Clinical trial NCT05602818
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2022-11-15; Completion date: 2023-07-07
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main aim is to evaluate the relative abuse potential of soticlestat in healthy adults who has used central nervous system (CNS) depressants for recreational nontherapeutic reasons.

Detailed description:
The drug being tested in this study is called soticlestat. Soticlestat is being tested in healthy participants. This study will assess the relative abuse potential of soticlestat compared to alprazolam and placebo in healthy adult, nondependent recreational drug users with CNS depressant experience. The study will enroll approximately 110 participants. Participants will be randomly (by chance, like flipping a coin) assigned to treatments of the study.

Treatment order will remain undisclosed to the participants and study doctor (unless there is an urgent medical need). This single center trial will be conducted in the United States. Participants will be followed up for up to 7 days after the last dose of study drug for a follow-up assessment. The overall time to participate in this study is approximately 11 weeks.

Arms: arm 1: Participants will receive a single oral dose of soticlestat 300 milligrams (mg). arm 2: Participants will receive a single oral dose of soticlestat 600 mg. arm 3: Participants will receive a single oral dose of soticlestat 900 mg. arm 4: Participants will receive a single oral dose of over encapsulated alprazolam 2 mg. arm 5: Participants will receive a single oral dose of matching placebo.
Interventions: intervention 1: Soticlestat 300 mg intervention 2: Soticlestat 600 mg intervention 3: Soticlestat 900 mg intervention 4: Alprazolam intervention 5: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally. intervention 3: Administered orally. intervention 4: Administered orally. intervention 5: Administered orally.

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


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Randomized, Double-Blind, Double-Dummy, Active- and Placebo-Controlled, 
5-Way Crossover Study Evaluating the Abuse Potential of Soticlestat (TAK-935) in Healthy
Adult Nondependent Recreational Drug Users With Central Nervous System Depressant
Experience 
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421 USA
Study Number:
TAK-935-1012
IND Number:
133627
EudraCT Number:
2018-002484-25
Compound:
Soticlestat
Date:
15 March 2023
Version/Amendment 
Number:
Amendment 1
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
15 March 2023
Amendment 1
Substantial
Global
29 August 2022
Initial protocol
Not Applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed (e)consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 2 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided in the study manual.
Takeda Development Center–sponsored investigators will be provided with emergency medical 
contact information cards at discharge or early termination to be carried by each participant.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the study site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study contact list.
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 4 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
prescribing information and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, life, dignity, integrity, confidentiality of personal information, safety, privacy, and 
well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, 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 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the investigator (Appendix B).
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 5 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
1.3
Protocol Amendment 01 Summary of Changes
Protocol Amendment 01 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 01. The 
primary reason for this amendment is to update the number of anticipated participants to be 
enrolled into the qualification phase and ultimately randomized into the treatment phase. The 
numbers of participants anticipated now in qualification and treatment phase are approximately 
140 and 65, respectively.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 01 
Summary of Changes Since the Last Version of the Approved Protocol
No.
Sections Affected by 
Change
Description 
Rationale
1
Section 2.0 STUDY 
SUMMARY
Section 13.3
Determination of Sample 
Size
Updated projected number of 
participants to be enrolled 
(qualification phase) and randomized 
(treatment phase).
The total number of participants 
expected to be enrolled and randomized 
has been increased due to a 
higher-than-expected number of early 
terminations.
2
Section 7.5.2 Diet, Fluid, 
and Activity Control
Updated the language to clarify that 
the study drug will be administered 
with water.
Note added to clarify water intake for 
dosing is excluded from the fasting 
period before and after dosing.
3
Section 8.1.4 Overdose
Additional condition added to 
definition of overdose specific to 
current study.
To clarify that because the study is 
blinded, ingestion of additional 
tablets/capsules will be considered an 
overdose. 
4
Section 8.5 Unblinding 
Procedure
Removed the requirement for 
providing emergency unblinding 
envelopes to study site.
As the study site pharmacy holds the 
randomization schedule for the study, 
these envelopes were not needed and 
subsequently not provided.
Note: The dispensing pharmacist can 
unblind participant’s treatment 
allocation without the envolopes.
5
Section 9.1.4 Vital Sign 
Procedure
Changed heart rate to pulse rate.
To align with schedule of events
6
Table 9.a Clinical 
Laboratory Tests
Replaced slash (/) with and/or
To clarify that urine drug screen (UDS) 
is applicable to all or any of the 
substances mentioned.
7
Section 9.1.9
Documentation of 
Substance Use History
Updated language to clarify the 
timeframe for site to collect substance 
use history.
To resolve uncertainty pertaining to the 
timeframe to collect substance use 
history. 
8
Section 9.1.9
Documentation of 
Substance Use History
Added specific quantities for various 
alcoholic beverages under alcohol 
history.
Adding definition of alcohol units to the 
protocol.
For non-commercial use only


For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 8 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 01 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................19
3.1
Study-Related Responsibilities.................................................................................19
3.2
Principal and Coordinating Investigator(s)...............................................................19
3.3
List of Abbreviations ...............................................................................................20
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit/Risk Profile .................................................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Objectives................................................................................................................24
5.1.1
Primary Objective............................................................................................24
5.1.2
Secondary Objectives ......................................................................................24
5.1.3
....................................................................................25
5.2
Estimands ................................................................................................................25
5.3
Endpoints.................................................................................................................25
5.3.1
Primary Endpoint.............................................................................................25
5.3.2
Secondary Endpoints, PD ................................................................................25
5.3.3
Secondary Endpoint, Safety.............................................................................25
5.3.4
Other Safety Endpoints....................................................................................25
5.3.5
..............................................................................25
5.3.6
................................................................................26
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design ...........................................................................................................26
6.2
Justification for Study Design, Dose, and Endpoints ................................................29
6.2.1
Dose Rationale ................................................................................................29
6.2.2
Rationale for Active Comparator .....................................................................29
6.3
Premature Termination or Suspension of Study or Study Site...................................30
6.3.1
Criteria for Premature Termination or Suspension of the Study........................30
6.3.2
Criteria for Premature Termination or Suspension of Study Site ......................30
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 9 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...........................................................................31
6.3.4
Duration of an Individual Participant’s Study Participation..............................31
6.3.5
End of Study/Study Completion Definition......................................................31
6.4
Posttrial Access .......................................................................................................31
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .....31
7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................32
7.3
Qualification Criteria (Applicable to Passing Qualification Phase)...........................34
7.4
Excluded Medications..............................................................................................35
7.5
On-Study Restrictions..............................................................................................36
7.5.1
Alcohol and Drug Use .....................................................................................36
7.5.2
Diet, Fluid, and Activity Control......................................................................36
7.6
Criteria for Discontinuation or Withdrawal of a Participant......................................37
7.7
Procedures for Discontinuation or Withdrawal of a Participant ................................38
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................38
8.1
Study Drug and Materials ........................................................................................38
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling of Study Drug ...........38
8.1.2
Storage ............................................................................................................39
8.1.3
Dose and Regimen...........................................................................................39
8.1.4
Overdose .........................................................................................................40
8.2
Study Drug Assignment and Dispensing Procedures ................................................41
8.2.1
Assignment of Participant Identification Number.............................................41
8.2.2
Study Drug Assignment...................................................................................41
8.3
Randomization Code Creation and Storage..............................................................41
8.4
Study Drug Blind Maintenance................................................................................41
8.5
Unblinding Procedure..............................................................................................42
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................42
9.0
STUDY PLAN ..............................................................................................................43
9.1
Study Procedures.....................................................................................................43
9.1.1
Informed (e)Consent Procedure .......................................................................43
9.1.2
Demographics, Medical History, and Medication History Procedure................44
9.1.3
Weight and Height...........................................................................................44
9.1.4
Vital Sign Procedure........................................................................................44
9.1.5
ECG Procedure................................................................................................44
9.1.6
Physical Examination Procedure......................................................................45
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 10 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
9.1.7
Procedures for Clinical Laboratory Samples ....................................................45
9.1.8
Documentation of Concomitant Medications ...................................................47
9.1.9
Documentation of Substance Use History ........................................................48
9.1.10
Documentation of Concurrent Medical Conditions...........................................48
9.1.11
Clinical Assessment of Suicidal Ideation and Behavior....................................48
9.1.12
Contraception and Pregnancy Avoidance Procedure ........................................49
9.1.12.1
Male Participants and Their Female Partners ...........................................49
9.1.12.2
Female Participants and Their Male Partners ...........................................49
9.1.12.3
Contraceptive Methods for Female Participants of Childbearing 
Potential ..................................................................................................49
9.1.12.4
General Guidance With Respect to the Avoidance of Pregnancy..............50
9.1.13
Pregnancy........................................................................................................50
9.1.14
Documentation of Screen Failure.....................................................................51
9.1.15
Documentation of Entry Into the Qualification Phase.......................................51
9.1.16
Documentation of Entry Into the Treatment Phase ...........................................52
9.2
Safety Monitoring....................................................................................................52
9.2.1
Reporting of Abnormal Liver Function Tests...................................................52
9.2.2
Reporting of QTcF Interval Increase................................................................53
9.3
.........................................................................53
9.3.1
..53
9.3.2
.....................................53
9.4
PD Assessments.......................................................................................................53
9.4.1
Subjective Effects VASs..................................................................................54
9.4.2
.......................................................................................55
9.5
................................................................56
9.5.1
Screening.........................................................................................................56
9.5.2
Qualification Phase..........................................................................................56
9.5.3
Treatment Phase ..............................................................................................56
9.5.4
Follow-up (Final Visit or ET) ..........................................................................57
10.0
ADVERSE EVENTS ....................................................................................................57
10.1
Definitions...............................................................................................................57
10.1.1
PTEs................................................................................................................57
10.1.2
TEAEs.............................................................................................................57
10.1.3
Additional Points to Consider for AEs .............................................................57
10.1.4
SAEs ...............................................................................................................60
10.1.5
Intensity of AEs...............................................................................................60
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 11 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
10.1.6
Causality of AEs..............................................................................................60
10.1.7
Relationship to Study Procedures.....................................................................60
10.1.8
Start Date.........................................................................................................61
10.1.9
Stop Date.........................................................................................................61
10.1.10 Frequency........................................................................................................61
10.1.11 Action Concerning Study Drug........................................................................61
10.1.12 Outcome..........................................................................................................61
10.2
Procedures...............................................................................................................62
10.2.1
Collection and Reporting of AEs .....................................................................62
10.2.1.1
AE Collection Period...............................................................................62
10.2.1.2
AE Reporting...........................................................................................62
10.2.2
Collection and Reporting of SAEs ...................................................................62
10.3
Follow-up of SAEs ..................................................................................................63
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities................63
10.3.2
Reporting of Abnormal Liver-Associated Test Results.....................................63
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................63
12.0
DATA HANDLING AND RECORDKEEPING............................................................64
12.1
eCRFs......................................................................................................................64
12.2
Record Retention .....................................................................................................64
13.0
STATISTICAL METHODS..........................................................................................65
13.1
Statistical and Analytical Plans ................................................................................65
13.1.1
Analysis Sets ...................................................................................................65
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................66
13.1.3
PD Analysis.....................................................................................................66
13.1.3.1
General Considerations............................................................................66
13.1.3.2
Primary Endpoint.....................................................................................67
13.1.3.3
Secondary Endpoints ...............................................................................68
13.1.3.4
.............................................................................68
13.1.4
.....................................................................................................68
13.1.5
Safety Analysis................................................................................................69
13.2
Interim Analysis ......................................................................................................69
13.3
Determination of Sample Size..................................................................................69
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................70
14.1
Study Site Monitoring Visits....................................................................................70
14.2
Protocol Deviations..................................................................................................70
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 12 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................71
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................71
15.1
IRB Approval ..........................................................................................................71
15.2
Participant Information, Informed (e)Consent, and Participant Authorization...........72
15.3
Participant Confidentiality .......................................................................................73
15.4
Clinical Trial Disclosures and Publication................................................................74
15.4.1
Publication and Disclosure...............................................................................74
15.4.2
Clinical Trial Registration................................................................................74
15.4.3
Clinical Trial Results Disclosure......................................................................74
15.5
Insurance and Compensation for Injury....................................................................74
16.0
REFERENCES..............................................................................................................75
LIST OF IN-TEXT TABLES
Table 6.a
Schematic of Study Design ................................................................................28
Table 8.a
Treatment Description........................................................................................40
Table 9.a
Clinical Laboratory Tests...................................................................................46
Table 9.b
VAS Descriptions ..............................................................................................55
Table 9.c
.........................................................................................56
LIST OF APPENDICES
Appendix A
............................................................................76
Appendix B
Responsibilities of the Investigator.....................................................................84
Appendix C
Elements of the Participant Informed (e)Consent................................................86
Appendix D
Trial Management During COVID-19 Pandemic................................................89
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 13 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
2.0
STUDY SUMMARY 
Name of Sponsor(s):
Takeda Development Center Americas, Inc
Compound:
Soticlestat (TAK-935)
Title of Protocol: A Phase 1, Randomized, Double-Blind, 
Double-Dummy, Active- and Placebo-Controlled, 5-Way 
Crossover Study Evaluating the Abuse Potential of 
Soticlestat (TAK-935) in Healthy Adult Nondependent 
Recreational Drug Users With Central Nervous System 
Depressant Experience 
IND No.: 133627
EudraCT No.:
2018-002484-25
Study Number: TAK-935-1012
Phase: 1
Study Design:
This is a phase 1, randomized, double-blind, double-dummy, active- and placebo-controlled, 5-way crossover study to 
determine the relative abuse potential of single oral doses of soticlestat compared to single oral doses of 2 mg of 
alprazolam and placebo in healthy adult, nondependent recreational drug users with central nervous system (CNS) 
depressant experience.
Participants who complete the study will be in the study for approximately 11 weeks (including approximately 
5 weeks in the qualification and treatment phases). This study includes:

Screening phase of up to 4 weeks. 

Qualification phase (4 days). 

Treatment phase (5 periods with at least a 7-day washout between each period).

Follow-up visit occurring 7 days after last treatment phase period and discharge from the clinical research unit 
(CRU).
Screen
ing 
Phase
Randomization to Sequence Q1 and Q2
Seque
nce
Qualification Phase
Randomization to Sequence 1 -10
Seque
nce
Treatment Phase a
Followup 
Phase
within 28 
days of 
qualificat
ion phase
Day 1
Day 2
Period 
1
Period 
2
Period 3
Period 4
Period 5
Discharge
Treatments
Treatments
Q1
Alprazol
am
Placebo
1
A
B
E
C
D
~7 ± 3 days 
after final 
dose given at 
the last 
treatment 
period
Q2
Placebo
Alprazol
am
2
B
C
A
D
E
3
C
D
B
E
A
4
D
E
C
A
B
5
E
A
D
B
C
6
D
C
E
B
A
7
E
D
A
C
B
8
A
E
B
D
C
9
B
A
C
E
D
10
C
B
D
A
E
a Treatment description – treatment phase.
Treatment A: Soticlestat 300 mg.
Treatment B: Soticlestat 600 mg.
Treatment C: Soticlestat 900 mg.
Treatment D: Alprazolam 2 mg.
Treatment E: Placebo.
Each participant will participate in a screening visit (Visit 1) to determine eligibility within 28 days of the first dose in 
the qualification phase. Eligible participants will participate in an inpatient, qualification phase (from Day -1 through 
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 15 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Dose Level(s):
Qualification phase: Alprazolam 2 mg and matching 
placebo.
Treatment phase: Soticlestat 300, 600, 900 mg; alprazolam 2 
mg; and corresponding matching placebo.
Route of Administration:
Oral
Duration of Treatment:
Qualfication phase: Two days of treatment (single doses of 
alprazolam and placebo).
Treatment phase: Five days of treatment (single doses of 
soticlestat 300, 600, 900 mg; alprazolam 2 mg; and placebo).
Period of Evaluation:
Approximately 11 weeks, which include:

Screening phase - up to 4 weeks. 

