A Phase 1, Open-Label Study to Evaluate the Effect of Itraconazole and Mefenamic Acid on the Single-Dose Pharmacokinetic Profile of Soticlestat in Healthy Participants
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Takeda



 
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-Label Study to Evaluate the Effect of Itraconazole and Mefenamic Acid on 
the Single-Dose Pharmacokinetic Profile of Soticlestat in Healthy Participants
Study Identifier:
TAK-935-1007
Compound:
Soticlestat (TAK-935)
Sponsor:
Takeda Development Center Americas, Inc  
95 Hayden Avenue
Lexington, MA 02421
Date:
23 August 2021
Version/Amendment 
Number:
Final protocol
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 2 of 75
Protocol 
23 August 2021
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................13
3.0
SCHEDULE OF STUDY PROCEDURES .................................................................. .15
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................. . ............21
4.1.1
Soticlestat (TAK-935)..................................................................... ...............21
4.1.2
Itraconazole ............................................................................. ......................22
4.1.3
Mefenamic acid ................................................................... . ........................23
4.2
Rationale for the Proposed Study......................................... . ................................23
4.3
Benefit/Risk Profile ............................................................ ....................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................... ............................................25
5.1
Hypothesis............................................................ .. ...............................................25
5.2
Study Objectives................................................. ....................................................25
5.2.1
Study Primary Objectives ................... ............................................................25
5.2.2
Study Secondary Objective........... . ................................................................25
5.3
Endpoints................................... . .........................................................................25
5.3.1
Primary Endpoints ...........................................................................................25
5.3.2
Secondary Endpoints .. ....................................................................................26
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design .. ... ....................................................................................................26
6.2
Dose Escalation .......................................................................................................28
6.3
Stopping Rules.........................................................................................................28
6.4
Rationale for Study Design, Dose, and Endpoints ....................................................28
6.4.1
Rationale of Study Design ...............................................................................28
6.4.2
Rationale for Dose...........................................................................................28
6.4.3
Rationale for Endpoints ...................................................................................29
6.4.4
Future Biomedical Research ............................................................................29
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures ............29
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.6
Study Beginning and End/Completion .....................................................................29
6.6.1
Definition of Beginning of the Study ...............................................................29
6.6.2
Definition of End of the Study.........................................................................30
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 3 of 75
Protocol 
23 August 2021
6.6.3
Definition of Study Completion.......................................................................30
6.6.4
Definition of Study Discontinuation.................................................................30
6.6.5
Criteria for Premature Termination or Suspension of the Study........................30
6.6.6
Criteria for Premature Termination or Suspension of a Site..............................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .. .31
7.1
Inclusion Criteria .............................................................................................. ......31
7.2
Exclusion Criteria ................................................................................... . ............31
7.3
Excluded Medications, Supplements, Dietary Products.......................... .................33
7.4
Diet, Fluid, Activity.......................................................................... ......................34
7.4.1
Diet and Fluid.................................................................. ...............................34
7.4.2
Activity ...........................................................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Participant......................................35
7.6
Procedures for Discontinuation or Withdrawal of a Participant ................................36
7.7
Participant Replacement ..................................... .. .................................................37
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................37
8.1
Clinical Study Drug ................................. ..............................................................37
8.1.1
Clinical Study Drug Labeling ........ .................................................................38
8.1.2
Clinical Study Drug Inventory and Storage......................................................38
8.1.3
Clinical Study Drug Blinding...........................................................................38
8.1.4
Randomization Code Creation and Storage......................................................38
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................38
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................38
9.0
STUDY PROCEDURES...............................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent Procedure............................................................................39
9.1.2
Inclusion and Exclusion...................................................................................39
9.1.3
Medical History/Demography..........................................................................39
9.1.4
Concomitant Medications ................................................................................39
9.2
Clinical Procedures and Assessments.......................................................................39
9.2.1
Physical Exam.................................................................................................40
9.2.2
Height and Weight...........................................................................................40
9.2.3
BMI.................................................................................................................40
9.2.4
Vital Signs.......................................................................................................40
9.2.5
12-Lead ECG...................................................................................................40
9.2.6
Study Drug Administration..............................................................................41
9.2.7
C-SSRS ...........................................................................................................41
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 4 of 75
Protocol 
23 August 2021
9.2.8
AE Monitoring ................................................................................................42
9.2.9
Laboratory Procedures and Assessments..........................................................42
9.3
Pharmacokinetic Samples ........................................................................................44
9.3.1
Pharmacokinetic Measurements.......................................................................44
9.3.2
Biomarker Measurements ........................................................................... .. .45
9.3.3
PGx Measurements................................................................................... ......46
9.3.4
Confinement................................................................................... . ............46
10.0
ADVERSE EVENTS .................................................................................. .................46
10.1
Definitions and Elements of AEs ...................................................... ......................46
10.1.1
SAEs ............................................................................... ...............................48
10.1.2
Special Interest AEs.........................................................................................49
10.2
AE Procedures............................................................. .... ......................................49
10.2.1
Assigning Severity/Intensity of AEs ............... ................................................49
10.2.2
Assigning Causality of AEs ........................ .. .................................................50
10.2.3
Start Date.............................................. . ........................................................50
10.2.4
End Date.......................................... ..............................................................51
10.2.5
Pattern of Adverse Event (Frequency)..............................................................51
10.2.6
Action Taken With Study Treatment................................................................51
10.2.7
Outcome........................... . ............................................................................51
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs........................ . .....................................................................................52
10.2.9
Safety Reporting to Investigators, Institutional Review Board (IRB)s or 
Independent Ethics Committee (IEC)s, and Regulatory Authorities .................54
11.0
STATISTICAL METHODS..........................................................................................54
11.1
Statistical and Analytical Plans ................................................................................54
11.1.1
Analysis Sets ...................................................................................................54
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................55
11.1.3
PK Analysis.....................................................................................................55
11.1.4
PD Analysis.....................................................................................................55
11.1.5
Safety Analysis................................................................................................55
11.2
Interim Analysis and Criteria for Early Termination ................................................57
11.3
Determination of Sample Size..................................................................................57
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................57
12.1
Study-Site Monitoring Visits ...................................................................................57
12.2
Protocol Deviations..................................................................................................58
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................58
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 5 of 75
Protocol 
23 August 2021
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................58
13.1
IRB and/or IEC Approval ........................................................................................58
13.2
Participant Information, Informed Consent, and Participant Authorization...............59
13.3
Participant Confidentiality .......................................................................................60
13.4
Publication, Disclosure, and Clinical Study Registration Policy .......................... .. .61
13.4.1
Publication and Disclosure........................................................................ ......61
13.4.2
Clinical Study Registration ............................................................. . ............61
13.4.3
Clinical Study Results Disclosure .................................................. .................62
13.5
Insurance and Compensation for Injury............................................. ......................62
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION......... ...............................62
14.1
Administrative Information......................................................................................62
14.1.1
Study Contact Information................................... .... ......................................62
14.1.2
INVESTIGATOR AGREEMENT .................. ................................................63
14.1.3
Study-Related Responsibilities.................... .. .................................................64
14.1.4
List of Abbreviations ............................ . ........................................................64
15.0
DATA HANDLING AND RECORD KEEPING...........................................................66
15.1
CRFs (Electronic and Paper).................. .................................................................66
15.2
Record Retention .....................................................................................................66
16.0
REFERENCES............................... . ............................................................................67
17.0
APPENDICES....................... . . . .................................................................................68
LIST OF IN-TEXT TABLES
Table 2.a
Study Design for Part 1......................................................................................13
Table 2.b
Dose Regimens for Study Drugs in Part 1 ..........................................................13
Table 2.c
Study Design for Part 2......................................................................................14
Table 2.d
Dose Regimens for Study Drugs in Part 2 ..........................................................14
Table 3.a
Part 1: DDI with Itraconazole.............................................................................15
Table 3.b
Part 2: DDI with Mefenamic Acid......................................................................18
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................34
Table 9.a
Primary Specimen Collections ...........................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................49
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Soticlestat (TAK-935)
Study No. TAK-935-1007
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Protocol 
23 August 2021
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................68
Appendix B
Elements of the Participant Informed Consent....................................................70
Appendix C
Investigator Consent to the Use of Personal Information .................................. .73
Appendix D
Pregnancy and Contraception.............................................................................74
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Study No. TAK-935-1007
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Protocol 
23 August 2021
Duration of Treatments:
Part 1: DDI with Itraconazole
Soticlestat: Single-dose on Day 1 Period 1 and 
single-dose on Day 5 Period 2
Itraconazole: QD on Days 1 to 11 Period 2
Part 2: DDI with Mefenamic acid
Soticlestat: Single-dose on Day 1 Period 1 and 
single-dose on Day 2 Period 2
Mefenamic acid: Q6H on Days 1 to 7 Period 2
Planned Study Duration:
Part 1: DDI with Itraconazole
Approximately 52 days including screening period and 
follow-up.
Part 2: DDI with Mefenamic acid
Approximately 48 days including screening period 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), 19- 55 years of age, inclusive, at 
screening.
2.
Male participants agrees to comply with any applicable contraceptive requirements of the protocol as detailed in 
Appendix D.
3.
Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. 
4.
Continuous non-smoker who has not used nicotine-containing products for at least 90 days prior to the first 
dosing.
5.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs or ECGs, as deemed by the Investigator or designee.

