soticlestat or rifampin.
6.3
Disposition of Participants
Disposition of participants (number of participants dosed, completed the study, discontinued 
from the study and/or study drug, and reason(s) for discontinuation(s)) will be summarized and 
listed by participant. 
6.4
Demographic and Other Baseline Characteristics
6.4.1
Demographics
Demographic and baseline characteristics will be summarized based on the safety set. Summary 
statistics (n, mean, SD, minimum, median, and maximum) will be generated for continuous 
variables (age, weight, height, and body mass index [BMI]) and the number and percentages of 
participants within each category will be presented for categorical variables (sex, race, and 
ethnicity). Height, weight, and BMI measured at screening will be used in the summaries. 
Demographic data will also be listed as recorded on the CRF, including the date of informed 
consent and protocol version. 
6.4.2
Medical History and Concurrent Medical Conditions
Medical history to be recorded will include determining whether the participant has any
significant conditions or diseases that resolved at or before signing the ICF. All medical history 
reported by the participant will be recorded regardless of how long ago it may have occurred. 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing the ICF. Each participant’s medical history and concurrent medical conditions 
will be listed.
Any medical condition starting or worsening after taking the first dose of study drug will be 
classified as a TEAE. All medical history will be coded using MedDRA® version specified in the 
data management plan (DMP). If available, the medical history and concurrent medical condition 
listings will include the coded term (preferred term [PT] and system organ class [SOC]), start 
date (if known) and end date (if known) or whether the condition was ongoing, and a description 
of the condition or event. No summaries or statistical analysis will be performed for these data. 
6.5
Medication History and Concomitant Medications 
Medication history to be obtained includes any medication stopped at or within 28 days prior to 
signing the ICF. Concomitant medication includes any medication other than study drug taken at 
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any time between ICF and the end of the study (including follow-up contact). All medication 
history and concomitant medications recorded during the study will be coded with the WHO 
Drug Dictionary version specified in the DMP and listed. If available, the listings will include 
the medication name, coded term, dosage, route of administration, start date and time (if known), 
end date and time (if known), or whether it continued after study completion, and indication for 
use. No summaries or statistical analysis will be performed for these data. 
6.6
Efficacy Analysis
Not applicable.
6.7
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and relationship(s) 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 
C-SSRS results will be reported as AEs, as applicable. All safety data will be listed by 
participant and assessment time points, including rechecks, unscheduled assessments, and early 
termination, 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.
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(s) (related or not 
related), relationship to COVID-19 or COVID-19 vaccine, frequency, and action relative to the 
study drug(s) as recorded in the CRF. Study procedure taken due to AE will also be listed. All 
AEs occurring during this study will be coded using the MedDRA® version specified in the DMP. 
Only TEAEs will be summarized.
A TEAE is defined as an AE that is starting or worsening at the time of or after the first dose of 
study drug administered in the study. Each TEAE will be attributed to the treatment prior to and 
the closest to the AE based on the AE onset date and time as described in Table 6.a.
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Table 6.a
AE Treatment Assignment Algorithm
Date and Time of AE With Respect to Date and Time of Dosing 
Treatment
Period 1 Day 1 soticlestat dosing ≤ Date and Time of AE < Period 2 Day 1 rifampin 
dosing
Soticlestat Alone
Period 2 Day 1 rifampin dosing ≤ Date and Time of AE < Period 2 Day 11 soticlestat 
dosing 
Rifampin Alone
Period 2 Day 11 soticlestat dosing ≤ Date and Time of AE
Soticlestat + Rifampin
If the onset time of an AE is missing and the onset date is the same as a treatment dosing date, 
then the AE will be counted under the treatment given on the same day. If onset time of an AE is 
missing and the onset date does not fall on a dosing date, then the AE will be considered 
treatment emergent for the most recent treatment administered. If the onset date of an AE is 
missing, then the AE will be considered treatment emergent and attributed to the first treatment 
received. If severity is missing, the AE will be counted under the highest severity, and if 
relationship is missing, the AE will be counted as related. Any medical condition starting or 
worsening after the ICF but before the first dose of study drug will be classified as pre-treatment 
event.
TEAEs will be tabulated by treatment (including overall), SOC, and PT. Summary tables will 
include number of participants reporting the TEAE and as percent of safety set by treatment and 
overall. The most commonly reported non-serious TEAEs (ie, those events reported by >5% of 
participants in any treatment (Soticlestat Alone, Rifampin Alone, or Soticlestat + Rifampin), 
excluding serious adverse events (SAEs)) will also be summarized. The denominators for 
percent calculations will be the number of participants dosed for each treatment. In addition, 
TEAEs will be summarized as number of TEAEs and percentage of TEAEs for each treatment 
and overall. 