Qualification phase - 4 days. 

At least 4-day washout between the qualification 
phase and the treatment phase.

Treatment phase - 5 periods with at least a 7-day 
washout between each period. 

Follow-up visit - occurring 7 days after last 
treatment phase period and discharge from the 
CRU.
Main Criteria for Inclusion:

The participant is 18 to 55 years of age, inclusive, at the screening visit.

The participant is healthy as determined by the investigator. 

Participant is a current CNS depressant user who has used CNS depressants (eg, benzodiazepines, barbiturates, 
zolpidem, eszopiclone, zopiclone, propofol/fospropofol, gamma-hydroxybutyrate) for recreational, 
nontherapeutic reasons at least 10 times in their lifetime and at least once in the 12 weeks before screening. 

Participant also must have recreational experience with at least 1 other drug class associated with abuse (eg, 
opioids, stimulants, cannabinoids, hallucinogens, dissociatives) at least 10 times in their lifetime.
Main Criteria for Exclusion:
Participant has a self-reported history of drug or alcohol dependence (within the past 1 year, except caffeine or 
nicotine, before the screening visit) and assessed by the investigator at screening visit or has ever participated in a 
treatment program or rehabilitation (lifetime) for alcohol or substance dependence (other than nicotine or caffeine).
Participant has a positive alcohol breathalyzer or urine drug screen (UDS) for substances of abuse at admission, 
excluding tetrahydrocannabinol (THC). If a participant presents with a positive UDS, excluding THC, the participant 
may be rescheduled to repeat the UDS and can only be admitted upon a negative UDS being obtained, excluding THC. 
Positive THC UDS will be permitted at admission as long as the participant is not impaired at admission, in the clinical 
judgment of the investigator. 
Participants have used any concomitant medications (including prescription and nonprescription medications, herbal 
remedies, or vitamin supplements) within 7 days (or 5 times the t1/2, if known) before the first study drug 
administration in the qualification phase and throughout the study. Exceptions include:

Thyroid hormone replacement medication may be permitted if the participant has been on the same stable dose for 
the immediate 3 months before first dosing in the qualification phase.

Oral contraceptive is allowed if its use is consistent (ie, no change in oral contraceptive) throughout the study.
The participant has any positive response on the Columbia Suicide Severity Rating Scale (C-SSRS) or has a risk of 
suicide according to the investigator’s judgment based on the assessment of the C-SSRS at screening or baseline or has 
made a suicide attempt in the previous 12 months before dosing in the qualification phase.
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 17 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
a)
Similar Emax scores (within a 5-point difference) for a participant across all treatments (including placebo)
OR
b)
Emax (positive control) ≤55
OR
c)
Emax (placebo) - Emax (positive control) ≥5.
This analysis set will be used for PD analyses.
PD Analysis: General Considerations:
PD endpoints will only be analyzed or summarized for the treatment phase unless otherwise stated.
For each PD endpoint, the number of participants with nonmissing values, mean, standard error, minimum, first 
quartile (Ql), median, third quartile (Q3) and maximum for each treatment and each paired difference among 
treatments will be reported for the treatment phase.
The mean response for each treatment over time will be plotted for the primary and secondary PD endpoints.
PD Analysis: Primary Endpoint:
The following hypotheses will be tested for the primary PD endpoint of Drug Liking “at this moment” VAS Emax.
1.
Validation test of the sensitivity and integrity of the study: Does the positive control (C) produce mean responses 
that show greater abuse potential compared with placebo (P)?
H0: µC - µP ≤15 vs Ha: µC - µP > 15
where µC and µP are the mean Drug Liking VAS Emax for alprazolam and placebo, respectively.
2.
Does the test drug (T) produce mean responses that show less abuse potential compared to positive control?
H0: µC - µT ≤0 vs Ha: µC - µT > 0
where µT is mean Drug Liking VAS Emax for soticlestat. This hypothesis will be tested separately for each soticlestat 
dose. Rejection of each null hypothesis would suggest lower relative abuse potential of soticlestat compared to 
alprazolam. 
3.
Does the test drug produce mean responses that show similar abuse potential compared with placebo?
H0: µT - µP ≥11 vs Ha: µT - µP < 11
This hypothesis will be tested separately for each soticlestat dose. Rejection of each null hypothesis would suggest that 
soticlestat does not produce an abuse-related signal.
All hypotheses for the primary endpoint will be tested at 1-sided 0.05 level of significance. The hypotheses will be 
tested sequentially in the order listed. Within the second and third hypotheses, testing will be ordered from low dose to 
high dose. No adjustments to p-values will be made. All hypotheses will be evaluated using nominal p-values.
Analysis of the primary endpoint will be performed on the modified completer analysis set. A linear mixed effects 
model containing treatment, period, sequence, and first-order carryover (if applicable) as fixed effects, and participant 
as random effect, is planned to be used to evaluate the hypotheses for the primary endpoint.
If the variances across treatment groups shows potential heterogeneity, the model will be fitted to allow unequal 
variances across treatment groups. If non-normality of residuals is detected in the model, a paired t-test or sign test will 
be used as appropriate for hypothesis testing. If a potential carryover effect is detected then a carryover effect term will 
be included in the mixed effects model. 
PD Analysis: Secondary Endpoints:
The following hypotheses will be evaluated for key and other secondary endpoints. Comparisons among treatments 
will be evaluated at 1-sided significance level 0.05 for hypothesis 1 and 2, and 2-sided significance level 0.10 for 
hypothesis 3.
1.
Positive control (alprazolam) (C) versus placebo (P): 
H0: µC - µP ≤0 vs Ha: µC - µP > 0
2.
Positive control (alprazolam) (C) versus each dose of soticlestat (T): 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 18 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
H0: µC - µT ≤0 vs Ha: µC - µT > 0
3.
Each dose of soticlestat (T) versus placebo (P):
H0: μT - μP = 0 vs Ha: μT - μP ≠ 0
No adjustments to p-values will be made. All hypotheses will be evaluated using nominal p-values.
Key and other secondary PD endpoints will be analyzed with the same linear mixed effects model or nonparametric 
approaches (as appropriate) as the primary endpoint analysis, using the modified completer analysis set and following 
the same strategy for determining the analysis method.
Safety Analysis
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and characterized as 
pretreatment and treatment-emergent according to the intake of the study drugs. TEAEs will be summarized by 
treatment showing the number and percentage of participants who experienced at least 1 TEAE and the number of 
TEAEs reported. A by-participant adverse event (AE) data listing including reported term, coded term, treatment, 
severity, and relationship to treatment will be provided. TEAEs leading to discontinuation and SAEs will be listed 
separately.
Vital signs data will be summarized by study phase and treatment and will be listed by participant. Observed values 
and changes from baseline will be presented.
Physical examination abnormalities, ECG results, clinical laboratory values, and C-SSRS responses will be listed by 
participant.
Sample Size Justification: 
The qualification phase of the study is based on a 2 × 2 crossover design with oral doses of alprazolam 2 mg and 
matching placebo. The treatment phase is based on a 5-treatment, 10-sequence, 5-period Williams square crossover 
design with treatments A, B, C, D, and E as defined previously. Approximately 140 participants will be enrolled into 
the qualification phase of the study, randomized equally to the 2 sequences. Approximately 65 qualified participants 
will be randomized equally to the 10 sequences in the treatment phase, with the intent to ensure that at least 39 
participants are in the modified completer analysis set. 
It is estimated that, in the treatment phase, a sample size of 39 participants in the modified completer analysis set will 
provide at least 90% power to test each of the hypotheses for the primary PD endpoint. Power calculations used a 
paired t-test and assumed a true SD of 23 points for within-participant differences for each planned treatment 
comparison on the Drug Liking VAS Emax, a true mean difference of 26 points between alprazolam 2 mg and placebo, 
and a true mean difference of 0 points between placebo and each dose of soticlestat. 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 19 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform these activities either 
in full or in partnership with the sponsor.
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
the study site (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and sub-investigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that must 
be signed by each investigator and sub-investigator before the study starts at their study site; in 
addition, any potential conflicts of interests that are not covered by this financial disclosure form 
should be disclosed separately to the sponsor before the start of the study at their study site.
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to sponsor before the start of the study.
3.2
Principal and Coordinating Investigator(s)
The principal investigator at the single study site has significant knowledge of the study protocol, 
the study drug, expertise in the therapeutic area, and the conduct of clinical research. The 
coordinating investigator for the study will be required to review and sign the clinical study report 
(CSR) and by doing so agrees that it accurately describes the results of the study.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 20 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
3.3
List of Abbreviations
24HC
24S-hydroxycholesterol
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC∞
area under the concentration-time cuve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to last quantifiable concentration
BID
twice daily
Bs
baseline
CDER
Center for Drug Evaluation and Research
CH24H
cholesterol-24 hydroxylase 
Cmax
maximum observed concentration
Cmax,u
unbound Cmax concentration
CNS
central nervous system
COVID-19
coronavarius disease 2019
CRU
clinical research unit
CSA
Controlled Substances Act
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P-450
DEE
developmental epileptic encephalopathy
DS
Dravet syndrome
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders-IV text revision
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
(e)consent
electronic or written consent
eCRF
electronic case report form
EDC
electronic data capture
Emax
maximum effect
ET
early termination
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
hCG
human chorionic gonadotropin
IB
investigator’s brochure
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 21 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
ICF
informed consent form
ICH
International Council for Harmonisation
INR
international normalized ratio
IRB
institutional review board
LGS
Lennox-Gastaut syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple-rising dose
MRHD
maximum recommended human dose
NMDA
N-methyl-D-aspartate
PD
pharmacodynamic(s)
P-Gp
P-glycoprotein
PK
pharmacokinetic(s)
PTE
pretreatment events
QD
once daily
QTcF
Fridericia-corrected QT interval
rSDV
remote source data verification
SAE
serious adverse event
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
tmax
time of first occurrence of Cmax
UDS
urine drug screen
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
WHO
World Health Organization
WOCBP
women of childbearing potential 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 22 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
Soticlestat is being developed for the treatment of seizures in patients with Dravet syndrome (DS) 
and Lennox-Gastaut syndrome (LGS). 
Soticlestat is a potent inhibitor of cholesterol-24 hydroxylase (CH24H) in the brain. Although the 
exact therapeutic mechanisms of soticlestat still remain to be fully understood, pharmacological 
modulation of CH24H can potentially alter the function of N-methyl-D-aspartate (NMDA) 
receptors because 24S-hydroxycholesterol (24HC), the metabolic product of CH24H reaction, is 
known as an endogenous modulator of the NMDA (Paul et al. 2013) receptors. Therefore, 
soticlestat can be considered an indirect NMDA modulator, which is mediated by reduction of 
24HC. 
Nonclinical studies have demonstrated that soticlestat modulates glutamatergic signaling and 
significantly reduces spontaneous seizure in murine models. The phase 2 clinical study 
TAK-935-2002 (ELEKTRA) showed efficacy of soticlestat in participants with DS or LGS who 
had seizures that were intractable to current antiseizure medications. 
Soticlestat is rapidly absorbed following oral administration with a median time to maximum 
plasma concentration of 0.5 to 0.75 hours (oral tablets; TAK-935-1005 and TAK-935-1004) and a 
mean terminal disposition phase half-life (t1/2) ranging from 2.6 to 8.7 hours (oral tablets). 
Exposure to soticlestat increased in a greater than dose-proportional manner over the single-dose 
range of 200 to 1200 mg (oral tablets; TAK-935-1004) and 15 to 1350 mg (oral solution; 
TAK-935-101). 
The positron emission tomography imaging data showed that the enzyme occupancy increased 
with increasing dose and plateaued at approximately 93% at 2 hours with 200 mg single dose. The 
maximum enzyme occupancy of approximately 96% at 2 hours was observed at the 600 mg single 
dose. Although soticlestat rapidly engages with the CH24H target, maximum reduction of 24HC 
levels (ie, the pharmacological mediator of soticlestat’s effects) was observed at approximately 16 
hours postdose after single 50, 200, and 600 mg doses and at approximately 48 hours postdose 
after single 900 and 1350 mg doses (TAK-935-101 CSR).
In addition, although soticlestat has a relatively short plasma elimination t1/2, the 
pharmacodynamic (PD) effect (ie, reduction of 24HC levels) returned slowly to baseline at 
96 hours postdose following single doses (TAK-935-101 CSR). Average change from baseline 
24HC during 12 hours at steady-state were simulated at increasing twice daily (BID) doses based 
on a population pharmacokinetics (PK) and 24HC model of pooled data from phase 1 and phase 2 
studies. Simulations with 100, 200, and 300 mg BID indicate that 24HC levels returned to baseline 
within 7 days after treatment stop (Population PK/24HC Memo dated 16 December 2021).
Since soticlestat is a central nervous system (CNS)–active new molecular entity, Takeda has 
conducted the agreed nonclinical abuse/dependence evaluation of the compound, as per United
States (US) Food and Drug Administration (FDA) guidelines. The nonclinical evaluation of abuse 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 23 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
potential showed that soticlestat did not have any significant 2-dimenisonal structural similarities 
to Schedule I to V compounds listed in the US Controlled Substances Act or bind to known 
abuse-related pharmacologic targets at clinicaly relevant concentrations (Investigator’s Brochure 
[IB] Edition 7).
In vivo, soticlestat was not found to produce physical dependence in a rat model of chronic 
soticlestat dosing and then withdrawal at plasma values that were up to approximately 20-fold the 
maximum observed concentration (Cmax) at the maximum recommended human dose (MRHD) of 
300 mg BID (Study 8478301). 
In addition, soticlestat did not have reinforcing properties in an intravenous (IV) 
self-administration model in rats at plasma levels of up to 1.4-fold the MRHD (Study 8478298) 
and did not generalize to the interoceptive cue produced by ketamine in rats at plasma 
concentrations of up to approximately 7.4-fold the Cmax at the MRHD (Study 8478299). 
Combining studies of phase 1 and the placebo-controlled parts of phase 2 studies, the incidence of 
abuse related, treatment-emergent adverse events (TEAEs) was 17.9% for soticlestat versus 9.6% 
for placebo and consisted mostly of dizziness and somnolence. Focusing on abuse-related TEAEs 
that emerged on Day 1 of treatment, the time most relevant to human abuse, the incidence of 
abuse-related TEAEs was 4.7% for participants on soticlestat versus 1.8% for participants on 
placebo (CSRs TAK-935-101, TAK-935-1002, TAK-935-1004, TAK-935-2008 [part A], 
TAK-935-2001 [part 1] and TAK-935-2002). 
There were 3 reports of euphoric mood by participants receiving soticlestat. Although there were 2 
cases of euphoric mood within 1 to 2 hours of soticlestat dosing, evaluation of PD parameters for 
these participants did not show a marked effect on 24HC concentrations at this time, indicating 
that the effects were unlikely related to soticlestat.
4.2
Rationale for the Proposed Study
As part of the comprehensive assessment of the relative abuse potential of soticlestat, which 
includes nonclinical and clinical assessments, and in accordance with guidelines provided by FDA 
and to meet the requirement for regulatory filing and registration, this study will be conducted to 
provide additional information on the relative abuse potential of soticlestat in healthy adult 
nondependent recreational drug users with CNS depressant experience.
4.3
Benefit/Risk Profile 
In the phase 1b/2a and phase 2 studies completed to date, the safety and tolerability data indicate 
that soticlestat was generally safe and well tolerated in participants with developmental epileptic 
encephalopathies (DEEs) at doses up to 300 mg BID (weight-based dosing for <60 kg) with initial 
dose up-titration.