Supine blood pressure is ≥90/40 mmHg and ≤140/90 mmHg at screening;

Supine pulse rate is ≥45 bpm and ≤100 bpm at screening;

QTcF is ≤450 msec (males) or ≤470 msec (females) and ECG findings considered normal or not clinically 
significant by the Investigator or designee at screening;

Estimated creatinine clearance ≥80 mL/min at screening;

Liver function tests including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤1.5 X 
the upper limit of normal (ULN) at screening and check-in.
6.
Able to swallow multiple tablets.
7.
Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the 
protocol.
Criteria for Exclusion:
Participants must not be enrolled in the study if they meet any of the following criteria 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 (GI) tract, gastric bypass surgery, or hepatic disorder or other 
clinical condition which, in the opinion of the Investigator or designee, may affect the absorption, distribution, 
metabolism, or elimination of study drugs.
4.
History or presence of any of the following, deemed clinically significant by the investigator:

epilepsy, seizure, or convulsion, tremor or related symptoms; 

arrhythmias or other cardiovascular disorder;
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Protocol 
23 August 2021

GI disorder (eg peptic ulcer disease, gastroesophageal reflux disease, impaction, chronic constipation, 
inflammatory bowel disease, ischemic colitis, vascular intestinal atherosclerosis, previous bowel resection, 
bowel obstruction, bariatric surgery, cholecystitis, intestinal ulceration or inflammation);

GI bleeding or perforation;

recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding);

known bleeding or coagulation disorders; 

history of thromboembolic events;

hyperkalemia.
5.
History or presence of cataracts or other clinically significant vision disturbances. 
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 participants 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.
Part 2 only: Known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with 
other CYP2C9 substrates. 
10. Any positive responses on the C-SSRS that in the clinical judgement of the Investigator has a risk of suicide or has 
made a suicide attempt in the previous 12 months prior to the first dosing.
11. Female participants of childbearing potential.
12. Female participants with a positive pregnancy test at screening or check-in or who is lactating.
13. Positive urine drug or alcohol results at screening or check-in.
14. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or 
hepatitis C virus (HCV).
15. 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. 