Additional TEAE summary tables will be presented by severity and relationship to study drug(s). 
If a participant has multiple TEAEs with different severity levels within the same PT, the 
participant will be counted in the most severe category only. For relationship to study drug(s), if 
a participant has both related and unrelated TEAEs with the same term, the participant will be 
counted as having related TEAEs.
An overview summary of TEAEs table, including number of participants with TEAEs, SAEs, 
treatment-related TEAEs, treatment-related SAEs, TEAEs by severity, and AEs leading to 
discontinuation will be provided.
Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAEs. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the CSR.
6.7.2
Adverse Events of Special Interest (if applicable)
Not applicable.
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6.7.3
Clinical Laboratory Evaluation
Serum chemistry, hematology, coagulation, and urinalysis will be performed at screening, 
Period 1 Day -1, Period 1 Day 3, Period 2 Day 11 predose, and Period 2 Day 13 predose (or at 
early termination if applicable).
Urine drug screening will be carried out at screening and Period 1 Day -1 only. In addition, 
laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the Investigator. 
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for laboratory test results and change from baseline at each 
scheduled visit. Baseline is defined as the last assessment including rechecks taken prior to the 
first dose in the study in Period 1. Postdose unscheduled or recheck assessments will not be used 
in analysis. All clinical laboratory data will be listed by participant. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. For each laboratory test, a shift table will be 
developed comparing the frequency and percentage of the results at baseline (above normal (H), 
normal (N), or below normal (L)) with the postdose time points. For urinalysis tests, the 
categories are normal (N) and abnormal (A). Out-of-range values and corresponding recheck 
results will be listed. 
6.7.4
Vital Signs
Vital sign measurements of pulse rate, blood pressure, respiration rate, and temperature will be 
obtained at screening, Period 1 Day 1 predose, Period 1 Day 1 Hours 0.5 and 1.5, Period 1 Day 2, 
Period 2 Day 11 predose, Period 2 Day 11 Hours 0.5 and 1.5, Period 2 Day 12 predose, and 
Period 2 Day 14 (or at early termination if applicable). Additional unscheduled vital signs 
measurements may be taken at other times, if deemed necessary by the Investigator.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be presented for vital 
sign results and change from baseline at each study scheduled visit. Baseline is defined as the 
last assessment including rechecks taken prior to the first dose in the study in Period 1. Postdose 
unscheduled or recheck assessments will not be used in analysis. Vital sign data will be listed by 
participant.
6.7.5
12-Lead Electrocardiogram
Single 12-lead ECGs will be collected at screening, Period 1 Day 1 predose, Period 2 Day 11 
predose, and Period 2 Day 14 (or at early termination if applicable). Additional unscheduled 
ECGs may be taken at other times, if deemed necessary by the Investigator.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from study baseline by time point of collection. Baseline is defined as the last 
assessment including rechecks taken prior to the first dose in the study in Period 1. Post-baseline 
unscheduled or recheck assessments will not be used in analysis. ECG data will also be listed by 
participant.
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In addition, shifts from baseline to the worst post baseline 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, 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 three categories: < 30, 30 – 60, and > 60. A subject will 
be counted only once even if the subject has more than 1 episode of the worst value.
6.7.6
Physical Examination
A full physical examination will be performed at screening and an abbreviated physical 
examination will be performed on Period 1 Day -1. Symptom-driven physical examinations may 
be performed at other times at the discretion of the Investigator. Physical examination findings 
will be presented in the data listings by participant.
6.7.7
Columbia Suicide Severity Rating Scale (C-SSRS)
At screening, the C-SSRS Baseline/Screening version will be administered. On Period 1 Day -1 
and Period 2 Day 14 (or at early termination, if applicable), the ‘Since Last Visit’ version will be 
administered. C-SSRS findings will be presented in the data listings by participant.
6.7.8
Overdose
All cases of overdose will be presented in a data listing by participant. Any AEs associated with 
overdose will be documented.
6.7.9
Extent of Exposure and Compliance
The date, time, and dose of single oral dose of soticlestat and multiple oral doses of rifampin will 
be listed by participant.