To date, Takeda has completed a total of 10 clinical studies including phase 1 single-rising 
dose (SRD) and multiple-rising dose (MRD) studies in healthy participants and phase 2 studies 
in DEE and patients with complex regional pain syndrome (CRPS). Overall, soticlestat was 
safe and well tolerated, and there were no observed dose responses for TEAEs in 2 SRD 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 24 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
studies where the healthy participants were dosed with up to 1350 mg (TAK-935-101) and 
1200 mg (Part 1 of TAK-935-1004). 

In the TAK-935-1002 MRD study, where dose up-titration/optimization was not implemented, 
soticlestat at 300 mg BID and 600 mg once daily (QD) did not appear to be well tolerated by 
healthy participants due to the emergence of multiple neurological and psychiatric events 
(reference TAK-935-1002, CSR). These events/TEAEs were all mild except for 1 case of acute 
psychosis (severe), insomnia (severe), and distractibility (moderate) reported by the same 
participant. The conditions of the TEAEs were reversible, and all participants recovered. There 
were no serious adverse events (SAEs). No clear dose-response relationship was observed for 
any specific TEAE across all dose cohorts.

All subsequent repeated-dose studies implemented dose up-titration/optimization to the target 
dose levels of up to 300 mg BID. No individual or population dose-response for safety events 
have been observed during the dose up-titration/optimization and maintenance periods. 
Soticlestat has been well tolerated up to 300 mg BID with dose up-titration/optimization
without emergence of any new safety issues to date.
This study evaluates 3 different single dose levels, including 300, 600, and 900 mg, all of which 
were generally safe and well tolerated in phase 1 studies. Further, single doses higher than 900 mg 
were also safe and well tolerated in phase 1 studies, as described above.
This is an inpatient study, and the participants will be closely monitored for the emergence of any 
adverse events (AEs), which will be managed at the earliest as required. 
More information about the known and expected benefits and risks of soticlestat may be found in 
the current edition of the IB. In this healthy adult nondependent recreational drug user with CNS 
depressant experience population, no beneficial effects are expected; however, this study will help 
evaluate the relative abuse potential of 3 different single dose levels of soticlestat compared with 
placebo and positive control alprazolam in humans and add further data to the profile of overall 
benefit-risk in DS and LGS. 
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To evaluate the relative abuse potential of soticlestat compared with placebo and alprazolam under 
fasted conditions in healthy adult nondependent recreational drug users with CNS depressant 
experience.
5.1.2
Secondary Objectives
To evaluate additional PD effects and safety of soticlestat compared with placebo and alprazolam 
under fasted conditions in healthy adult nondependent recreational drug users with CNS 
depressant experience.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 28 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Table 6.a
Schematic of Study Design
Screening 
Phase
Randomization to Sequence Q1 and Q2
Seque
nce
Qualification Phase
Randomization to Sequence 1 -10
Seque
nce b
Treatment Phasea
Follow-up 
Phase
within 28 
days of 
qualification 
phase
Day 1
Day 2
Period 1
Period 2
Period 3
Period 4
Period 5
Discharge
Treatment
Treatment
~7 ± 3 days 
after final 
dose given 
at the last 
treatment 
period
Q1
Alprazolam
Placebo
1
A
B
E
C
D
Q2
Placebo
Alprazolam
2
B
C
A
D
E
3
C
D
B
E
A
4
D
E
C
A
B
5
E
A
D
B
C
6
D
C
E
B
A
7
E
D
A
C
B
8
A
E
B
D
C
9
B
A
C
E
D
10
C
B
D
A
E
a Treatment description – treatment phase.
Treatment A: Soticlestat 300 mg.
Treatment B: Soticlestat 600 mg.
Treatment C: Soticlestat 900 mg.
Treatment D: Alprazolam 2 mg.
Treatment E: Placebo.
b Sequences are based on a Williams design (Williams 1949) (ie, uniform within sequences, unform within periods, and balanced with respect to first-order 
carryover effects). The specific sequences used here were calculated using the crossdes package (Package ‘crossdes,’ Construction of crossover designs, April, 
2022) in R (R Core Team [2021]. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria).
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 29 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Dose Rationale
This study is undertaken to assess the relative human abuse potential of a single dose of soticlestat 
at the highest proposed therapeutic level of 300 mg administered BID and supratherapeutic dose 
levels (600 and 900 mg). 
Three dose levels are chosen to determine dose response, if any. A supratherapeutic dose of 
600 and 900 mg will represent an adequate 2- and 3-fold difference from the highest proposed 
therapeutic dose level, respectively (FDA, Guidance for Industry Assessment of Abuse Potential 
of Drugs, January, 2017). 
The supratherapeutic dose levels of 600 and 900 mg also present >2- and >3-fold difference from 
the Cmax and area under the concentration-time curve (AUC) from time 0 to the last quantifiable 
concentration (AUClast) and from time 0 to infinity (AUC∞) than the highest proposed therapeutic 
dose level of 300 mg, respectively, as exposure of soticlestat generally increased more than dose 
proportionally from 200 to 1200 mg (oral tablets; TAK-935-1004 CSR). In the clinical setting 
soticlestat is administered as BID doses and no clinically meaningful accumulations were 
observed following multiple BID doses (accumulation ratio 1.05; TAK-935-1004 CSR).
In addition, measured CH24H enzyme occupancy increased with increasing dose and plateaued at 
200 mg single dose (approximately 93% at 2 hours; TAK-935-1003 CSR). The maximum enzyme 
occupancy was achieved at a 600 mg single dose, the highest dose tested in the study 
(approximately 96% at 2 hours). 
Soticlestat was safe and well tolerated when administered as a single dose up to 1350 mg 
(TAK-935-101 CSR). In vitro screening of soticlestat against a panel of more than 100 known 
molecular targets such as receptors, ion channels and enzymes revealed no relevant off-target 
activity at tested concentrations (3735 ng/mL [reports TAK-935-10077, 100054231 and 
OTI-20-21]) higher than the unbound Cmax concentration (Cmax,u) associated with a single 1350 mg 
dose [Cmax 7953 ng/mL (TAK-935-101 CSR); Cmax,u 2338 ng/mL assumes 70.6% bound 
(TAK-935-1005)]. 
6.2.2
Rationale for Active Comparator
Alprazolam 2 mg has been selected as the active comparator based on the following:

According to FDA guidance (US Department of Health and Human Services, FDA, Center for 
Drug Evaluation and Research (CDER): Assessment of Abuse Potential of Drugs, January 
2017), ideally, “the positive control should be an FDA-approved drug that is 
pharmacologically similar to the test drug and scheduled under the [Controlled Substances Act] 
CSA.”

Soticlestat is a novel compound that is not pharmacologically similar to any existing drugs of 
abuse. Although soticlestat may exert its pharmacological action through indirect effects on 
NMDA receptors, it did not generalize to ketamine in a rat drug discrimination study, 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 30 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
indicating that it does not share subjective similarities to ketamine, a prototypic NMDA 
receptor antagonist. For a compound with novel mechanism of action, such as soticlestat, FDA 
recommended an appropriate positive control of a depressant listed under schedule IV of the 
CSA (eg, a benzodiazepine). 

Soticlestat produced no abuse-like behavioral effects in rats or dogs, eg, excitation, 
hyperactivity, stereotypy, somnolence, sedation, or “wetdog” shakes, at doses ≤500 mg/kg 
(juvenile rats), ≤300 mg/kg (adult rats) or ≤30 mg/kg (dogs). In humans, acute and chronic 
administration of soticlestat in patients and healthy participants did not produce effects 
(ie, sedative, stimulant, mood-elevating, or hallucinogenic effects) consistent with those of 
abused drugs, even when administered at supratherapeutic doses. 

Overall, the data with soticlestat do not suggest any particular class of drugs of abuse as an 
ideal positive control; therefore, a benzodiazepine has been selected as a positive control, as 
these have some similarities in therapeutic effects to soticlestat (ie, anticonvulsant effects) and 
a similar potential general indication (ie, treatment of seizure disorders). 

Benzodiazepines, and more specifically alprazolam, has been used, as positive control, in a 
number of prior human abuse potential studies of anti-epileptic drugs with novel 
pharmacology (Levy-Cooperman et al. 2016; Schoedel et al. 2017; Schoedel et al. 2018a; 
Schoedel et al. 2018b).

Because of the flat dose-response observed with benzodiazepines on subjective measures such 
as Drug Liking (Levy-Cooperman et al. 2016), only 1 dose will be included in the current study. 
The 2 mg dose of alprazolam was selected because it has been used in previous human abuse 
potential studies mentioned above and is not expected to produce the sedation often observed 
with the higher 3 mg dose, which may interfere with the collection of subjective PD measures. 
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination (ET) of the study.

New information or other evaluation regarding the safety or PD of the study drug that indicates 
a change in the known risk/benefit profile for the compound, such that the risk/benefit profile 
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.
6.3.2
Criteria for Premature Termination or Suspension of Study Site
A study site may be terminated prematurely or suspended if the study site (including the 
investigator) is found in significant violation of GCP, protocol, or contractual agreement, is unable 
to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 31 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
ET or suspension will be provided by the sponsor; the procedure will be followed by the study site 
during the course of termination or study suspension.
6.3.4
Duration of an Individual Participant’s Study Participation
Participants who complete the study* will be in the study for approximately 11 weeks (including 
approximately 5 weeks (in the qualification and treatment phases).
This study includes: 

Screening phase of up to 4 weeks. 

Qualification phase (4 days). 

Treatment phase (5 periods with at least a 7 day washout between each period).†

Follow-up visit occurring 7 days after last treatment phase period and discharge from the CRU.
6.3.5
End of Study/Study Completion Definition
The end of the study for an individual participant is defined as the last protocol-specified contact 
with that participant. The overall end of the study is defined as the last protocol-specified contact 
with the last participant ongoing in the study.
6.4
Posttrial Access
Not applicable in this healthy participant study.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
All entry criteria, including test results, need to be confirmed before entry into the study.
7.1
Inclusion Criteria
Participant eligibility is determined according to the following criteria before entry into the study:
1. The participant is willing and able to understand and fully comply with study procedures and 
requirements (including digital tools and applications), in the opinion of the investigator.
2. The participant has provided written, signed, and dated informed consent and any required 
privacy authorization before the initiation of any study procedures.
3. The participant is 18 to 55 years of age, inclusive, at the screening visit.
                                               
* The site may extend the participant’s participation by extending the duration between qualification phase and 
Treatment phase to maximize site efficiency/scheduling.
† At minimum, there will be a 4-day washout between the qualification phase and the treatment phase.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 32 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
4. The participant is healthy as determined by the investigator. Healthy is defined as no clinically 
relevant abnormalities identified by a detailed medical history, complete physical examination, 
vital signs, 12-lead ECG, and clinical laboratory tests.
5. Participant is a current CNS depressant user who has used CNS depressants (eg,
benzodiazepines, barbiturates, zolpidem, eszopiclone, zopiclone, propofol/fospropofol, 
gamma-hydroxybutyrate) for recreational, nontherapeutic reasons at least 10 times in their 
lifetime and at least once in the 12 weeks before screening. Participant must also have 
recreational experience with at least 1 other drug class associated with abuse (eg, opioids, 
stimulants, cannabinoids, hallucinogens, dissociatives) at least 10 times in their lifetime.
6. The participant has a body mass index of 18.5 to 35.0 kg/m2, inclusive, and a minimum body 
weight of 50.0 kg at screening.
7. Female participants of childbearing potential (defined in Section 9.1.12.2) must have a 
negative pregnancy test at screening and agree to use an effective or highly effective method of 
birth control, as listed in Section 9.1.12.3, during the study and for 32 days following the last 
dose of study drug.
7.2
Exclusion Criteria
Any participant who meets any of the following criteria will not qualify for entry into the study: 
1. The participant has a self-reported history of drug or alcohol dependence (within the past 
1 year, except caffeine or nicotine, before the screening visit) as defined by the Diagnostic and 
Statistical Manual of Mental Disorders-IV text revision (DSM-IV-TR; [American Psychiatric 
Association, 2000]) and assessed by the investigator at screening visit or has ever participated 
in a treatment program or rehabilitation (lifetime) for alcohol or substance dependence (other 
than nicotine or caffeine).
2. The participant has a positive alcohol breathalyzer or urine drug screen (UDS) for substances 
of abuse at admission, excluding tetrahydrocannabinol (THC). If a participant presents with a 
positive UDS, excluding THC, the participant may be rescheduled to repeat the UDS and can 
only be admitted upon a negative UDS being obtained, excluding THC. Positive THC UDS 
will be permitted at admission as long as the participant is not impaired at admission, in the 
clinical judgment of the investigator. 
3. The participant is a heavy smoker or user of other types of nicotine products (>20 cigarettes 
equivalent per day).
4. The participant is unable to abstain from smoking for at least 2 hours before and at least 
8 hours after dosing. 
5. The participant consumes excessive amounts, defined as greater than 4 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
6. The participant has used any concomitant medications (including prescription and 
nonprescription medications, herbal remedies, or vitamin supplements) within 14 days (or 5 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 33 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
times the t1/2, if known) before the first study drug administration in the qualification phase and 
throughout the study. 
Exceptions include:
–
Thyroid hormone replacement medication may be permitted if the participant has been on 
the same stable dose for the immediate 3 months before first dosing in the qualfication 
phase.
–
Oral contraceptive is allowed if its use is consistent (ie, no change in oral contraceptives) 
throughout the study
7. The participant has used any drug known to be a significant inducer of cytochrome P-450 
(CYP) 3A, CYP2C19, uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 or UGT2B4 
enzymes, and/or P-glycoprotein (P-gp), including St. John’s wort, within 28 days before the 
first dose in the qualification phase. (Appropriate sources [eg, Flockhart Table] will be 
consulted to confirm lack of PK-PD interaction with study drug.)
8. The participant has received: 
–
An investigational drug within 5 × the known elimination t1/2, or, if the t1/2 is unknown, 
within 30 days of first anticipated study drug administration in the qualification phase. 
–
An investigational biologic product within 90 days before the first anticipated study drug 
administration in the qualification phase.
9. The participant took part in a previous soticlestat clinical study.
10. The participant has a history or current presence of any clinically significant medical 
conditions, which in the opinion of the Investigator would jeopardize the safety of the 
participant or the validity of the study results (eg, any major cardiovascular, pulmonary, 
hepatic, renal, hematologic, gastrointestinal, endocrine, ophthalmologic, immunologic, 
dermatologic, neurologic, oncologic, musculoskeletal, psychiatric disease [including an 
established diagnosis of an underlying psychotic illness], or clinical assessment abnormality 
[as found in physical examination, medical history, 12-lead ECG, vital signs, or clinical 
laboratory values]).
11. The participant has a history or presence of any of the following specific ECG abnormalities: 
–
Established QT prolongation.
–
Atrial fibrillation.
–
Long QT syndrome.
–
Torsades de pointes.
–
Bradyarrhythmia.
–
Uncompensated heart failure.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 34 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
–
Any 12-lead ECG with repeated demonstration of Fridericia-corrected QT interval (QTcF) 
≥470 msec in female participants, ≥450 msec in male participants, and/or a QRS interval 
≥120 msec at screening.
12. The participant has a family history (anamnesis or first degree relative with history) of 
unexplained sudden death or long QT syndrome. 
13. The participant has evidence of clinically significant hepatic or renal impairment including 
(but not limited to) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× 
the upper limit of normal (ULN), or clinically significant renal impairment as shown by 
estimated creatinine clearance < 80 mL/min (using the Cockcroft-Gault equation).
14. The participant has a history of severe allergic reaction (including anaphylaxis) to any food, 
medications, or bee sting, or a history of previous status asthmaticus.
15. The participant has a history of allergy or hypersensitivity to alprazolam or related drugs.
16. The participant tests positive for hepatitis B, hepatitis C, or HIV at the screening visit.
17. The participant has had any significant illness, of any nature, including coronavirus disease 
2019 (COVID-19) –related fever and symptoms, requiring hospitalization, emergency 
treatment, or isolation (community mandated quarantine) within 4 weeks before screening or 
during the study and as determined by the investigator. 
18. The participant has donated or lost more than 500 mL of whole blood within 30 days preceding 
anticipated entry into the treatment phase.
19. The participant is currently pregnant or breastfeeding.
20. The participant has any positive response on the C-SSRS or has a risk of suicide according to 
the investigator’s judgment based on the assessment of the C-SSRS or has made a suicide 
attempt in the previous 12 months.
21. The participant is considered unsuitable or unlikely to comply with the study protocol for any 
reason by the investigator.
7.3
Qualification Criteria (Applicable to Passing Qualification Phase)
Participants will be required to meet all of the following qualification criteria to be eligible to enter 
the treatment phase:
1. The participant continues to meet all of the inclusion criteria and none of the exclusion criteria 
above.
2. The participant satisfactorily completes the qualification phase.
3. On the assessment of drug liking (“at the moment” Drug Liking VAS): 
–
The participant’s Emax on “at the moment” Drug Liking VAS in response to alprazolam is 
numerically ≥15 points higher than that of placebo, and the participant has an Emax of ≥65 
points with alprazolam.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 35 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
–
The participant has an acceptable placebo response based on the Drug Liking VAS, 
defined as a Emax between 40 and 60 points (ie, a score considered neutral on the scale, 
meaning neither like nor dislike), inclusive.
–
The participant has acceptable overall responses to alprazolam and placebo on the 
subjective measures, as judged by the investigator or designee.
4. The safety data available following study drug administration suggest that the participant will 
be able to tolerate the alprazolam 2 mg dose planned for the treatment phase, as judged by the 
investigator, including no missing PD assessments within 4 hours of drug administration.
5. The participant's general behavior suggests that the participant could successfully complete the 
study, as judged by the investigator.
7.4
Excluded Medications
All nonstudy medications, including prescription, over-the-counter, herbal therapies, or vitamin 
supplements used by the participant will be documented for the 30 days before screening and 
throughout the study. The investigator will determine if the prior/concomitant medication(s) affect 
the participant’s eligibility to participate or continue to participate in the study. The following 
restrictions on concomitant medications will be in place during the study: 