Any drugs known to be significant inducers of CYP3A, CYP2C9 (Part 2), CYP2C19, UGT1A9 or UGT2B4 
enzymes and/or P gp, including St. John’s Wort, within 28 days prior to the first dosing. Appropriate sources 
(eg, Flockhart TableTM) will be consulted to confirm lack of PK/pharmacodynamics interaction with study 
drug.
16. 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).
17. 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.
18. 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.
19. Donation of blood or significant blood loss within 56 days prior to the first dosing.
20 Plasma donation within 7 days prior to the first dosing.
21. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-day window 
or 5 half-lives will be derived from the date of the last blood collection or dosing, whichever is later, in the 
previous study to Day 1 of Period 1 of the current study.
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Study No. TAK-935-1007
Page 11 of 75
Protocol 
23 August 2021
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 itraconazole (Part 1) or mefenamic acid (Part 2):
!
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)
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.
Statistical Considerations:
Pharmacokinetics:
For each part, 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 itraconazole/mefenamic acid) as a 
fixed effect and participant as a random effect. The point estimates and the 90% confidence intervals (CIs) for the 
geometric mean ratios (GMRs) for soticlestat with versus without itraconazole/mefenamic acid will be calculated.
The following treatment contrast will be evaluated separately: itraconazole + soticlestat relative to soticlestat alone 
and mefenamic acid + soticlestat relative to soticlestat alone. 
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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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 12 of 75
Protocol 
23 August 2021
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 13 of 75
Protocol 
23 August 2021
2.0
STUDY SCHEMATIC
Table 2.a
Study Design for Part 1
S
Period 1
Period 2
FU
C-I and 
Predose 
Assessments
Soticlestat 
Dosing, PK 
Sampling 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Itraconazole 
Dosing and 
Study 
Assessments
Co-administration 
(Itraconazole and 
Soticlestat), PK 
Sampling and 
Study 
Assessments
Itraconazole 
Dosing, PK 
Sampling 
and Study 
Assessments
Study Exit c
(PK 
Samping and 
Study 
Assessments)
Within 
28 days 
prior to 
first 
dosing
Day -1
Day 1
Day 2 – 5 a
Day 1 a - 4
Day 5
Day 6 - 11
Day 12
15 (± 2) 
days 
following 
last 
soticlestat 
dose
---------------------------Confinement b-------------------------------------
Contact
a Day 1 of Period 2 will also be considered Day 5 of Period 1.
b Participants will start the confinement on Day -1 of Period 1 and remain confined until Day 12 of Period 2.
c Study Exit is defined as the end of last treatment period.
Abbreviations: C-I = Check-in, FU = Follow-up, PK = Pharmacokinetic, S = Screening.
Table 2.b
Dose Regimens for Study Drugs in Part 1
Study Drug
Dose
Dose Regimen
Number of Days on Study Drug
Soticlestat 
300 mg 
Single dose, oral
Day 1 Period 1 and Day 5 Period 2
Itraconazole (oral solution)
200 mg (10 mL of 20 mg/mL oral 
solution)
QD, oral
Days 1 through 11 Period 2
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 14 of 75
Protocol 
23 August 2021
Table 2.c
Study Design for Part 2
S
Period 1
Period 2
FU
C-I and 
Predose 
Assessments
Soticlestat 
Dosing, PK 
Sampling, 
and Study 
Assessments
PK 
Sampling 
and Study 
Assessments
Mefenamic 
Acid Dosing 
and Study 
Assessments
Co-administration 
(Mefenamic Acid 
and Soticlestat),
PK Sampling, and 
Study 
Assessments
Mefenamic 
Acid 
Dosing, PK 
Sampling, 
and Study 
Assessments
Study Exit c
(PK 
Sampling 
and Study 
Assessments)
Within 
28 days 
prior to 
first 
dosng
Day -1
Day 1
Day 2 – 5 a
Day 1 a
Day 2
Day 3 - 7
Day 8
15 (± 2) 
days
following 
last 
soticlestat 
dose
---------------------------Confinement b-------------------------------------
Contact
a Day 1 of Period 2 will also be considered Day 5 of Period 1 
b Participants will start the confinement on Day -1 of Period 1 and remain confined until Day 8 of Period 2.
c Study Exit is defined as the end of last treatment period.
Abbreviations: C-I = Check-in, FU = Follow-up, PK = Pharmacokinetic, S = Screening.
Table 2.d
Dose Regimens for Study Drugs in Part 2
Study Drug
Dose
Dose Regimen
Number of Days on Study Drug
Soticlestat 
300 mg 
Single dose, oral
Day 1 Period 1 and Day 2 Period 2
Mefenamic acid 
(capsules)
500 mg (2 x 250 mg capsules)
Once, oral
Initial dose - Morning of Day 1 of Period 2
250 mg (1 x 250 mg capsule)
Q6H, oral
All subsequent doses following the morning dose 
on Day 1 of Period 2 – Days 1 through 7 of 
Period 2
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 17 of 75
Protocol 
23 August 2021
CONFIDENTIAL
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 
the serum chemistry sample is taken.
i
To be performed within 24 hours prior to dosing of soticlestat.
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 following 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 dose to determine if any AEs have occurred and/or any concomitant medications were taken since the last study visit.
o
On Days 1 to 4 and Days 6 to 11, participants will receive 200 mg itraconazole QD as an oral solution on an empty stomach (no food from 1 hour before until 2 hours after 
dosing). On Day 5 participants will receive 200 mg itraconazole QD as an oral solution on an empty stomach (no food from at least 10 hours before until at least 4 hours after 
dosing).
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, C-SSRS = Columbia-Suicide Severity Rating Scale, Chem = Chemistry, 
Coag = Coagulation, ConMeds = Concomitant medication, COVID-19 = coronavirus 2019, CRU = Clinical research unit, ECG = Electrocardiogram, ET = Early Termination, 
FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, PK = Pharmacokinetics, PR = Pulse rate, Preg = Pregnancy, 
RR = Respiratory rate, S = Screening, T = Temperature, UA = Urinalysis.
Pr
 
 
 
 
 
 
 
 
 
 
 
 
 
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 20 of 75
Protocol 
23 August 2021
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
After an overnight fast of at least 10 hours (Day 1 of Period 1) or 6 hours (Day 2 of Period 2), soticlestat will be administered. 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 AEs have occurred and/or any concomitant medications were taken since the last study visit.
o
Participants will receive mefenamic acid QID on Days 1 to 7. The initial dose of 500 mg will be administered under fed conditions in the morning of Day 1 and all subsequent 
doses will be 250 mg administered Q6H under fed conditions (except for the morning dose on Day 2; no food from 6 hours before until 4 hours after dosing) through Day 7. 
Participants should not lie down for at least 10 minutes after taking mefenamic acid.
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, C-SSRS = Columbia-Suicide Severity Rating Scale, Chem = Chemistry, 
Coag = Coagulation, ConMeds = Concomitant medication, COVID-19 = coronavirus 2019, CRU = Clinical research unit, ECG = Electrocardiogram, ET = Early Termination, 
FSH = Follicle-stimulating hormone, FU = Follow-up, Hem = Hematology, HIV = Human immunodeficiency virus, PK = Pharmacokinetics, PR = Pulse rate, Preg = Pregnancy, 
Q6H = every 6 hours, QID = four times a day, RR = Respiratory rate, S = Screening, T = Temperature, UA = Urinalysis.
Pr
 
 
 
 
 
 
 
 
 
 
 
 
 