6.8
Pharmacokinetic Analysis
Blood samples for assessment of plasma soticlestat, 
 concentrations will be 
collected as outlined in Table 6.b below: 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Statistical Analysis Plan Final
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Table 6.b
Collection of Blood Samples for Pharmacokinetic Analysis
Analytes
Matrix
Period
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, 
and 96** hours post soticlestat dose. 
2
Predose, and 0.133, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 14, 24, 36, 48, and 
72 hours post soticlestat dose.
*The actual dates and times of sample collection will be recorded on the source document in the CRF. 
**Hour 96 in Period 1 will be predose of Period 2.
Concentrations of plasma soticlestat, 
 at each sampling time will be listed 
and summarized descriptively by treatment using the following descriptive statistics: n, mean, 
SD, CV%, SEM, minimum, median, and maximum. Excluded concentrations will be presented 
and footnoted as such in the concentration table listings, and those values will be excluded from 
the descriptive statistics. 
Individual participant concentration-time curves will be plotted by treatment on linear and 
semi-log scales. Arithmetic mean profiles of the concentration-time data will be plotted by
treatment on linear (with and without SD) and semi-log scales. For arithmetic mean 
concentration-time plots, the nominal PK sampling times will be used. For individual participant 
concentration-time plots, the actual PK sampling times will be used. 
The PK parameters will be calculated from plasma soticlestat, 
concentration-time profiles using non-compartmental analysis methods where all calculations 
will be based on actual sampling times after soticlestat dosing. The PK parameters will be 
summarized by treatment using the following descriptive statistics: n, mean, SD, CV%, SEM, 
minimum, median, maximum, Geom Mean, and Geom CV%. Excluded parameters will be 
presented and footnoted as such in the PK parameter table listings, and those values will be 
excluded from descriptive statistics.
Linear Mixed-Effects Model
Ln-transformed soticlestat Cmax, AUClast, and AUC∞data will be analyzed using a linear 
mixed-effects model, separately. The model will include treatment (Soticlestat + Rifampin, 
Soticlestat Alone) as a fixed effect and participant as a random effect. The point estimates and 90% 
CIs for the GMRs of Cmax, AUClast, and AUC∞for Soticlestat + Rifampin versus Soticlestat Alone 
will be calculated using the exponentiation of the point estimates of the difference between 
treatment regimen and the corresponding 90% CIs from the analyses on the ln-transformed Cmax,
AUClast, and AUC∞.
Property of Takeda: Fo
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For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Page 20 of 21
Statistical Analysis Plan Final
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The model will be run separately using data for each analyte, as appropriate. The following 
SAS® code will be used to perform the analysis:
PROC MIXED DATA=xxx;
CLASS TREAT PARTICIPANT;
MODEL LN_PARAM = TREAT / DDFM=KR;
RANDOM PARTICIPANT;
ESTIMATE “Soticlestat + Rifampin vs Soticlestat Alone” TREAT -1 1 / CL ALPHA=0.1 E;
LSMEANS TREAT;
RUN;
Non-Parametric Analysis
Soticlestat tmax will be analyzed using nonparametric analysis for paired samples (the Wilcoxon 
Signed Rank Test statistic). The difference of medians (treatment effect) and the corresponding 
90% CI will be estimated using the Hodges-Lehmann method and Walsh Averages. tmax will not 
be ln-transformed. The comparison of interest is the same as for the linear mixed-effects analysis 
above.
.
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
Not applicable.
6.10
Interim Analyses
No interim analysis is planned for this study.
6.11
Preliminary Analyses
Preliminary PK analyses will be completed as described in the CPAP and Section 6.8 of the SAP, 
with the following changes: 1) QCed data will be used (not QAed); 2) nominal times (not actual 
sampling times) will be used for the calculation of PK parameters; and 3) tables and figures will 
be created using Phoenix® WinNonlin® Version 8.1 or higher.
6.12
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
Not applicable.
7.0
REFERENCES
Kupper, L. L. and Hafner, K.B., How appropriate are popular sample size formulas? Am Stat, 
1989. 43(2): 101-105.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Statistical Analysis Plan Final
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8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
The protocol indicates that C-SSRS results will be summarized by point of time of collection. 
Due to the nature of the questionnaire, these results will be listed but not summarized. C-SSRS 
responses of interest will be discussed in the CSR. 
9.0
APPENDIX 
9.1
Changes From the Previous Version of the SAP
Not applicable.
9.2
Analysis Software 
SAS® Version 9.4 or higher will be used for all statistical analyses provided in the clinical study 
report.
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