The use of prescription drugs (except hormonal contraceptives and hormone replacement 
therapy), vitamins, or mineral supplements and natural health products (eg, herbal remedies) 
will be restricted for at least 14 days (or 5 times the t1/2 of the drug, if known) before first study 
drug administration in the qualification phase and throughout the study (exceptions include 
alprazolam administered as positive control and thyroid hormone replacement medication as 
long as the participant has been on the same stable dose for the immediate 3 months before the 
first study drug administration in the qualification phase).

The use of over-the-counter medications (except acetaminophen or ibuprofen) will be 
restricted for at least 14 days (or 5-times the t1/2 of the drug, if known) before first study drug 
administration in the qualification phase and throughout the study.

The use of investigational drugs will be restricted for 5 × the known t1/2 or, if the t1/2 is 
unknown, for 30 days, before the first anticipated study drug administration in the qualification 
phase and throughout the study. 

The use of investigational biologic products will be restricted for 90 days, before the first 
anticipated study drug administration in the qualification phase and throughout the study.

Any drugs known to be significant inducers of CYP3A, CYP2C19, UGT1A9, or UGT2B4 
enzymes and/or P-gp, including St. John’s wort, will be restricted within 28 days before the 
first study drug administration in the qualification phase and throughout the study. Appropriate 
sources (eg, Flockhart Table) will be consulted to confirm lack of PK/PD interaction with 
study drug.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 36 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
7.5
On-Study Restrictions
Participants will enter the study site the day before dosing (Day -1) of the qualification phase.
In addition to the inclusion/exclusion criteria, the participant must agree to abide by the study 
restrictions listed in Sections 7.5.1 and 7.5.2.
7.5.1
Alcohol and Drug Use

Participants will be asked to abstain from alcohol for 24 hours before each study visit. If a 
participant presents with a positive breath alcohol test at any visit after the screening visit, the 
participant may be rescheduled to repeat the breathalyzer test at the respective admission visit 
and can only be admitted upon a negative result being obtained.

Participants will be asked to abstain from recreational drug use/experience throughout the 
study, from screening until after the follow-up visit or ET. Abstinence will be confirmed via 
UDS (at screening, at admission [Day -1] to the qualification phase and at check-in for the 
treatment phase. (Note: If participant is released at investigator discretion from the clinic 
during the treatment phase [during washout], participant will be checked in again upon 
readmittance to the clinic for the next treatment period.)
–
If a participant presents with a positive UDS at screening, investigator may determine if the 
screening visit may continue that day or if it should be continued another day. In these 
cases, investigator may conduct a screening visit over multiple days. In these cases, ] at 
investigator discretion, screening procedures may be repeated.
–
If a participant presents with a positive UDS (excluding THC) at admission to the 
qualification phase, the participant will not be admitted but may, at the discretion of the 
investigator, repeat the UDS at a later date and be admitted to the qualification phase upon 
a negative UDS being obtained. (Note: In case of discharge between qualification phase 
and treatment phase same conditions apply.)
–
Positive THC UDS will be permitted at admission to the qualification phase as long as the 
participant is not impaired at admission, in the clinical judgment of the investigator. 
Participants will be advised that no THC use is permitted during the inpatient qualification 
or treatment phases.
7.5.2
Diet, Fluid, and Activity Control

Participants will be required to fast (abstain from food) for at least 8 hours before dosing and 
for at least 4 hours postdose on the day of dosing. Water will be permitted ad libitum except for 
approximately 1 hour before dosing and for approximately 1 hour postdose (except water 
provided with each dosing). Note: Study drug will be administered with approximately 240 ml 
of water. If additional water is needed for a participant to ingest the study drug, up to 50 ml of 
additional water may be provided.

Participants will be asked to abstain from strenuous physical activity for 48 hours before 
admission, and during inpatient stays at the study site.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 37 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL

Participants will be asked to abstain from the following foods from 1 week before admission to 
the qualification phase until after the follow-up visit or ET: 
–
Grapefruit, pomegranate, pomelo, and star fruit and their juices/products. 
–
Poppy seeds and Seville oranges and foods containing them (eg, orange marmalade). 
–
Drinks/foods containing quinine (eg, tonic water). 

Participants will be asked to refrain from blood donation from screening until 30 days after the 
last study drug administration.

Participants will be asked not to consume more 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 from 1 week before admission to the qualification phase until after the 
follow-up visit or ET. Participants will not be permitted to consume caffeine-containing 
beverages during inpatient stays at the study site. 

Participants will be required to abstain from smoking or vaping for at least 2 hours before and 
8 hours after dosing on the day of dosing in the inpatient qualification phase and treatment 
phase sequences. Smoking or vaping will be permitted at short breaks after at least the 8-hour 
postdose procedures, at the discretion of the study site staff. Participants will not be permitted 
to use other nicotine-containing products (including nicotine topical patches, nicotine gum, or 
nicotine lozenges) during the inpatient periods.

Participants will be required to follow the informed consent form (ICF) and the clinic code of 
conduct.
7.6
Criteria for Discontinuation or Withdrawal of a Participant
A participant is free to withdraw his/her consent and discontinue participation in the study at any 
time for any reason. 
The primary reason for discontinuation or withdrawal of the participant from the study or study 
drug should be recorded in the electronic case report form (eCRF) using the categories listed below. 
For screen failure participants, refer to Section 9.1.14.

Withdrawal by participant.

Withdrawal of consent.

Failure to meet continuation criteria.

Protocol violation:
–
Noncompliance with study drug or study schedule.
–
Use of unacceptable concomitant medication(s).
–
Use of prohibited substances (positive THC UDS will be permitted at admission to the 
qualification phase as long as the participant is not impaired at admission, in the clinical 
judgment of the investigator).
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 38 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
–
Other major protocol violation.

AE.

Physician decision.

Pregnancy.

Study terminated by sponsor or study site terminated by sponsor.

Lost to follow-up.

Other.
The investigator must maintain a record of all participants who discontinue from the study before 
completion; the reason(s) for study discontinuation will be documented. In the event that a 
participant chooses to withdraw from the study, the investigator should make a reasonable attempt 
to obtain and record the reason(s) for withdrawal, if possible, although the participant is not 
obligated to provide such a reason. 
In the event that a participant is discontinued while at the study site, the ET procedures shown in 
 should be performed before discharge from the 
study site. For any case of early discontinuation (whether or not the participant is at the study site), 
the investigator should ask the participant to participate in the follow-up visit procedures, provided 
that the participant has not withdrawn consent for those procedures. If a participant refuses to 
complete ET and/or the follow-up procedures, this information will be recorded.
7.7
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 discontinuation criteria described in Section 7.6. In addition, 
a participant may discontinue his or her participation without giving a reason at any time during 
the study. Should a participant’s participation be discontinued, the primary criterion for 
termination must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the ET visit. 
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling of Study Drug
In this protocol, the term study drug refers to all or any of the drugs defined below.
Investigational product: soticlestat 300, 600, or 900 mg orally administered via 100 mg immediate 
release tablets or matching placebo.
Reference therapy: overencapsulated alprazolam 2 mg or matching placebo.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 39 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Study drug will be administered in a double-blind, double-dummy manner with the oral doses of 
soticlestat or matching placebo and overencapsulated alprazolam 2 mg or matching placebo 
administered at each treatment period in the treatment phase. 
The sponsor will supply study site(s) with soticlestat (TAK-935) 100 mg tablets, and placebo for 
match 100 mg tablets. Soticlestat 300 mg tablets may be used instead of 100 mg if bioequivalence 
is demonstrated in an ongoing BE study TAK-935-1014.‡
Study drug will be supplied in high-density polyethylene bottles with induction seal and 
child-resistant caps. Each bottle will contain a label that includes pertinent study information and 
caution statements. For more information on the study drug, please see the study pharmacy 
manual.
Soticlestat clinical study material will be labeled according to the country’s regulatory 
requirements. Soticlestat and placebo will be provided in open-label configuration, and unblinded 
study site staff will prepare blinded dosing before administration to participants.
Alprazolam 2 mg and matching placebo will be compounded and supplied for use in this protocol. 
Instructions for preparation of overencapsulated alprazolam 2 mg and matching placebo can be 
found in the pharmacy manual.
8.1.2
Storage
Sponsor-supplied study drug must be kept in an appropriate, limited-access, secure place until it is 
dispensed or returned to the sponsor or designee for destruction. Study drug must be stored under 
the conditions specified on the label and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every day.
Please refer to the pharmacy manual for additional information related to the study drug. In 
instances where the protocol and pharmacy manual text conflict, the pharmacy manual text shall 
supersede the text in the protocol.
Site staff should follow their internal processes for managing, storing and dispensing 
controlled-substances.
8.1.3
Dose and Regimen
Route of administration: oral.
Dose regimen: single dose, once on Day 1 of each treatment period.
Duration of evaluation and treatment: Participants who complete the study will be in the study for 
approximately 11 weeks (including approximately 5 weeks in the qualification and treatment 
phases combined).
This study includes: 

Screening phase of up to 4 weeks. 
                                               
‡ Protocol will be updated accordingly.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 40 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL

Qualification phase (4 days).

Treatment phase (5 periods with 7-day washout between each study drug administration).§

Follow-up visit occurring 7 days after last treatment period and discharge from the CRU.
Table 8.a describes the dose and tablet/capsule count that will be provided to each group.
Table 8.a
Treatment Description
Treatment
Soticlestat 
(100 mg)
Placebo for Soticlestat 
(100 mg) a
Alprazolam b
(2 mg)
Placebo for Alprazolam 
(2 mg) c
Number of Tablets/capsules
A
3 
6
0
1
B
6 
3
0
1
C
9 
0
0
1
D
0
9
1
0
E
0
9
0
1
a Placebo that matches 100 mg soticlestat tablets. 
b Overencapsulated alprazolam.
c Placebo that matches overencapsulated alprazolam 2 mg. 
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study participant, at a dose above that which is assigned to that individual participant according to 
the study protocol. 
Note: Because of the double-blind nature of the study, any additional tablets or capsules ingested 
at a dosing event will be considered an overdose during the period in which the study is blinded. 
Investigator to refer to Section 8.5 for decisions regarding unblinding for medical treatment.
All cases of overdose (with or without associated AEs) will be documented. Cases of overdose 
without manifested signs or symptoms are not considered AEs. AEs associated with an overdose 
will be documented on AE eCRF(s) according to Section 10.0.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.1.4.
In the event of drug overdose, the participant should be treated symptomatically.
                                               
§ At minimum, there will be a 4-day washout between the qualification phase and the treatment phase.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 41 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
8.2
Study Drug Assignment and Dispensing Procedures
8.2.1
Assignment of Participant Identification Number
A unique 8-digit participant identification number (participant number) will be assigned to each 
participant at the time that informed consent is explained; this participant number will be used 
throughout the study.
8.2.2
Study Drug Assignment
Each participant will be assigned a treatment sequence in each double-blind phase 
(ie, 1 qualification phase and 1 treatment phase), in accordance with the randomization schedule 
(refer to Section 6.1).
Refer to the study manual for details concerning sample tracking.
8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization 
table/schedule and will provide it to the unblinded study site staff (eg, pharmacist) before the start 
of the study. All randomization information will be stored in a secured area, accessible only by 
authorized personnel.
The qualification phase of this study will be double-blind. The treatment phase of the study will be 
double-blind and double dummy; the investigator and participants are blinded to treatment 
assignment. The study drug will be provided to the site as soticlestat 100 mg tablets and matching 
placebo tablets in an unblinded manner. Blinding of treatment will be performed by the unblinded 
study site staff.
8.4
Study Drug Blind Maintenance 
The study drug blind is maintained through a randomization schedule held by the dispensing 
pharmacist. The study drug blind will be maintained for persons responsible for the ongoing 
conduct of the study (monitors, investigators, etc) and those responsible for data analysis and 
interpretation of results at the conclusion of the study, such as biometrics personnel. The treatment 
phase blind shall not be broken by the investigator unless information concerning the study drug is 
necessary for the medical treatment of the participant. The sponsor or designee must be notified as 
soon as possible if the blind is broken.
Since the maintenance of the blind may be compromised because of results from drug 
concentrations and/or pharmacodynamics assessments, such results should not be disclosed before 
blind breaking. In the event that results must be reported to the investigator before breaking the 
blind, all efforts should be made to maintain the blind (eg, as changing a medication identification 
number in order to avoid identification of participants by the laboratory site personnel).
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 42 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
8.5
Unblinding Procedure
If the participant is found to be not eligible for the qualification phase, the investigator should 
record the primary reason for failure on the applicable eCRF.
A group of participants that start the qualification phase on the same day will be considered a 
cohort for unblinding purposes. Upon completion of each qualification phase cohort, the 
randomization codes for these participants will be unblinded (site), and the eligibility of 
participants to participate in the treatment phase will be assessed as described in Section 7.3.
Any other instance of unblinding should only be considered for the safety of the participant. The 
study drug blind shall not be broken by the investigator unless information concerning the study 
drug is necessary for the medical treatment of the participant. All study assessments and causality 
assessment should be performed, if possible, before unblinding. In the event of a medical 
emergency, if possible, the medical monitor and the Takeda trial clinician should be contacted 
before the study drug blind is broken to discuss the need for unblinding. If unblinding is deemed 
necessary by the investigator, the investigator can unblind the participant’s treatment allocation by 
contacting the dispensing pharmacist.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the source documents and the same information 
(except the time) must be recorded on the eCRF.
If any study site personnel are unblinded, study drug must be stopped immediately and the 
participant must be withdrawn from the study. 
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the study site before being returned to the sponsor 
or designee, or destroyed by the site where allowed by institutional process and as per sponsor 
instructions. Any remaining supplies there were purchased by site will be destroyed, as appropriate, 
by the site.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to participants enrolled in the study. To document appropriate 
use of sponsor-supplied drug (soticlestat tablets or matching placebo), the investigator or designee 
must maintain records of all sponsor-supplied drug delivery to the study site, study site inventory, 
dispensation and use by each participant, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by signing bottom half of the packing list and 
emailing as per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Takeda must be contacted to resolve the issue. The 
packing list should be filed in the investigator’s essential document file.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 43 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
(soticlestat and matching placebo) received and dispensed during his or her entire participation in 
the study. Proper drug accountability includes, but is not limited to, the following requirements:

If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.