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 21 of 75
Protocol 
23 August 2021
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 (SOC) 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 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.
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 23 of 75
Protocol 
23 August 2021
4.4 hours (with food) postdose. Itraconazole is highly protein bound (> 99%) and distributes 
extensively into human tissue [3]. 
Itraconazole is extensively metabolized, predominantly by the CYP3A4 enzymes, and is known to 
undergo enterohepatic recirculation. Hydroxyitraconazole is the major metabolite and shows 
antifungal activity equal to that of the parent [3]. Itraconazole is a competitive CYP3A4 inhibitor, 
and following multiple dosing, ~40% of overall CYP3A inhibition is attributed to 
hydroxyitraconazole [4]. 
The terminal t½ of itraconazole typically ranges from 16 - 28 hours after a single dose and 
increases to 34 - 42 hours with multiple dosing, due to non-linear PK. Itraconazole is mainly 
excreted as inactive metabolites in the urine (35%) and feces (54%) [3]. 
Overall, itraconazole is associated with infrequent mild adverse reactions. The exceptions are rare 
cases of hepatotoxicity, hearing loss (transient or permanent, but the hearing loss usually resolves 
upon treatment cessation), and QT prolongation [3]. 
Refer to the full prescribing information for more detailed background on itraconazole [3].
4.1.3
Mefenamic acid
Mefenamic acid is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic 
properties. It is rapidly absorbed after oral administration with peak plasma levels attained within 2 
to 4 hours and has a short half-life of approximately 2 hours. Following multiple doses, plasma 
levels have shown to be proportional to dose with no evidence of drug accumulation. In 
participants receiving 1 gram dose Q6H, steady-state concentrations were reached on the second 
day of dosing, consistent with the short half-life [5].
Mefenamic acid undergoes glucuronidation and is also metabolized by CYP2C9 to 
3-hydroxymethyl mefenamic acid that may undergo further oxidation to a 3-carboxymefenamic 
acid metabolite. The activity of these metabolites has not been studied [5].
Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as 
glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3-carboxymefenamic 
acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form 
of unconjugated 3-carboxymefenamic acid [5].
Refer to the full prescribing information for more detailed background on mefenamic acid [5].
4.2
Rationale for the Proposed Study
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 24 of 75
Protocol 
23 August 2021
Itraconazole is selected for Part 1 as it is a well characterized, competitive, strong inhibitor of 
CYP3A4 and a potent P-gp inhibitor. Moreover it is considered a strong index inhibitor of CYP3A 
as per the Food and Drug Administration (FDA): Drug Development and Drug Interactions: Table 
of Substrates, Inhibitors, and Inducers [6]. It is also among choices of inhibitors of P-gp; as 
soticlestat is a weak substrate of P-gp, co-administration of itraconazole will also inform strategies 
for management of potential DDI with P-gp inhibitors. 
Mefenamic acid is proposed for Part 2 as a UGT1A9 inhibitor. In a clinical DDI study with 
ertugliflozin, a medication used to treat type 2 diabetes with metabolism and elimination 
properties similar to soticlestat, mefenamic acid was used as a UGT1A9 inhibitor. Ertugliflozinis 
mainly metabolized by glucuronidation (88%), predominantly by UGT1A9 with minor 
contributions from UGT2B4/2B7, whereas oxidative metabolism (10%) and renal elimination of 
unchanged drug (2%) are minor. Co-administration of ertugliflozin with mefenamic acid led to a 
51% increase in ertugliflozin exposure (ratio of the area under the plasma concentration–time 
curves (AUCR) = 1.51) [8]. Similar results were observed when mefenamic acid was used as a 
UGT1A9 inhibitor with dapagliflozin, another medication used to treat type 2 diabetes and mainly 
metabolized by UGT1A9. [7].
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 was found to be safe and well tolerated.
The doses of itraconazole and mefenamic acid administered in this study are not anticipated to 
induce any potential risk or benefit to participants participating in this study, as they are being 
administered according to the dosing recommendations presented in the labelling.
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 25 of 75
Protocol 
23 August 2021
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 examination) are adequate to protect the participant’s safety and should detect all TEAEs. 
In addition, in Part 2, participants who are known or suspected to be poor CYP2C9 metabolizers 
based on previous history/experience with other CYP2C9 substrates will be excluded as they may 
have abnormally high plasma levels due to reduced metabolic clearance. 
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. 
5.2
Study Objectives
5.2.1
Study Primary Objectives
!
Part 1: To assess the effect of multiple-dose administration of itraconazole, a strong CYP3A 
inhibitor, on the single-dose PK of soticlestat.
!
Part 2: To assess the effect of multiple-dose administration of mefenamic acid, a strong 
UGT1A9 inhibitor, on the single-dose PK of soticlestat.
5.2.2
Study Secondary Objective
!
Part 1 and Part 2: To evaluate the safety and tolerability of soticlestat following a single oral 
dose in healthy adult participants with/without strong CYP3A and UGT1A9 inhibitors.
5.3
Endpoints
5.3.1
Primary Endpoints
The following PK parameters will be analyzed for soticlestat, when administered alone and when 
co-administered with itraconazole (Part 1) or mefenamic acid (Part 2):
!
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)
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 26 of 75
Protocol 
23 August 2021
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.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a 2 part, open-label, DDI study to evaluate the effect of a strong CYP3A inhibitor, 
itraconazole (Part 1), and a strong UGT1A9 inhibitor, mefenamic acid (Part 2), on the single-dose 
PK of soticlestat (TAK-935) in healthy adult participants. 
Each part will be conducted independently as a 2-period, fixed-sequence design. Study schematics 
of the study design and dose regimen are shown in Table 2.a, Table 2.b, Table 2.c and Table 2.d. A 
schedule of assessments is shown in Schedule of Study Procedures (Section 3.0).
The two study parts may be conducted concurrently. Participants can only participate in one study 
part. 
Part 1: DDI with itraconazole
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first 
dosing on Day 1 of Period 1). Upon completion of screening, qualified participants will be 
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 27 of 75
Protocol 
23 August 2021
admitted to the study site on Day -1 of Period 1 and will remain confined until completion of study 
procedures on Day 12 of Period 2. 
In Period 1, on Day 1, participants will receive a single oral dose of 300 mg soticlestat 
. Blood samples for the PK of soticlestat 
 will be collected at 
scheduled time points from predose through 96 hours postdose. There will be a washout period of 
exactly 4 days between soticlestat dose in Period 1 and the first itraconazole dose in Period 2.
In Period 2, from Days 1 to 11, participants will receive a QD oral dose of 200 mg itraconazole. On 
the morning of Day 5, participants will receive a single oral dose of 300 mg soticlestat 
 co-administered with the single oral dose of 200 mg itraconazole. Blood samples for 
the PK of soticlestat 
will be collected at scheduled time points from predose on 
Day 5 through 168 h
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory
evaluations, physical examinations, C-SSRS, 12-lead ECGs, and vital signs.
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 15 (±2) days after the last soticlestat administration by telephone or other methods per 
CRU standards to determine if any AEs have occurred and/or any concomitant medications were 
taken since the last study visit. If clinically significant findings are observed upon discharge, 
participants may return to the CRU for re-evaluation per Investigator’s discretion.
Part 2: DDI with mefenamic acid
Participants will be screened within 4 weeks (28 days) prior to the first dosing (Day -28 to first 
dosing on Day 1 of Period 1). Upon completion of screening, qualified participants will be 
admitted to the study site on Day -1 of Period 1 and will remain confined until completion of study 
procedures on Day 8 of Period 2. 
In Period 1, on Day 1, participants will receive a single oral dose of 300 mg soticlestat 
. Blood samples for the PK of soticlestat 
 will be collected at 
scheduled time points from predose through 96 hours postdose. There will be a washout period of 
exactly 4 days between soticlestat dose in Period 1 and the first mefenamic acid dose in Period 2. 
In Period 2, participants will receive mefenamic acid QID (Q6H) from Day 1 to 7. The initial oral 
dose on the morning of Day 1 will be 500 mg and all subsequent oral doses will be 250 mg. On the 
morning of Day 2, participants will receive a single oral dose of 300 mg soticlestat 
 co-administered with the morning dose of 250 mg mefenamic acid. Blood samples for the 
PK of soticlestat 
will be collected at scheduled time points from predose on 
Day 2 through 144 hours postdose. 
Safety and tolerability will be assessed throughout the study by TEAEs, clinical laboratory
evaluations, physical examinations, C-SSRS 12-lead ECGs, and vital signs. 
After discharge, the CRU will contact all participants (including participants who terminate the 
study early) 15 (±2) days after the last soticlestat administration by telephone or other methods per 
CRU standards to determine if any AEs have occurred and/or any concomitant medications were 
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 28 of 75
Protocol 
23 August 2021
taken since the last study visit. If clinically significant findings are observed upon discharge, 
participants may return to the CRU for re-evaluation per Investigator’s discretion.
6.2
Dose Escalation
Not applicable. 
6.3
Stopping Rules
Not applicable.
6.4
Rationale for Study Design, Dose, and Endpoints
6.4.1
Rationale of Study Design 
The study design of each part is an open-label, 2-period, fixed sequence to evaluate both the effect
of CYP3A4 (Part 1) and UGT1A9 (Part 2) inhibitors. The fixed-sequence design selected to allow 
for simple management of washout period, improves feasibility, and prevents any carryover effect 
of the study treatment. It also has the advantage of reducing the residual variability since 
participants act as their own control. There will be a washout period of exactly 4 days between the 
soticlestat dosing alone (Day 1 of Period 1) and the first itraconazole dose or mefenamic acid dose 
(Day 1 of Period 2) and it is considered sufficient to prevent carryover effect of the treatment.
6.4.2
Rationale for Dose 
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 29 of 75
Protocol 
23 August 2021
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, 12-lead ECGs, clinical laboratory evaluations, C-SSRS, and physical 
examinations.
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
soticlestat 
, and is to be collected as close to the scheduled times defined in this 
protocol as possible.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drugs to any participant may not be modified. 
Unscheduled procedures might be performed for safety reasons. If necessary, a participant may be 
discontinued for the reasons described in Section 7.5 and Section 7.6.
6.6
Study Beginning and End/Completion
6.6.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first participant.
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Soticlestat (TAK-935)
Study No. TAK-935-1007
Page 30 of 75
Protocol 
23 August 2021
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.
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’s welfare.
The Sponsor reserves the right to suspend or terminate the study at any time for any reason.
6.6.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for participants participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises participant safety.
6.6.6
Criteria for Premature Termination or Suspension of a Site
6.6.6.1
Criteria for Premature Termination or Suspension
A study site may be terminated prematurely or suspended if the site (including the Investigator) is 
found in significant violation of GCP, the study protocol, or contractual agreement; if the site 
(including the Investigator) is unable to ensure adequate performance of the study; or as otherwise 
permitted by the contractual agreement.
6.6.6.2
Procedures for Premature Termination or Suspension
In the event that the sponsor, an Institutional Review Board (IRB)/Independent Ethics Committee
(IEC), or a regulatory authority elects to terminate or suspend the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational site(s) 
during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
7.1
Inclusion Criteria 
Participants must fulfill the following inclusion criteria before the first dose to be eligible for 
participation in the study:
1. Healthy, adult, male or female of non-childbearing potential (Appendix D), 19- 55 years of 
age, inclusive, at screening.
2. Male participants or female of non-childbearing potential 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 Investigator or designee.