The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(soticlestat) on a sponsor-approved drug accountability log. 

All study drug not returned to the study site by a participant must be investigated by the study 
site and appropriately documented on the drug accountability log.

Before study site closure or at appropriate intervals, a representative from the sponsor or its 
designee will perform sponsor-supplied drug accountability and reconciliation before 
sponsor-supplied drugs are returned to the sponsor or its designee for destruction. Destruction 
may be completed by the study site after full accountability is completed with sponsor 
preapproval. The study site must have destruction procedures in place and be able to supply a 
“Certificate of Destruction” or similar document. The investigator or designee will retain a 
copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.

The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the 
study site must complete all instructions outlined in the notification, including segregation of 
expired sponsor-supplied drug for return to the sponsor or its designee for destruction.

In the event of expiry date extension of sponsor-supplied drug already at the study site, sponsor 
supplied drugs may be relabeled with the new expiry date at that study site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the study site.
9.0
STUDY PLAN 
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
participants are to be assessed by the same investigator or study site personnel whenever possible. 
9.1.1
Informed (e)Consent Procedure
Informed electronic or written consent ([e]consent) must be obtained before the participant enters 
into the study and before any protocol-directed procedures are performed.
A unique participant identification number (participant number) will be assigned to each 
participant at the time that informed (e)consent is obtained; this participant number will be used 
throughout the study.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 44 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Participants consenting via (e)consent, where available, will electronically sign consent forms 
(paper consent forms will be used instead if required by local regulations).
(e)consent provides the same information as written consent forms, but in an electronic format that 
may include multimedia components. (e)consent does not replace the important discussion 
between the participants and study site staff or investigator. Regardless of the consent 
format—written or (e)consent—the study site is responsible for the consenting process. The 
requirements of informed consent are described in Section 15.2.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, and 
race as described by the participant at screening.
Medical history to be obtained will include determining whether the participant has any significant 
conditions that resolved at or before signing informed consent. Ongoing conditions are considered 
concurrent medical conditions (see Section 9.1.10).
Any medication relevant to eligibility criteria and efficacy/safety evaluation stopped at or within 6 
months before signing of informed consent will be obtained. 
9.1.3
Weight and Height
Weight and height will be measured while the participant is wearing indoor clothing and with 
shoes off. If unable to obtain height or weight, data may be collected from other sources 
(eg, medical records). The investigator must record in the source document the reason for not 
obtaining height or weight (eg, the participant is in a wheelchair).
The values should be reported to 1 decimal place by rounding. 
9.1.4
Vital Sign Procedure
The following vital signs will be recorded 
: systolic and 
diastolic blood pressure (mm Hg), pulse rate (beats/minute), respiratory rate (breaths/minute), and 
temperature (°C or °F). If clinically significant vital sign changes from screening/baseline are 
noted, the changes will be documented as AEs in the AE eCRF. Screening/baseline events will be 
documented in the medical history eCRF. Clinical significance is defined as any variation in vital 
signs that has medical relevance and may result in an alteration in medical care. The investigator 
will continue to monitor the participant until the parameter returns to baseline or until the 
investigator determines that follow-up is no longer medically necessary.
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
9.1.5
ECG Procedure
For each participant, 12-lead digital ECGs will be collected 
 
 Participants must be supine for approximately 5 minutes before ECG 
collection and remain supine but awake during ECG collection.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 45 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
ECGs may be obtained at additional times, when deemed clinically necessary. Collection of more 
ECGs (more replicates) than expected at a particular time point is allowed, when needed to ensure 
high-quality recordings.
ECGs will initially be interpreted by a qualified physician (the investigator or qualified designee) 
at the study site as soon as possible after the time of ECG collection, and ideally while the 
participant is still present at the study site, to determine whether the participant meets entry criteria 
at the relevant visit(s) and for immediate participant management, should any clinically relevant 
findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT interval from baseline 
or other clinically significant quantitative or qualitative change from baseline is identified, the 
participant will be assessed by the investigator for symptoms (eg, palpitations, near syncope, 
syncope) and to determine whether the participant can continue in the study, and the medical 
monitor or the sponsor should be contacted. The investigator or qualified designee is responsible 
for determining if any change in participant’s management is needed and must document his/her 
review of the ECG printed at the time of evaluation from at least 1 of the replicate ECGs from each 
time point.
Any clinically significant finding that was not present at baseline will be reported and discussed 
with the medical monitor or the sponsor. When there are differences in ECG interpretation 
between the investigator (or qualified designee) and the study site/local cardiologist, the 
investigator (or qualified designee’s) interpretation will be used for study entry and immediate 
participant management. The investigator (or qualified designee) must document his/her review of 
the ECGs printed at the time of collection.
9.1.6
Physical Examination Procedure
A physical examination will be performed 
. A full 
examination will include the following assessments: eyes; ears; nose; throat; cardiovascular 
system; respiratory system; gastrointestinal system; dermatologic system; musculoskeletal system; 
extremities; nervous system; lymph nodes; and other.
If clinically significant changes from screening/baseline are noted, the changes will be 
documented as AEs in the AE eCRF. Screening/baseline events will be documented in the medical 
history eCRF. Clinical significance is defined as any variation in physical findings that has 
medical relevance and may result in an alteration in medical care. The investigator will continue to 
monitor the participant until the parameter returns to baseline or until the investigator determines 
that follow-up is no longer medically necessary.
9.1.7
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of these 
procedures and specimen handling will be given in the laboratory manual. 
Table 9.a lists the tests that will be obtained for each laboratory specimen.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 46 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Erythrocytes
Hemoglobin
Hematocrit
Red blood cell indices
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Red cell distribution width
White blood cell count and differential
Neutrophils, segmented
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Mean platelet volume
Sodium
Potassium
Total bilirubin
Direct bilirubin
Indirect bilirubin
Alkaline phosphatase
ALT
AST
Gamma glutamyl transferase (-)
Blood urea nitrogen
Creatinine a
Urea
Calcium
Phosphate
Glucose
Albumin
Protein
Carbon dioxide
Magnesium
Chloride
Alpha 1-acid glycoprotein (baseline only) b
pH
Protein
Glucose
Ketones
Bilirubin
Erythrocytes
Leukocyte esterase
Nitrite
Urobilinogen
Calcium
Calcium/creatinine
Microscopy c
Swab test
Severe acute respiratory syndrome coronavirus 2 
Other Serum
HIV
Hepatitis B virus surface antigen
Hepatitis B core antibody
Hepatitis C virus antibody
Female participants only:
Beta human chorionic gonadotropin, for pregnancy (WOCBP only)
FSH, if menopause is suspected
Other Urine
UDS for alcohol, if available or a breath test, amphetamines, barbiturates, benzodiazepines, buprenorphineand/or 
metabolite, cannabinoids/THC, cocaine and/or metabolites, 3-methoxy-4,5-methylenedioxyamphetamine, 
methadoneand/or metabolite, opiates, oxycodone and/or oxymorphone, phencyclidine. Note: for any UDS after taking 
the first dose of study drug exclude benzodiazepines. 
Female participants only:
Beta human chorionic gonadotropin, for pregnancy (WOCBP only)
ALT: alanine aminotransferase: AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; THC: 
tetrahydrocannabinol; UDS; urine drug screen; WOCBP: women of child-bearing potential.
a Site to calculate the creatinine clearance only at screening visit for inclusion criteria.
b Collected at baseline; however, results are not required to assess participant eligibility. 
c 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.
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 48 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
The list of excluded medications is provided in Section 7.4.
9.1.9
Documentation of Substance Use History
A history of all drugs used for recreational/nonmedicinal purposes (ie, psychoactive effects) in the 
past 2 years will be collected. History, including drug preference (ie, drug of choice) and 
frequency of use (ie, average number of uses per week before screening) and date/time of last use, 
will be collected using reported drug names, by drug class (eg, cannabinoids, depressants, 
dissociative anesthetics, hallucinogens, opioids and morphine derivatives, stimulants). 
A history of alcohol use (ie, average number of drinks [beer [354 mL/12 oz], wine [118 mL/4 oz], 
or distilled spirits [29.5 mL/1 oz]] per week and number of occasions of binge drinking [more than 
3 drinks/5 drinks in a sitting for female/male participants]) in the 6 months before screening and 
smoking (smoker/non-smoker, if smoker, number of cigarettes per day) will also be collected.
DSM-IV-TR modules will be included as a part of the recreational drug/alcohol use history and 
used to screen for alcohol and substance dependence.
9.1.10
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of the ICF. These include clinically significant laboratory, ECG, or physical 
examination abnormalities noted at Visit 1, according to the judgment of the investigator. The 
condition (ie, diagnosis) should be described and recorded in the eCRF.
9.1.11
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed by use of the C-SSRS. The C-SSRS is a 3-part 
scale that measures suicidal ideation (eg, participant endorses thoughts about a wish to be dead or 
has other thoughts of suicide), intensity of ideation (frequency), and suicidal behavior (actually, 
interrupted, and aborted attempts at suicide) (Posner et al. 2011).
The versions of the C-SSRS used for all participants in this inpatient study will be the 
screening/baseline and Since-Last-Visit C-SSRS. When administering the screening/baseline 
version, both lifetime and within the last 12 months will be assessed. 
Study staff trained in the administration of the C-SSRS will assess participant suicidality using the 
C-SSRS. Ultimately, the determination of the presence of suicidal ideation or behavior depends on 
the clinical judgment of the investigator.
If a participant exhibits signs of suicidal ideation or behavior as per the clinical judgement of the 
investigator, the participant will be withdrawn from the study as described in Section 7.7. With the 
identification of positive symptoms of depression and suicidal ideation, the participant will be 
referred for professional psychiatric assessment and necessary follow-up.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 49 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
9.1.12
Contraception and Pregnancy Avoidance Procedure
9.1.12.1
Male Participants and Their Female Partners
Male participants who participate in the study are not required to use barrier contraception. 
Donation of sperm is not allowed during the study and within 90 days following the last 
administration of the study drug.
9.1.12.2
Female Participants and Their Male Partners
Pregnancy testing at screening, admission to the qualification phase (before receiving any study 
drug), admission to the treatment phase, and the participant’s last clinic visit will be processed 
using the local laboratory. Additional pregnancy tests (serum or urine) may be performed 
throughout the study at the investigator’s discretion. 
Please refer to Section 7.1 for inclusion criteria for detailed contraception requirements.
The following definitions apply for contraception and pregnancy avoidance procedures.
A woman is considered a woman of child-bearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy, 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 postmenopausal state in younger women (eg, those <45 
years 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.
Female participants of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at screening and at the end of treatment They must have a 
negative urine hCG pregnancy test before dosing on Day -1 of the qualification phase and on the 
day preceding each dose in the treatment phase 
 for subjects who are discharged 
during washout. If urine cannot be collected at the specified visit, the reason should be documented 
in the source document. The results of the serum pregnancy test obtained at screening must be 
confirmed to be negative by the investigator before receiving study drug. During the course of the 
study, participants will receive continued guidance with respect to the avoidance of pregnancy and 
ova donation as part of the study procedures (not allowed within 32 days of the last dose). An 
additional serum or urine hCG pregnancy test will be performed at the final visit.
9.1.12.3
Contraceptive Methods for Female Participants of Childbearing Potential

Effective contraceptive methods include the following:
–
Double-barrier method (contraceptive sponge, diaphragm, or cervical cap with spermicidal 
jellies or creams PLUS male condom).
–
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, PLUS condom with or without spermicide.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 50 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL

Highly effective contraceptive methods include the following:
–
Nonhormonal Methods:
a) IUD (intrauterine device).
b) Bilateral tubal occlusion or bilateral tubal ligation or vasectomized partner (provided 
that partner is the sole sexual partner of the trial participant and that the vasectomized 
partner has received medical assessment of the surgical success).
c) Sexual abstinence: Sexual abstinence may be considered as a method only if defined as 
refraining from heterosexual intercourse and determined to be the usual lifestyle before 
entering the study with reliability of abstinence for the duration of the study 
participation and for 32 days after last dose of study drug.

Hormonal methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with inhibition 
of ovulation initiated at least 3 months before the first dose of study drug OR combined 
with a barrier method (male condom, female condom or diaphragm) if for shorter duration 
until she has been on contraceptive for 3 months.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation initiated 
at least 3 months before the first dose of study drug OR combined with a barrier method 
(male condom, female condom or diaphragm) if shorter until she has been on the 
contraceptive for 3 months.
9.1.12.4
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Assessment of participants compliance through such questions as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late? (Even in women with irregular or infrequent menstrual cycles, a 
pregnancy test must be performed if the answer is “yes.”)
–
Is there a chance you could be pregnant?
9.1.13
Pregnancy
If any participants is found to be pregnant during the study, she should be withdrawn immediately 
and the study 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.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 51 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
If the pregnancy occurs during administration of active study drug, or within 90 days of the last 
dose of active study drug, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 1.1.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the participant of their right to receive treatment information. If the participant chooses to 
receive unblinded treatment information, the individual blind should be broken by the investigator. 
Participants randomized to placebo need not be followed.
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 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.
9.1.14
Documentation of Screen Failure
Investigators must account for all participants with a signed informed consent. If the participant is 
found to be ineligible for the study before randomization, the investigator should record the 
primary reason for screen failure in the eCRF.
Participants may be rescreened after consultation with the medical monitor or sponsor.
The primary reason for screen failure is recorded in the eCRF using the following categories:

Pretreatment events (PTE)/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Withdrawal by participant.

Study terminated by sponsor.