Supine blood pressure is ≥90/40 mmHg and ≤140/90 mmHg at screening;

Supine pulse rate is ≥45 bpm and ≤100 bpm at screening;

QTcF is ≤450 msec (males) or ≤470 msec (females) and ECG findings considered normal 
or not clinically significant by the Investigator or designee at screening;

Estimated creatinine clearance ≥80 mL/min at screening.

Liver function tests including ALT or 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, GI tract, gastric bypass surgery, or hepatic disorder or other 
clinical condition which, in the opinion of the Investigator or designee, may affect the 
absorption, distribution, metabolism, or elimination of study drugs. 
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4. History or presence of any of the following, deemed clinically significant by the investigator:

epilepsy, seizure, or convulsion, tremor or related symptoms; 

arrhythmias or other cardiovascular disorder;

GI disorder (eg peptic ulcer disease, gastroesophageal reflux disease, impaction, chronic 
constipation, inflammatory bowel disease, ischemic colitis, vascular intestinal 
atherosclerosis, previous bowel resection, bowel obstruction, bariatric surgery, 
cholecystitis, intestinal ulceration or inflammation);

GI bleeding or perforation;

recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or 
bleeding);

known bleeding or coagulation disorders; 

history of thromboembolic events;

hyperkalemia.
5. History or presence of cataracts or other clinically significant vision disturbances. 
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 participants 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. Part 2 only: Known or suspected to be poor CYP2C9 metabolizers based on previous 
history/experience with other CYP2C9 substrates. 
10. Any positive responses on the C-SSRS that in the clinical judgement of the Investigator has a 
risk of suicide or has made a suicide attempt in the previous 12 months prior to the first dosing.
11. Female participants of childbearing potential.
12. Female participants with a positive pregnancy test at screening or check-in or who is lactating.
13. Positive urine drug or alcohol results at screening or check-in.
14. Positive results at screening for HIV, HBsAg or HCV.
15. 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. 
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
Any drugs known to be significant inducers of CYP3A, CYP2C9 (Part 2), CYP2C19, 
UGT1A9 or UGT2B4 enzymes and/or P gp, including St. John’s Wort, within 28 days 
prior to the first dosing. Appropriate sources (eg, Flockhart TableTM) will be consulted to 
confirm lack of PK/pharmacodynamics interaction with study drug.
16. 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).
17. 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.
18. 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.
19. Donation of blood or significant blood loss within 56 days prior to the first dosing.
20. Plasma donation within 7 days prior to the first dosing.
21. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. 
The 30-day window or 5 half-lives will be derived from the date of the last blood collection or 
dosing, whichever is later, in the previous study to Day 1 of Period 1 of the current study.
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2 and 
throughout the study, including the follow-up period. After the first dose, ibuprofen (up to 1.2 g 
per 24 hour period) may be administered at the discretion of the Investigator or designee. Thyroid 
hormone replacement medication may be permitted if the participant has been on the same stable 
dose for the immediate 3 months prior to the first dosing.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the participant may continue participation in the study.
All medications taken by participants during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing (Days 
-28 to predose [Day 1])
After First Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from first dosing until 
the end of PK collection.
Xanthine and/or caffeine
Prohibited from 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.
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.
(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 morning dose, but will be allowed ad libitum at all other times in Period 2 of Part 2, when 
dosing occurs at the CRU. Other fluids may be given as part of meals and snacks but will be 
restricted at all other times throughout the confinement period.
Part 1: DDI with itraconazole: On Day 1 of Period 1 and on Day 5 of Period 2, participants will 
fast overnight for at least 10 hours prior to dosing and will continue to fast for at least 4 hours 
postdose. On all other dosing days in Period 2, participants will fast at least 1 hour before until at 
least 2 hours postdose.
Part 2: DDI with mefenamic acid: On Day 1 of Period 1 participants will fast overnight for at least 
10 hours prior to soticlestat dosing and will continue to fast for at least 4 hours postdose. On the 
first morning dose of Day 2 of Period 2, participants will fast overnight for at least 6 hours prior to 
mefenamic and soticlestat dosing and will continue to fast for at least 4 hours postdose. For all 
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other mefenamic acid dosing in Period 2, participants will consume a standard meal or snack 
immediately prior to dosing, and the participant will fast for at least 2 hours postdose. The last 
mefenamic acid dose on Day 1 of Period 2 (the 4th dose) should only be taken with a light snack. 
Participants should not lie down for at least 10 minutes after taking mefenamic acid.
When confined, standard meals and snacks will be provided at appropriate times, except when
they are required to fast. When confined in the CRU, participants will be required to fast from all 
food and drink except water between meals and snacks.
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each period.
7.4.2
Activity
All participants will remain seated for the first 4 hours following the morning dose of soticlestat, 
except when they are supine or semi reclined for study procedures. Participants will then resume 
normal activity.
However, should AEs occur at any time, participants may be placed in an appropriate position or 
will be permitted to lie down on their right side. During the first 4 hours post soticlestat dose, 
participants may be allowed to rise for brief periods under supervision (eg, in order to use the toilet 
facilities).
Participants will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of the 
study. 
7.5
Criteria for Discontinuation or Withdrawal of a Participant
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form (CRF) using the following categories.
1. Pretreatment event (PTE) or AE: The participant has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
participant’s health or the participant is unwilling to continue because of the PTE or AE.
Liver Function Test (LFT) Abnormalities
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 9.2.8), if the following circumstances occur at any time during study drug 
treatment:

ALT or AST >8x ULN, or

ALT or AST >5x ULN and persists for more than 2 weeks, or

ALT or AST >3x ULN in conjunction with elevated total bilirubin >2 x ULN or 
international normalized ratio (INR) >1.5, or
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
ALT or AST >3x ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
QTcF interval: 
Study drug should be discontinued immediately with appropriate clinical follow-up if a QTcF 
interval >500 msec or if there is an increase of QTcF >60 msec above screening/baseline 
detected by ECG and confirmed with a repeat ECG. Appropriate clinical follow-up includes a 
repeat ECG.
2. Significant protocol deviation: The discovery post-enrollment that the participants failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the participant’s health.
3. Lost to follow-up: Attempts to contact the participants were unsuccessful. Attempts to contact 
the participant must be documented in the participant’s source documents.
4. Voluntary withdrawal: The participants (or participant’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be recorded 
in the case report form (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 
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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 that 12 PK-evaluable participants 
complete each part of the study.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Investigational Medicinal Product(s) (Parts 1 and 2)
Product Name: 
Soticlestat (TAK-935)
Strength: 
Dose: 
300 mg 
Dosage Form/Formulation: 
Dosing regimen: 
Single dose 
Route of Administration: 
Oral
Interacting Drug (Part 1) 
Product Name: 
Itraconazole 
Strength: 
10 mg/mL 
Dose: 
200 mg (20 mL of 10 mg/mL)
Dosage Form/Formulation: 
Solution
Dosing regimen:
Multiple dose (QD)
Route of Administration:
Oral
Preference for generic or brand name: 
Brand name or generic.
Interacting Drug (Part 2) 
Product Name: 
Mefenamic acid
Strength:
250 mg 
Dose: 
250 mg (1 x 250 mg strength)
(500 mg [2 x 250 mg strength] for the first dose)
Dosage Form/Formulation:
Capsule
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Dosing regimen:
Multiple dose (QID)
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 itraconazole and mefenamic acid to allow completion 
of this study.
For all study medications (ie, soticlestat, itraconazole, and mefenamic acid), the same lot number 
will be used throughout the study. The lot numbers and expiration dates (where available) of the 
study drugs supplied will be recorded in the final report. Study drugs will be stored according to 
the product labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study. 
8.1.4
Randomization 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.
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9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the participants in non-technical terms. Participants will be required to read, sign, and 
date an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care.
Participants will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening 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 first 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.
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.
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For this study, collection of blood for soticlestat 
 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.
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 2.0). 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.
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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 measured within 2 hours prior to dosing. 
When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point.
9.2.6
Study Drug Administration
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 and Table 2.d.
After initial morning dosing of mefenamic acid on Day 1 of Period 2, each subsequent first daily 
dose will be administered within ± 1 hour of dosing time established on Day 1 of Period 2. Each 
subsequent dose on the same day will be approximately 6 hours after the morning dose on that day.
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/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 
designee will use a flashlight and a tongue depressor to check the participant’s mouth. 
Participants’ hands will also be verified to ensure that the study drug(s) was ingested.
9.2.7
C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures for each study part (Section 3.0). Two versions of the C-SSRS will be used in 
this study: the Screening/Baseline C-SSRS Lifetime and the Since-Last-Visit C-SSRS. It is 
recommended that the same rater be used to administer the scale to the participant at all timepoints 
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.
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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 2.0).
Coagulation test will consist of the following tests:
Activated partial thromboplastin time (aPPT)
Prothrombin time (PT)/ INR
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, participants may not have fasted for 8 hours prior to when the serum chemistry sample 
is taken.
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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
BloodBlood *
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.
Pharmacokinetic parameters of soticlestat 
 will be 
calculated from the individual concentration-time profiles from all evaluable participants using 
noncompartmental analysis methods. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. 
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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.
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.
No value for AUC∀, AUCextrap%, 
ill be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile.
No PK parameters will be calculated for participants with detectable concentrations at 2 or fewer 
consecutive time points. 
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
Additional PK parameters may be estimated as appropriate.
9.3.2
Biomarker Measurements 
Not applicable.
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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 12 of Period 2 for Part 1 or until after the last 
blood draw and/or study procedures on Day 8 of Period 2 for Part 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 participants 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 by telephone or other methods per CRU 
standards to determine if any AEs have occurred and/or any 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.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation participants 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 
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additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
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 electronic CRF, in order to capture this important safety information consistently in 
the database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the participant should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
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6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
COVID-19 pneumonia
Neuroleptic malignant syndrome / malignant hyperthermia
COVID-19-related disease
Spontaneous abortion / stillbirth and fetal death
Abbreviations: COVID-19 = Coronavirus disease-2019
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
Special Interest AEs
There are no AEs of Special Interest for this study.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
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Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
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.
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10.2.4
End Date 
The end date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae or the participant died.
10.2.5
Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
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 – participants 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 participants 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.
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10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the participant signs the informed consent. Routine collection of AEs will continue until 
the follow-up contact on 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.
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10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Participant identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Reporting Special Interest AEs 
There are no AEs of Special Interest for soticlestat
10.2.8.5
Reporting of Abnormal LFTs
If a participant is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a participant is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
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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). 
10.2.9
Safety Reporting to Investigators, Institutional Review Board (IRB)s or 
Independent Ethics Committee (IEC)s, 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 analysis 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 
analysis set. More details will be provided in SAP.
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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 (Part 1 soticlestat alone 
[Period 1 Day 1 – Period 1 Day 5 predose]; itraconazole alone [Period 2 Day 1 postdose – Period 2 
Day 5 predose]; soticlestat + itraconazole [Period 2 Day 5 postdose to end of study]; Part 2: 
soticlestat alone [Period 1 Day 1 – Period 1 Day 5 predose]; mefenamic acid alone [Period 2 Day 1 
postdose – Period 2 Day 2 predose]; soticlestat + mefenamic acid [Period 2 Day 2 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.
11.1.5.2
Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by baseline and treatment days (Part 1 soticlestat 
alone [Period 1 Day 1 – Period 1 Day 5 predose]; itraconazole alone [Period 2 Day 1 postdose –
Period 2 Day 5 predose]; soticlestat + itraconazole [Period 2 Day 5 postdose to end of study]; 
Part 2: soticlestat alone [Period 1 Day 1 – Period 1 Day 5 predose]; mefenamic acid alone 
[Period 2 Day 1 postdose – Period 2 Day 2 predose]; soticlestat + mefenamic acid [Period 2 Day 2 
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 (Part 1 soticlestat 
alone [Period 1 Day 1 – Period 1 Day 5 predose]; itraconazole alone [Period 2 Day 1 postdose –
Period 2 Day 5 predose]; soticlestat + itraconazole [Period 2 Day 5 postdose to end of study]; 
Part 2: soticlestat alone [Period 1 Day 1 – Period 1 Day 5 predose]; mefenamic acid alone 
[Period 2 Day 1 postdose – Period 2 Day 2 predose]; soticlestat + mefenamic acid [Period 2 Day 2 
postdose to end of study]) 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 (Part 1 soticlestat alone [Period 1 Day 1 – Period 1 Day 5 
predose]; itraconazole alone [Period 2 Day 1 postdose – Period 2 Day 5 predose]; soticlestat + 
itraconazole [Period 2 Day 5 postdose to end of study]; Part 2: soticlestat alone [Period 1 Day 1 –
Period 1 Day 5 predose]; mefenamic acid alone [Period 2 Day 1 postdose – Period 2 Day 2 
predose]; soticlestat + mefenamic acid [Period 2 Day 2 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.
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11.2
Interim Analysis and Criteria for Early Termination
Not applicable.
11.3
Determination of Sample Size
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 (CRO) 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 
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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 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 Harmonization (ICH) Harmonized 
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 
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and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, participant recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and participant 
informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The Sponsor will ship drug/notify site once the Sponsor has confirmed the adequacy 