Other (specify reason).
9.1.15
Documentation of Entry Into the Qualification Phase
Only participants who meet all of the inclusion criteria (Section 7.1) and none of the exclusion 
criteria (Section 7.2) are eligible for entrance into the qualification phase.
If the participant is found to be not eligible for the qualification phase, the investigator should 
record the primary reason for failure on the applicable eCRF;
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 52 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
The primary reason for qualification failure is recorded in the eCRF using the following 
categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Did not meet qualification criteria (specify reason)

Significant protocol deviation.

Lost to follow-up.

Withdrawal by participant.

Study terminated by sponsor.

Other (specify reason).
9.1.16
Documentation of Entry Into the Treatment Phase
Participants who meet the criteria in Section 7.3 will be randomized to 1 of the 10 sequences in the 
treatment phase (Section 6.1).
If the participant is found to be not eligible for the treatment phase, the investigator should record 
the primary reason for failure on the applicable eCRF.
9.2
Safety Monitoring
The sponsor’s medical monitor and/or pharmacovigilance physician will monitor safety data 
throughout the course of the study.
9.2.1
Reporting of Abnormal Liver Function Tests
If participants experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a 
minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was noted. (Refer to Section 7.6 and Section 10.2.1 for the appropriate guidance participant 
discontinuation and on reporting AEs.)
If a participant is noted to have elevated ALT or AST >3 times the ULN on 2 consecutive 
occasions, the abnormality should be recorded as an SAE. In addition, eCRFs must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed. The investigator must contact 
the medical monitor for discussion of the relevant participant details and possible alternative 
etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.1).
If a participant is noted to have ALT or AST >3 × the ULN, and total bilirubin >2 × the ULN or 
INR >1.5, for which an alternative etiology has not been identified, a CRF must be completed and 
transmitted with the SAE report form (as per Section 10.2.2). The investigator must contact the 
medical monitor for discussion of the relevant participant details, possible alternative etiologies, 
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 54 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
participants who appear to have difficulty differentiating between bipolar and unipolar VAS (eg, 
making errors such as selecting 50 as neutral for a unipolar scale) or difficulty distinguishing 
between “at this moment” and “next-day” measures during the qualification phase will undergo 
additional practice training on the difference between the scale types. Additional training sessions 
will be documented in source files.
Testing conditions for PD assessments should remain as consistent as possible across the study. 
Participants will be monitored carefully to ensure that they are completing the PD assessments 
appropriately; all reasonable attempts should be made to rouse participants who fall asleep during 
testing cycles.
9.4.1
Subjective Effects VASs
All VAS will be scored on a 100-point scale, as shown in Table 9.b. The VAS may be administered 
as bipolar or unipolar scales, as appropriate, and the choice is determined by the nature of the 
subjective effect being measured. When VAS are administered as bipolar scales, the neutral point 
equals 50 (Drug Liking, Overall Drug Liking, Take Drug Again, Alertness/Drowsiness VAS). The 
neutral point will also be labeled with an anchor, such as “neither like nor dislike.” When VAS are 
administered as unipolar scales, the neutral point equals 0, and anchors will be presented using text 
such as “Not at all” (score = 0) to “Extremely” (score = 100; eg, Good, Bad, High, and Any Effects 
VASs). Scales that refer specifically to drug (eg, Drug Liking, Good Effects VAS, Bad Effects 
VAS, and Any Effects VAS) are not administered predose.
For non-commercial use only


For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 57 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Participants eligible for the treatment phase of the study will be randomized to receive orally 
administered treatments (1 in each of 5 treatment periods) as shown in Section 6.1. The exact date 
and time of the study drug administration will be recorded in the eCRF. Participants will remain in 
the CRU for at least 24 hours after the last dose of the final period, then be discharged and 
scheduled for the follow-up procedures. After the first study treatment in the treatment phase, there 
will be a washout interval of at least 7 days before the subsequent study drug administration.
9.5.4
Follow-up (Final Visit or ET)
The final visit (can be a phone call) will be study Day 37 (7 days ±3 days following Day 1 of 
treatment period 5, which is the last dosing day in the study) or 7 days (±3 days) following the ET 
visit. 
For all participants receiving study drug, the investigator must complete the end of study eCRF 
page.
10.0
ADVERSE EVENTS
10.1
Definitions
In this study, AEs refers to both PTEs and TEAEs. PTEs are AEs that started before receiving any 
study drug. TEAEs are AEs that started after the first study drug administration.
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation participant who 
has signed informed consent to participate in a study but before administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
TEAEs
A TEAE is defined as any untoward medical occurrence in a clinical investigation participant who 
has been administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
A TEAE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
10.1.3
Additional Points to Consider for AEs

An untoward finding generally may:
–
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)
–
Necessitate therapeutic intervention.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 58 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
–
Require an invasive diagnostic procedure.
–
Require discontinuation or a change in dose of study drug or a concomitant medication.
–
Be considered unfavorable by the investigator for any reason.

AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as AEs.

Diagnoses versus signs and symptoms:
–
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).

Laboratory values and ECG findings:
–
Changes in laboratory values or ECG findings are only considered to be 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 or ECG re-test and/or continued monitoring of an abnormal value or finding 
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 serum creatinine in renal failure), the diagnosis only 
should be reported appropriately as an AE.

Pre-existing conditions:
–
Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. However, if the 
participant experiences a worsening or complication of such a concurrent medical 
condition, the worsening or complication should be recorded appropriately as an AE 
(worsening or complication occurs after start of study drug). 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 concurrent medical condition (eg, asthma, 
epilepsy), any occurrence of an episode should only be captured as an AE if the condition 
becomes more frequent, serious or severe in nature. Investigators should ensure that the AE 
term recorded captures the change in the condition from baseline (eg “worsening of…”).
–
If a participant has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as an AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE 
term recorded captures the change in the condition (eg, “worsening of…”).
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 59 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL

Worsening of AEs:
–
If the participant experiences a worsening or complication of an AE after any change in 
study drug, 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 intensity of AEs:
–
If the participant experiences changes in intensity of an AE, the event should be captured 
once with the maximum intensity recorded.

Preplanned procedures (surgeries or interventions):
–
Preplanned procedures (surgeries or therapies) that were scheduled before 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 recorded 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. Note: Because of the 
double-blind nature of the study, any additional tablets or capsules ingested at a dosing 
event will be considered an overdose during the period in which the study is blinded. 
Investigator to refer to Section 8.5for decisions regarding unblinding for medical 
treatment.All cases of overdose (with or without associated AEs) will be documented on an 
overdose page of the eCRF, 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.
–
SAEs of overdose should be reported according to the procedure outlined in Section 10.2.
–
In the event of drug overdose, the participant should be treated symptomatically.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 60 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
10.1.4
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. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
10.1.5
Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the participant.
Moderate:
The event causes the participant discomfort and interrupts the participant’s usual activities.
Severe:
The event causes considerable interference with the participant’s usual activities.
10.1.6
Causality of AEs
The relationship of each AE to study drug(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 possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments.
10.1.7
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 61 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
10.1.8
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the participant 
and/or investigator.
10.1.9
Stop Date
The stop date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae, or the participant died.
10.1.10
Frequency
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.1.11
Action Concerning Study Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE (eg, the 
study has been terminated, the participant died, dosing with study drug was already stopped 
before the onset of the AE).

Dose interrupted – the dose was interrupted due to the particular AE.
10.1.12
Outcome

Recovered/resolved – participant returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
sign/symptom has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to baseline; the participant died from a cause other than the 
particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, sign/symptom, or laboratory value on the last day of the observed 
study period is 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.”

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 – the AE is considered as the cause of death.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 62 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the participant’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
AE Collection Period
Collection of AEs will commence from Visit 1. Routine collection of AEs will continue until the 
follow-up visit.
10.2.1.2
AE Reporting
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.
All participants experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until a satisfactory explanation for the changes is 
observed. All AEs will be documented in the AE page of the eCRF, whether or not the investigator 
concludes that the event is related to the drug treatment. The following information will be 
documented for each event:
1. Event term.
2. Start and stop date and time.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug.
8. Outcome of event.
9.
Seriousness.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure:

A sponsor 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.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 63 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL

Regardless of causality, SAEs must be reported to the sponsor Global Pharmacovigilance 
department or designee, to the attention of the contact listed in Section 1.1, within 24 hours of 
becoming aware of the event. This will be done by transmitting an electronic data capture 
(EDC) SAE report. If transmission of an EDC SAE report is not feasible within 24 hours, then 
a facsimile of the completed paper-based SAE form should be sent. If SAEs are reported via 
fax or by email, EDC must be updated as soon as possible with the appropriate information.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
10.3
Follow-up of SAEs
If information 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 
transmit 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.
10.3.1
Safety Reporting to Investigators, IRBs, 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 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 to the regulatory authorities as expedited report 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 a study drug/sponsor supplied drug or 
that would be sufficient to consider changes in the study drug/sponsor-supplied drug 
administration or in the overall conduct of the trial. The study site also will forward a copy of all 
expedited reports to his or her IRB.
10.3.2
Reporting of Abnormal Liver-Associated Test Results 
For any participant with ALT >3 × ULN AND total bilirubin >2 × ULN OR INR >1.5 × ULN for 
which an alternative etiology has not been found, report the event as an SAE, contact the medical 
monitor and Takeda trial clinician within 24 hours, and follow the additional monitoring, 
evaluation, and follow-up recommendations in Appendix D.
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 64 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan.
AEs and concurrent medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Drugs will be coded using the WHO Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each participant who signs an ICF.
The sponsor or its designee will supply study site with access to eCRFs. The sponsor will make 
arrangements to train appropriate study site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
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 study site.
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
After submission of the eCRFs to the sponsor, any change to, modification of, or addition to the 
data on eCRFs should be made by the investigator with use of change and modification records of 
eCRFs (data clarification form) provided by the sponsor. The investigator must review the data 
clarification form for completeness and accuracy, and must sign and date the form.
After the lock of the study database, any change to, modification of, or addition to the data on the 
eCRFs should be made by the investigator with the approval from the sponsor. The investigator 
must review the data change for completeness and accuracy, and must sign and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. 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 eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, medical records, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated informed (e)consent forms, ICFs, participant 
authorization forms regarding the use of personal health information (if separate from the ICFs), 
including consent to use digital tools and applications, if applicable, electronic copy of eCRFs, 
including the audit trail, and detailed records of drug disposition to enable evaluations or audits 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 65 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
from regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the study site and filed with the 
original in the participant’s chart to ensure long term legibility. Furthermore, International Council 
for Harmonisation (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 study site 
agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized before unblinding of treatment 
assignments. This document will provide further details regarding the definition of analysis 
variables and the statistical analysis methodology to address all study objectives.
13.1.1
Analysis Sets

Qualification randomized analysis set: All participants who are randomized in the qualification 
phase.

Randomized analysis set: All participants who are randomized in the treatment phase.

Qualification safety analysis set: All participants who receive at least 1 dose of study drug (ie, 
placebo or alprazolam) in the qualification phase. All safety evaluations in the qualification 
phase will be performed using this analysis set.

Safety analysis set: All participants who receive at least 1 dose of study drug in the treatment 
phase. All safety evaluations in the treatment phase will be performed using this analysis set.

Completer analysis set: All participants in the randomized analysis set who complete all 
treatment periods of the treatment phase and have at least 1 response on the VAS for Drug 
Liking “at this moment” within 2 hours postdose (hence within approximately 2 hours of 
historical time of first occurrence of Cmax [tmax] of soticlestat and alprazolam) for each 
treatment. This analysis set may be used for supportive PD analyses.
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 67 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
13.1.3.2
Primary Endpoint
The following hypotheses will be tested for the primary PD endpoint of Drug Liking “at this 
moment” VAS Emax.
1. Validation test of the sensitivity and integrity of the study: Does the positive control (C) 
produce mean responses that show greater abuse potential compared with placebo (P)?
H0: µC - µP ≤15 vs Ha: µC - µP > 15
where µC and µP are the mean Drug Liking VAS Emax for alprazolam and placebo, 
respectively. The margin of 15 was selected based on previous studies of this type (US 
Department of Health and Human Services, FDA, CDER: Statistical review and evaluation 
Application Number: 215904, Statistical Reviews, 2022). 
2. Does the test drug (T) produce mean responses that show less abuse potential compared to 
positive control?
H0: µC - µT ≤0 vs Ha: µC - µT > 0
where µT is mean Drug Liking VAS Emax for soticlestat. This hypothesis will be tested 
separately for each soticlestat dose. Rejection of each null hypothesis would suggest lower 
relative abuse potential of soticlestat compared with alprazolam. 
3. Does the test drug produce mean responses that show similar abuse potential compared with 
placebo?
H0: µT - µP ≥11 vs Ha: µT - µP < 11
This hypothesis will be tested separately for each soticlestat dose. Rejection of each null 
hypothesis would suggest that soticlestat does not produce an abuse-related signal. The margin of 
11 was selected based on Chen and Bonson (Chen and Bonson 2013).
All hypotheses for the primary endpoint will be tested at 1-sided 0.05 level of significance. The 
hypotheses will be tested sequentially in the order listed. Within the second and third hypotheses, 
testing will be ordered from low dose to high dose. No adjustments to p-values will be made. All 
hypotheses will be evaluated using nominal p-values.
Analysis of the primary endpoint will be performed on the modified completer analysis set. A 
linear mixed effects model containing treatment, period, sequence, and first-order carryover (if 
applicable) as fixed effects, and participant as random effect, is planned to be used to evaluate the 
hypotheses for the primary endpoint.
If the variances across treatment groups shows potential heterogeneity, the model will be fitted to 
allow unequal variances across treatment groups. If non-normality of residuals is detected in the 
model, a paired t-test or sign test will be used as appropriate for hypothesis testing.
Carryover effects are defined as the effect of the treatment administered in the previous treatment 
period. If the carryover effect is found to be significant at a level of 0.25, then it will be included in 
the mixed-effects model as a fixed effect. Otherwise, carryover effect will be dropped from the 
model.
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 69 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
13.1.5
Safety Analysis
Safety analyses for the qualification phase will be based on the qualification safety analysis set. 
Safety analyses for the treatment phase will be based on the safety analysis set.
All AEs will be coded using the MedDRA and characterized as pretreatment and 
treatment-emergent according to the intake of the study drugs. TEAEs will be summarized by 
treatment showing the number and percentage of participants who experienced at least 1 TEAE 
and the number of TEAEs reported. A by-participant AE data listing including reported term, 
coded term, treatment, severity, and relationship to treatment will be provided. TEAEs leading to 
discontinuation and SAEs will be listed separately.
Vital signs data will be summarized by study phase and treatment and will be listed by participant. 
Observed values and changes from baseline will be presented.
Physical examination abnormalities, ECG results, clinical laboratory values, and C-SSRS 
responses will be listed by participant.
13.2
Interim Analysis
No interim analysis is planned.
13.3
Determination of Sample Size
The qualification phase of the study is based on a 2 × 2 crossover design with oral doses of 
alprazolam 2 mg and matching placebo. The treatment phase is based on a 5-treatment, 
10-sequence, 5-period Williams square crossover design with treatments A, B, C, D, and E as 
defined previously. 
Approximately 140 participants will be enrolled into the qualification phase of the study, 
randomized equally to the 2 sequences. Approximately 65 qualified participants will be 
randomized equally to the 10 sequences in the treatment phase, with the intent to ensure that at 
least 39 participants are in the modified completer analysis set. 
Participants who are randomized but who prematurely discontinued or are eliminated from the 
modified completer analysis set may be replaced to ensure that the size of the modified completer 
analysis set is sufficient, sequences are approximately balanced, and there is at least 1 participant 
per sequence. Replacement participants will be assigned to the same treatment sequence as the 
original participant.
It is estimated that, in the treatment phase, a sample size of 39 participants in the modified 
completer analysis set will provide at least 90% power to test each hypothesis for the primary PD 
endpoint. 
Power calculations used a paired t-test and assumed a true SD of 23 points for within-participant 
differences for each planned treatment comparison on the Drug Liking VAS Emax, a true mean 
difference of 26 points between alprazolam 2 mg and placebo, and a true mean difference of 
0 points between placebo and each dose of soticlestat. 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 70 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
The assumptions on the mean and SD of the difference between alprazolam and placebo were 
derived from published data (Chen and Bonson 2013; Levy-Cooperman et al. 2016; Schoedel et al. 
2018a).
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
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. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator guarantees access to source documents by the sponsor or its designee (contract 
research organization) and by the IRB.
All aspects of the study and its documentation will be participant to review by the sponsor or 
sponsor’s designee, including but not limited to the investigator’s binder, study drug, participant 
medical records, informed (e)consent documentation, documentation of participant authorization 
to use personal health information and review of eCRFs and associated source documents. It is 
important that the investigator and other study personnel are available during the monitoring visits 
and that sufficient time is devoted to the process.
In case of prolonged access restrictions to external visits (study monitors) to a study site due to 
COVID-19 pandemic and wherever possible by local regulations, remote source data verification 
(rSDV) may be considered for critical data related to participant’s safety and any key variables to 
ensure data accuracy and integrity.
If rSDV is required, full details of the process will be included in the clinical monitoring plan 
following any applicable local guidance for secure access to remote source documents and data 
security provisions to protect personal data.
14.2
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, as required) to determine the appropriate course of action. There 
will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria.
The study site should document all protocol deviations in the participant’s source documents. In 
the event of a significant deviation, the study site should notify the sponsor or its designee (and 
IRB, as required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the participant, or confound interpretation of primary study 
assessment. A protocol deviation form should be completed by the study site and signed by the 
sponsor or designee for any significant deviation from the protocol.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 71 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be participant to quality assurance audits by the sponsor or designees. In 
this circumstance, the sponsor-designated auditor will contact the study site in advance to arrange 
an auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan, Center 
for Drug Evaluation in China). If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and study site guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1.
15.0
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 ICH Harmonised Tripartite Guideline for GCP. Each investigator 
will conduct the study according to applicable local or regional regulatory requirements and align 
his or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed (e)consent and investigator responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable state and federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained. If the study site is unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the US Department of Health and Human Services 
(for studies including Takeda Development Center Americas).
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the IB, the informed (e)consent form, and, if 
applicable, participant recruitment materials and/or advertisements and other documents required 
by all applicable laws and regulations, must be submitted to a central or local IRB for approval. 
The IRB’s written approval of the protocol and participant informed (e)consent must be obtained 
and submitted to the sponsor or designee before commencement of the study. The IRB approval 
must refer to the study by exact protocol title, number, and version date; identify versions of other 
documents (eg, informed (e)consent form) reviewed; and state the approval date. The sponsor will 
notify the study site once the sponsor has confirmed the adequacy of study site regulatory 
documentation and, when applicable, the sponsor has received permission from competent 
authority to begin the study.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 72 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Study site must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed (e)consent form, 
recruitment materials intended for viewing by participants, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB 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 and sponsor.
15.2
Participant Information, Informed (e)Consent, and Participant Authorization
Written and (e)consent documents will embody the elements of informed (e)consent as described 
in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed (e)consent form, participant authorization form (if 
applicable), and participant information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the participant’s personal and personal health information for 
purposes of conducting the study, including the use of electronic devices and associated 
technologies (if applicable). The informed (e)consent form and the participant information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and benefits, 
as well as the date informed consent is given. The informed (e)consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed 
(e)consent form and if applicable, the participant authorization form. The informed (e)consent 
form, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be approved by both the IRB and the sponsor before use.
The informed (e)consent form, participant authorization form (if applicable), and participant 
information sheet (if applicable) must be written in a language fully comprehensible to the 
prospective participant. It is the responsibility of the investigator to explain the detailed elements 
of the informed (e)consent form, participant authorization form (if applicable), and participant 
information sheet (if applicable) to the participant. Information should be given in both oral and 
written form whenever possible and in the manner deemed appropriate by the IRB. In the event the 
participant is not capable of rendering adequate informed (e)consent, then the participant’s legally 
acceptable representative may provide such consent for the participant in accordance with 
applicable laws and regulations.
The participant, or the participant’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the study and (2) decide whether or not to participate in 
the study. If the participant, or the participant’s legally acceptable representative, determines he or 
she will participate in the study, then the informed (e)consent form and participant authorization 
form (if applicable) must be signed and dated by the participant, or the participant’s legally 
acceptable representative, at the time of consent and before the participant entering into the study. 
The participant or the participant’s legally acceptable representative should be instructed to sign 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 73 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
using their legal names, not nicknames, using a ballpoint pen with either blue or black ballpoint ink 
in the case of written consent. The investigator must also sign and date the informed (e)consent 
form and participant authorization (if applicable) at the time of consent or after the receipt of 
participant signature (in the case of (e)consent) and before participant entering into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable.
Once signed, the original informed (e)consent form or certified copy (if applicable), participant 
authorization form (if applicable), and participant information sheet (if applicable) will be 
maintained by the study site. The investigator must document the date the participant signs the 
informed (e)consent in the participant’s medical record. Copies of the signed informed (e)consent 
form, the signed participant authorization form (if applicable), and participant information sheet 
(if applicable) shall be provided to the participant.
All revised informed (e)consent forms must be reviewed and signed by relevant participants or the 
relevant participant’s legally acceptable representative in the same manner as the original 
informed (e)consent. The date the revised (e)consent was obtained should be recorded in the 
participant’s medical record, and the participant should receive a copy of the revised informed 
(e)consent form.
15.3
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 trial database or documentation via a participant identification number. As 
permitted by all applicable laws and regulations, limited participant attributes, such as sex, age, or 
date of birth, and participant initials, may be used to verify the participant and accuracy of the 
participant’s unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, 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 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 (e)consent process (see Section 9.1.1).
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 eCRF).
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 74 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
15.4
Clinical Trial Disclosures and Publication
15.4.1
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 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.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda policy/standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda policy/standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each participant in the study must be insured in accordance with the regulations applicable to the 
study 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.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 75 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
16.0
REFERENCES
Chen, L. and Bonson, K. R. 2013. An equivalence test for the comparison between a test drug and 
placebo in human abuse potential studies. J Biopharm Stat, 23(2), 294-306.
Levy-Cooperman, N., Schoedel, K. A., Chakraborty, B., Blum, D. and Cheng, H. 2016. Abuse 
liability assessment of eslicarbazepine acetate in healthy male and female recreational 
sedative users: a phase I randomized controlled trial. Epilepsy Behav, 61, 63-71.
Paul, S. M., Doherty, J. J., Robichaud, A. J., Belfort, G. M., Chow, B. Y., Hammond, R. S., et al. 
2013. The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent 
allosteric modulator of N-methyl-D-aspartate receptors. J Neurosci, 33(44), 17290-300.
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., et al. 2011. 
The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. Am J Psychiatry, 168(12), 
1266-77.
Schoedel, K. A., Andreas, J. O., Doty, P., Eckhardt, K. and Sellers, E. M. 2017. Randomized, 
double-blind, placebo- and active comparator-controlled crossover study evaluating the 
abuse potential of the antiepileptic drug lacosamide in healthy recreational drug users. J 
Clin Psychopharmacol, 37(6), 675-83.
Schoedel, K. A., Stockis, A. and Sellers, E. M. 2018a. Human abuse potential of brivaracetam in 
healthy recreational central nervous system depressant users. Epilepsy Behav, 78, 194-201.
Schoedel, K. A., Szeto, I., Setnik, B., Sellers, E. M., Levy-Cooperman, N., Mills, C., et al. 2018b. 
Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: a 
randomized, double-blind, controlled trial. Epilepsy Behav, 88, 162-71.
Williams, E. J. 1949. Experimental designs balanced for the estimation of residual effects of 
treatments. Aust J Chem, 2(2), 149-68.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 76 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Appendix A
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 77 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 79 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
 
 
 
 
 
 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 80 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 81 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
For non-commercial use only


For non-commercial use only


For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 84 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are participant to ICH GCP and all the 
applicable local laws and regulations. The responsibilities imposed on investigators by the FDA 
are summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed 
and signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who 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 (non routine/non standard panel) 
screening assessments are NOT performed on potential participants, before 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 that conform to 21 
CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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, and 
issue a final report within 3 months of study completion.
8. Ensure that requirements for informed (e)consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed (e)consent from each participant who participates in the study, and 
document the date of (e)consent in the participant’s medical chart. Valid informed (e)consent 
is the most current version approved by the IRB. Each informed (e)consent form should 
contain a participant authorization section that describes the uses and disclosures of a 
participant’s personal information (including personal health information) that will take place 
in connection with the study. If an informed (e)consent form does not include such a 
participant authorization, then the investigator must obtain a separate participant authorization 
form from each participant or the participant’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 85 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
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.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 86 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Appendix C
Elements of the Participant Informed (e)Consent
In seeking informed (e)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, and the monitor may inspect the records. By signing an informed (e)consent form, the 
participant or the participant’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the participant for participating in the study.
17. The anticipated expenses, if any, to the participant for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB 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 
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 87 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
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. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.
24. A participant authorization (either contained within the informed (e)consent form or provided 
as a separate document) describing to the participant the contemplated and permissible uses 
and disclosures of the participant’s personal information (including personal health 
information) for purposes of conducting the study. The participant authorization must contain 
the following statements regarding the uses and disclosures of the participant’s personal 
information:
a) that personal information (including personal health information) may be processed by 
or transferred to other parties in other countries for clinical research and safety 
reporting purposes, including, without limitation, to the following: (1) Takeda, its 
affiliates, and licensing partners; (2) business partners assisting Takeda, its affiliates, 
and licensing partners; (3) regulatory agencies and other health authorities; and 
(4) IRBs;
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 drug(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.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 88 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
25. Female participants of childbearing potential (eg, nonsterilized, premenopausal female 
participants) who are sexually active must use effective or highly effective contraception (as 
defined in the informed consent) from the time of signing informed consent throughout the 
duration of the study, and for 32 days following the last dose of study drug. Regular pregnancy 
tests will be performed throughout the study for all female participants of childbearing 
potential. If a participant is found to be pregnant during study, study drug will be discontinued.
26. Male partners of female participants must use effective or highly effective contraception (as 
defined in the informed consent) if required as part of the method (eg, double-barrier, 
vasectomized partner) from signing the informed consent throughout the duration of the study, 
and for a minimum of 32 days following the last dose of study drug.
For non-commercial use only


Soticlestat
Study No. TAK-935-1012
Page 89 of 89
Protocol Incorporating Amendment 1
15 March 2023
CONFIDENTIAL
Appendix D
Trial Management During COVID-19 Pandemic
The purpose of this section is to safeguard the safety of study participants, ensure continuation of 
study conduct and uninterrupted maintenance of treatment, and preserve the integrity of the study, 
in case of a general public health crisis or pandemic, such as COVID-19. This section addresses 
situations in which scheduled in-person clinic visits are not feasible due to local, regional or 
national restrictions.
The principal investigator holds the ultimate responsibility for the safety and well-being of study 
participants and shall maintain compliance with the current local and health authority guidelines 
and recommendations pertaining to the pandemic. The study procedures outlined in this protocol 
may be modified subsequently according to any emerging or revised health authority guidelines 
during conduct of the trial due to the ongoing COVID-19 pandemic. These modified study 
procedures are to be used only during the COVID-19 pandemic.
Due to the COVID-19 pandemic, study participants may not be able to attend scheduled in-person 
clinic visits as per protocol. The study site should follow local and country health and government 
authorities’ restrictions and recommendations on conduct of clinical trials during the pandemic.
COVID-19 vaccination of participants is allowed during the study.
Any protocol deviations, missing visits, or missing assessments related to COVID-19 restrictions 
will be recorded and reported in the CSR.
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-935-1012 
Study Title: A Phase 1, Randomized, Double-Blind, Double-Dummy, Active- and Placebo-
Controlled, 5-Way Crossover Study Evaluating the Abuse Potential of Soticlestat (TAK-935) in 
Healthy Adult Nondependent Recreational Drug Users With Central Nervous System Depressant 
Experience 
Phase: 1 
Version: Amendment 2 
Date: 10-AUG-2023 
Prepared by: 
 
, Statistics 
 
, Statistics 
Based on: 
Protocol Version: Amendment 1 
Protocol Date: 15 March 2023 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
For non-commercial use only


TAK-935-1012 
Page 2 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original version  
21-OCT-2022 
Not Applicable 
Amendment 1 
20-JUL-2023 
Address the changes outlined in Protocol Amendment 1 
Amendment 2 
10-AUG-2023 
Clarify methodology and add supplementary analyses 
 
For non-commercial use only


TAK-935-1012 
Page 3 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................7 
1.1 
Objectives ......................................................................................................................7 
1.1.1 
Primary Objective ..................................................................................................7 
1.1.2 
Secondary Objectives ............................................................................................7 
1.1.3 
 ..........................................................................................7 
1.2 
Endpoints .......................................................................................................................7 
1.2.1 
Primary Endpoint ...................................................................................................7 
1.2.2 
Secondary Endpoints, PD ......................................................................................7 
1.2.2.1 
Key Secondary Endpoints .............................................................................7 
1.2.2.2 
Other Secondary Endpoints ..........................................................................7 
1.2.3 
Secondary Endpoint, Safety ..................................................................................7 
1.2.4 
Other Safety Endpoints ..........................................................................................8 
1.2.5 
 ....................................................................................8 
1.2.6 
 .....................................................8 
1.3 
Estimand ........................................................................................................................8 
2.0 
STUDY DESIGN.................................................................................................................8 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................10 
3.1 
Statistical Hypotheses ..................................................................................................10 
3.2 
Multiplicity Adjustment ...............................................................................................11 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................11 
5.0 
ANALYSIS SETS .............................................................................................................12 
5.1 
Qualification Phase ......................................................................................................12 
5.1.1 
Qualification Randomized Analysis Set ..............................................................12 
5.1.2 
Qualification Safety Analysis Set ........................................................................12 
5.2 
Treatment Phase ...........................................................................................................12 
5.2.1 
Randomized Analysis Set ....................................................................................12 
5.2.2 
Safety Analysis Set ..............................................................................................13 
5.2.3 
Completer Analysis Set .......................................................................................13 
5.2.4 
Modified Completer Analysis Set .......................................................................13 
5.2.5 
 ...................................................................................................13 
6.0 
STATISTICAL ANALYSIS .............................................................................................13 
6.1 
General Considerations ................................................................................................13 
6.1.1 
Handling of Treatment Misallocations ................................................................14 
6.2 
Study Information ........................................................................................................14 
For non-commercial use only