of site regulatory documentation and, when applicable, the Sponsor has received permission from 
competent authority to begin the study. Until the site receives drug/notification no protocol 
activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by participants, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the Sponsor or its 
designee.
Participant incentives should not exert undue influence for participation. Payments to participants 
must be approved by the IRB or IEC and Sponsor.
13.2
Participant Information, Informed Consent, and Participant Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, participant authorization form (if applicable), and 
participant information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the participant’s personal and personal health information for purposes of 
conducting the study. The ICF and the participant information sheet (if applicable) further explain 
the nature of the study, its objectives, and potential risks and benefits, as well as the date informed 
consent is given. The ICF will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care.
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The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the participant authorization form. The ICF, participant authorization form (if 
applicable), and participant information sheet (if applicable) must be approved by both the IRB or 
IEC and the Sponsor prior to use.
The ICF, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective participant. It is 
the responsibility of the investigator to explain the detailed elements of the ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) to the 
participant. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB or IEC. In the event the participant is not capable of 
rendering adequate written informed consent, then the participant’s legally acceptable 
representative may provide such consent for the participant in accordance with applicable laws and 
regulations.
The participant, or the participant’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the study, and (2) decide whether or not to participate in 
the study. If the participant, or the participant’s legally acceptable representative, determines he or 
she will participate in the study, then the ICF and participant authorization form (if applicable) 
must be signed and dated by the participant, or the participant’s legally acceptable representative, 
at the time of consent and prior to the participant entering into the study. The participant or the 
participant’s legally acceptable representative should be instructed to sign using their legal names, 
not nicknames, using blue or black ballpoint ink. The investigator must also sign and date the ICF 
and participant authorization (if applicable) at the time of consent and prior to participant entering 
into the study; however, the Sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original ICF, participant authorization form (if applicable), and participant 
information sheet (if applicable) will be stored in the investigator’s site file. The investigator must 
document the date the participant signs the informed consent in the participant’s medical record. 
Copies of the signed ICF, the signed participant authorization form (if applicable), and participant 
information sheet (if applicable) shall be given to the participant.
All revised ICFs must be reviewed and signed by relevant participants or the relevant participant’s 
legally acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the participant’s medical record, and the 
participant should receive a copy of the revised ICF.
13.3
Participant Confidentiality
The Sponsor and designees affirm and uphold the principle of the participant’s right to protection 
against invasion of privacy. Throughout this study, a participant’s source data will only be linked 
to the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited participant attributes, such as sex, age, or 
date of birth, and participant initials may be used to verify the participant and accuracy of the 
participant’s unique identification number.
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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit 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.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2
Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for America’s investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once participants receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
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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
14.1.1
Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
E-mail: PVSafetyAmericas@tpna.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 Harmonization, 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 A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C 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
ADME
Absorption, distribution, metabolism and elimination 
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
CDD
CDKL5 deficiency disorder
COVID-19
Coronavirus 2019
CFR
Code of Federal Regulations
CH24H
Cholesterol 24S hydroxylase
CI
Confidence interval
Cmax
Maximum observed concentration 
CRF
Case report form
CRPS
Complex regional pain syndrome
CRU
Clinical Research Unit
CSR
Clinical study report
CV
Coefficient of variance
CYP
Cytochrome P450
DDI
Drug-drug interaction
DEE
Developmental and Epileptic Encephalopathies
DS
Dravet Syndrome
Dup15
15q11-q13 duplication syndrome
ECG
Electrocardiogram
FSH
Follicle stimulating hormone
CCI
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GCP
Good Clinical Practice
GI
Gastrointestinal
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
ICH
International Council for Harmonization
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®
NOAEL
No-observed-adverse-effect-level
OATP
organic-anion-transporting polypeptide
P-gp
P-glycoprotein
PBPK
Physiologically-based PK
PK
Pharmacokinetic(s)
PTE
Pretreatment event
Q6H
Every 6 hours 
QD
Daily
QID
Four times a day
QTcF
QT interval corrected for pulse rate using Fridericia’s formula
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SOC
Standard of care
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
tmax
Time of first occurrence of Cmax
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal
US
United States
USA
United States of America
CCI
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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15.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization Drug 
Dictionary.
15.1
CRFs (Electronic and Paper)
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the 
Investigator. The final signed CRFs are provided to the Sponsor in the format as decided upon 
between Celerion and the Sponsor (eg, CD, flashdrive, SFTP). This will be documented in the 
Data Management Plan (if applicable).
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the investigator with use of change and modification records of the 
CRFs. The principal investigator must review the data change for completeness and accuracy, and 
must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the participant’s 
medical and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed 
CRFs are the sole property of the Sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, medical records, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated ICFs, participant authorization forms regarding 
the use of personal health information (if separate from the ICFs), electronic copy of CRFs, 
including the audit trail, and detailed records of drug disposition to enable evaluations or audits 
from regulatory authorities, the Sponsor or its designees. Any source documentation printed on 
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degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
the participant’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
16.0
REFERENCES
1. 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. Sporanox® (itraconazole) oral solution 10 mg/mL, product monograph. Janssen 
Pharmaceuticals, Inc. website (document revised: 04/2019). Available at: 
http://www.janssenlabels.com/package-insert/product-monograph/prescribinginformation/SP
ORANOX-Oral+Solution-pi.pdf. 
4. Isoherranen N, et al. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab 
Dispos. 2004;32(10):1121-31.
5. Ponstel® (mefenamic acid) capsules, Full prescribing information (electronic monograph; 
document revised 04/2021). Available at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/015034s045lbl.pdf 
6. Food and Drug Administration: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors, and Inducers. (26 September 2016). Available at: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteracti
onslabeling/ucm093664.htm.
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. Callegari, E., et al., PhysiologicallyBased Pharmacokinetic Modeling of the Drug–Drug 
Interaction of the UGT Substrate Ertugliflozin Following CoAdministration with the UGT 
Inhibitor Mefenamic Acid. CPT Pharmacometrics Syst Pharmacol, 2021. 10(2):127-136.
9. Chen et al. Recommendations for the Design of Clinical Drug–Drug Interaction Studies With 
Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Mode CPT 
Pharmacometrics Syst. Pharmacol. (2019) 8, 685–695;
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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 ICF should contain a participant 
authorization section that describes the uses and disclosures of a participant’s personal 
information (including personal health information) that will take place in connection with the 
study. If an ICF does not include such a participant authorization, then the investigator must 
obtain a separate participant authorization form from each participant or the participant’s 
legally acceptable representative.
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 ICF, the participant or 
the participant’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the participant for participating in the study.
17. The anticipated expenses, if any, to the participant for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the participant.
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 
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participant’s legally acceptable representative may discontinue participation at any time 
without penalty or loss of benefits to which the participant is otherwise entitled.
20. The consequences of a participant’s decision to withdraw from the research and procedures for 
orderly termination of participation by the participant.
21. A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.
23. A written participant authorization (either contained within the ICF or provided as a separate 
document) describing to the participant the contemplated and permissible uses and disclosures 
of the participant’s personal information (including personal health information) for purposes 
of conducting the study. The participant authorization must contain the following statements 
regarding the uses and disclosures of the participant’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
participants the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that participants agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the participant’s identity will remain confidential in the event that study results are 
published.
24. Regular pregnancy tests will be performed throughout the study for all female participants.
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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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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Participants 
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.
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General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of participant compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
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/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.
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