TAK-935-1012 
Page 4 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
6.3 
Disposition of Participants ...........................................................................................14 
6.4 
Demographic and Other Baseline Characteristics .......................................................15 
6.4.1 
Demographics ......................................................................................................15 
6.4.2 
Medical History and Concurrent Medical Conditions .........................................15 
6.5 
Medication History and Concomitant Medications .....................................................15 
6.6 
Substance Use History .................................................................................................16 
6.7 
PD Analysis .................................................................................................................16 
6.7.1 
PD Endpoints .......................................................................................................16 
6.7.1.1 
Subjective Effects........................................................................................16 
6.7.1.2 
 ...........................................................................................18 
6.7.2 
PD Analysis: General Considerations .................................................................19 
6.7.3 
PD Analysis: Primary Endpoint ..........................................................................19 
6.7.3.1 
Derivation of Endpoint ................................................................................19 
6.7.3.2 
Main Analytical Approach ..........................................................................19 
6.7.3.3 
Supplementary Analyses .............................................................................21 
6.7.4 
PD Analysis: Secondary Endpoints .....................................................................21 
6.7.4.1 
Secondary Endpoints Analysis ....................................................................21 
6.7.4.2 
Main Analytical Approach ..........................................................................22 
6.7.4.3 
Sensitivity and Supplementary Analysis .....................................................22 
6.7.5 
 ...................................................................22 
6.8 
Safety Analysis ............................................................................................................22 
6.8.1 
Adverse Events ....................................................................................................22 
6.8.2 
Other Safety Analysis ..........................................................................................23 
6.8.2.1 
Vital Signs ...................................................................................................23 
6.8.2.2 
12-Lead ECG ..............................................................................................24 
6.8.2.3 
Clinical Laboratory .....................................................................................24 
6.8.2.4 
C-SSRS .......................................................................................................24 
6.8.2.5 
Physical Examination ..................................................................................24 
6.8.3 
Extent of Exposure and Compliance ...................................................................24 
6.9 
 .................................................................................................................24 
6.10 
Interim Analyses ..........................................................................................................24 
6.11 
Data Monitoring Committee/Internal Review Committee ..........................................24 
7.0 
REFERENCES ..................................................................................................................25 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................25 
9.0 
APPENDIX ........................................................................................................................25 
For non-commercial use only


TAK-935-1012 
Page 5 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
9.1 
Changes From the Previous Version of the SAP .........................................................25 
9.1.1 
Definition of Visit Windows ...............................................................................26 
9.2 
Analysis Software ........................................................................................................26 
 
LIST OF IN-TEXT TABLES 
Table 6.a  
VAS Endpoint Descriptions ...................................................................................17 
 
LIST OF IN-TEXT FIGURES 
Figure 2.a  
Schematic of Study Design (Table 6.a from Study Protocol) ................................10 
 
For non-commercial use only


TAK-935-1012 
Page 6 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ANOVA 
analysis of variance 
 
 
 
 
BLQ 
below the limit of quantitation 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019  
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
Emax 
maximum effect 
 
 
H0 
null hypothesis 
Ha 
alternative hypothesis 
ICF 
informed consent form 
Mean 
arithmetic mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
number of observations 
PD 
pharmacodynamic 
 
 
PT 
Preferred Term (MedDRA) 
Q1 
25th percentile 
Q3 
75th percentile 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
System Organ Class 
t1/2 
terminal disposition phase half-life 
TEAE  
treatment-emergent adverse event 
 
 
 
 
tmax 
time of first occurrence of Cmax 
VAS 
visual analogue scale 
WHO 
World Health Organization 
 
For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-935-1012 
Page 9 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
inpatient, qualification phase (from Day -1 through Day 3) to determine if participants are able 
to discriminate the drug effects of the positive control, 2 mg of alprazolam, when compared to 
placebo, and to demonstrate that they are able to tolerate the administered alprazolam 2 mg 
dose. 
Each participant will be randomized to receive alprazolam or placebo in a double-blind, 
crossover manner. On each dosing day during the qualification phase, participants will fast for 
at least 8 hours predose and for 4 hours postdose. Drug administration on the 2 qualification 
phase days will be separated by an approximately 24-hour washout period. Selected PD and 
safety assessments will be performed prior to and after each study drug administration. 
Eligible participants who qualify in the qualification phase (criteria described in Section 7.3 of 
the study protocol) may be released from the study site and if continue to meet eligibility criteria 
will enter the inpatient treatment phase. The last study drug administration in the qualification 
phase and the first study drug administration in the treatment phase will be separated by a 
washout interval of at least 4 days. If participants are released after the qualification phase, they 
will enter into the clinical research unit (CRU) the day before dosing (baseline [Bs]/treatment 
Day -1) of the treatment period. 
If participants are confined to the clinic from qualification phase to treatment phase, they need 
not perform the Bs/treatment Day -1 assessments. Site should ensure participant meets 
qualification eligibility criteria prior to randomizing these participants and continue to monitor 
for SAEs (serious adverse events) and document concomitant medications. 
During the treatment phase of the study, participants will receive medication (double-dummy) on 
each dosing day and they should remain confined throughout the treatment phase. If participants 
are confined to the clinic throughout the treatment phase, they need not repeat the Bs/treatment 
Day -1 procedures prior to each treatment period. Treatment periods will be separated by a 
minimum of 7 days between dosing. 
Each participant will be randomized to receive oral treatments (1 in each treatment phase 
period) in a double-blind, crossover fashion as shown in Figure 2.a (Table 6.a of study protocol). 
The treatment phase will include 5 treatment periods as described in Figure 2.a (Table 6.a of 
study protocol). 
Study drug administration during each treatment phase period will occur on the first day (a 
single dose) of each treatment period followed by PD,
 and safety assessments for up to 
24 hours postdose at the study site. At each treatment phase period, participants will fast for at 
least 8 hours predose and for 4 hours postdose. Although soticlestat has a relatively short 
plasma t1/2 (2.6 to 8.7 hours for oral tablets), study drug administrations during the treatment 
phase periods will be separated by a washout interval of 7 days because the PD biomarker for 
soticlestat treatment (ie, 24HC reduction in plasma) returns to baseline slowly but within 7 days 
after treatment is stopped (ie, PD washout).  
All participants, including those who discontinue early (except those who withdraw consent and 
refuse further contact), will complete the safety follow-up visit 1 week (± 3 days) after the last 
administered blinded study drug in the treatment phase. 
For non-commercial use only


For non-commercial use only


TAK-935-1012 
Page 11 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
2. Does the test drug (T) produce mean responses that show less abuse potential compared 
to positive control? 
H0: µC - µT ≤ 0 vs Ha: µC - µT >0 
where µT is mean Drug Liking VAS Emax for soticlestat. This hypothesis will be tested 
separately for each soticlestat dose. Rejection of each null hypothesis would suggest 
lower relative abuse potential of soticlestat compared to alprazolam. 
3. Does the test drug produce mean responses that show similar abuse potential compared 
to placebo? 
H0: µT - µP ≥11 vs Ha: µT - µP <11 
This hypothesis will be tested separately for each soticlestat dose. Rejection of each null 
hypothesis would suggest that soticlestat does not produce an abuse-related signal. The 
margin of 11 was selected based on Chen and Bonson (Chen and Bonson 2013) 
All hypotheses for the primary endpoint will be tested at 1-sided 0.05 level of significance. The 
hypotheses will be tested sequentially in the order listed. Within the second and third hypotheses, 
testing will be ordered from low dose to high dose.  
In the sequential testing procedure, a non-statistically significant test will result in cessation of 
testing the subsequent hypotheses. 
3.2 
Multiplicity Adjustment 
Hypotheses are tested sequentially and testing subsequent hypotheses will cease when a test is 
not statistically significant. All hypotheses will be evaluated using nominal p-values. 
4.0 
SAMPLE-SIZE DETERMINATION 
The qualification phase of the study is based on a 2x2 crossover design with oral doses of 
alprazolam 2 mg and matching placebo. The treatment phase is based on a 5-treatment, 
10-sequence, 5-period Williams square crossover design with treatments A, B, C, D, and E as 
defined previously. 
Approximately 140 participants will be enrolled into the qualification phase of the study, 
randomized equally to the 2 sequences. Approximately 65 qualified participants will be 
randomized equally to the 10 sequences in the treatment phase, with the intent to ensure that at 
least 39 participants are in the modified completer analysis set. 
Participants who are randomized but who are prematurely discontinued or eliminated from the 
modified completer analysis set may be replaced to ensure that the size of the modified completer 
analysis set is sufficient, sequences are approximately balanced, and there is at least 1 
participant per sequence. Replacement participants will be assigned to the same treatment 
sequence as the original participant. 
For non-commercial use only


TAK-935-1012 
Page 12 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
It is estimated that, in the treatment phase, a sample size of 39 participants in the modified 
completer analysis set will provide at least 90% power to test each of the hypotheses for the 
primary PD endpoint. 
Power calculations used a paired t-test and assumed a true standard deviation (SD) of 23 points 
for within-participant differences for each planned treatment comparison on the Drug Liking 
VAS Emax, a true mean difference of 26 points between alprazolam 2 mg and placebo, and a true 
mean difference of 0 points between placebo and each dose of soticlestat. 
The assumptions on the mean and standard deviation of the difference between alprazolam and 
placebo were derived from published data. (Chen and Bonson 2013, Levy-Cooperman, et al. 
2016, Schoedel, Stockis and Sellers 2018) 
The derivation of SD for within-participant differences was based on SD of 16 for alprazolam 
2 mg and 17 for placebo, and correlation of 0. The resulting SD of 23 for the difference was then 
used in power calculations for all other hypotheses. 
Alternatively, because soticlestat is believed to have similar abuse potential to placebo, if 
soticlestat and placebo are assumed to have the same SD of 17 and correlation 0.7, then the SD 
of within-participant differences would be approximately 13. With this assumed SD, the power 
with a sample size of 39 participants in the modified completer analysis set is at least 95% for 
testing the hypothesis comparing each dose of soticlestat to placebo if the assumed mean 
difference between them is at most 4 points. Correspondingly, if the mean difference between 
each dose of soticlestat and alprazolam 2 mg is at least 22 (=26-4) points, and correlation is 
0 (hence SD is 23 for within-participant differences), the power is at least 99% to test the 
hypothesis comparing each dose of soticlestat to alprazolam 2 mg. 
5.0 
ANALYSIS SETS 
5.1 
Qualification Phase 
5.1.1 
Qualification Randomized Analysis Set 
All participants who are randomized in the qualification phase. 
5.1.2 
Qualification Safety Analysis Set 
All participants who receive at least 1 dose of study drug (ie, placebo or alprazolam) in the 
qualification phase. All safety evaluations in the qualification phase will be performed using this 
analysis set. 
5.2 
Treatment Phase 
5.2.1 
Randomized Analysis Set 
All participants who are randomized in the treatment phase. 
For non-commercial use only


For non-commercial use only


TAK-935-1012 
Page 14 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
 safety endpoints will be 
presented by treatment and overall; demographics will be presented overall. All log 
transformations will be based on natural logarithms. 
Counts will be presented as integers. Percentages will be presented to one decimal. For 
continuous variables, the level of precision will be presented as follows: minimum/maximum in 
the same precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be presented 
as an integer. 
Baseline will be the predose value within a treatment period where available. Otherwise, baseline 
will be last observation prior to taking any study drug (placebo, alprazolam, or soticlestat). 
All p-values will be rounded to 4 decimal places prior to assessment of statistical significance, 
and will be reported to 4 decimal places, with p-values that would round to 0.0000 presented as 
<0.0001. 
6.1.1 
Handling of Treatment Misallocations 
Unless otherwise stated, participants who are misallocated treatments will be analyzed per the 
treatment they received rather than per the treatment regimen to which they were randomized. 
6.2 
Study Information 
An overall study information table will be generated including the following items: date of first 
participant’s signed informed consent form (ICF), date of first dose of study drug, date of last 
dose of study drug, date of last participant’s last visit/contact, date of last participant’s last 
procedure for collection of data for primary endpoint, the version of Medical Dictionary for 
Regulatory Activities (MedDRA®), the version of World Health Organization (WHO) 
Dictionary, and SAS version used for creating the datasets. 
6.3 
Disposition of Participants 
For each study phase (qualification and treatment phases), disposition of participants (number of 
participants randomized, dosed, completed the study, discontinued from the study, and reason(s) 
for discontinuation(s)) will be summarized for each group by randomized treatment sequence 
and overall. Study completion status, including reason for discontinuation, will also be listed by 
participant. 
A listing of participants not meeting the qualification criteria together with reason for failure to 
pass the qualification phase will be provided. 
All protocol deviations will be listed and significant protocol deviations will be flagged.  
A summary table for all analysis sets will be created. A listing indicating whether each 
participant was included or excluded from each analysis set will be provided. 
For non-commercial use only


TAK-935-1012 
Page 15 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
The qualification randomized analysis set and the randomized analysis set will be used for 
presenting the above tables and listings for the qualification phase and treatment phase, 
respectively. 
Participants who failed screening will be listed with primary reasons for screen failure. 
6.4 
Demographic and Other Baseline Characteristics 
6.4.1 
Demographics 
Demographic data will be summarized using the qualification safety analysis set and the safety 
analysis set. Results for each analysis set will be presented overall. Variables to be presented 
include age, sex, ethnicity, race, height, weight, and body mass index. Demographic data will 
also be listed as recorded on the CRF, including the date of informed consent and protocol 
version. The listing will be based on the qualification safety analysis set and will include an 
identifier indicating whether the participant was dosed in the treatment phase. 
6.4.2 
Medical History and Concurrent Medical Conditions 
Medical history to be obtained will include determining whether the participant has any 
significant conditions that resolved at or before signing informed consent.  
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of the ICF. These include clinically significant laboratory, ECG, or physical 
examination abnormalities noted at Visit 1, according to the judgment of the investigator. The 
condition (ie, diagnosis) should be described and recorded in the eCRF.  
Each participant’s medical history and concurrent medical conditions will be listed using the 
qualification safety analysis set with a flag indicating whether the participant was dosed in the 
treatment phase. If available, the medical history and concurrent medical condition listings will 
include the coded term (preferred term [PT] and system organ class [SOC]), start date (if known) 
and end date (if known) or whether the condition was ongoing, and a description of the condition 
or event. No summaries or statistical analysis will be performed for these data. 
6.5 
Medication History and Concomitant Medications 
Any medication relevant to eligibility criteria and efficacy/safety evaluation stopped at or within 
6 months before signing of informed consent will be obtained. 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the participant over the counter. Concomitant 
medication is not provided by the sponsor. At each study visit, participants will be asked whether 
they have taken any medication other than the study drug (used from signing of informed 
(e)consent through the end of the study), and all medication including vitamin supplements, 
over-the-counter medications, and oral herbal preparations, must be recorded in the eCRF. 
All medication history and concomitant medications recorded during the study will be coded 
using the World Health Organization (WHO) Drug Dictionary and listed by participant. If 
For non-commercial use only


TAK-935-1012 
Page 16 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
available, the listings will include the medication name, coded term, dosage, route of 
administration, start date and time (if known), end date and time (if known), or whether it 
continued after study completion, and indication for use. Medications stopped before the 
administration of study drug will be identified as “prior” in the listing. 
6.6 
Substance Use History 
A history of all drugs used for recreational/non-medicinal purposes (ie, psychoactive effects) in 
the past 2 years will be collected. History, including drug preference (ie, drug of choice) and 
frequency of use (ie, average number of uses per week before screening) and date/time of last 
use, will be collected using reported drug names, by drug class (eg, cannabinoids, depressants, 
dissociative anesthetics, hallucinogens, opioids and morphine derivatives, stimulants). 
A history of alcohol use (ie, average number of drinks [beer [354 mL/12 oz], wine [118 mL/4 
oz], or distilled spirits [29.5 mL/1 oz]] per week and number of occasions of binge drinking 
[more than 3 drinks/5 drinks in a sitting for female/male participants]) in the 6 months before 
screening and smoking (smoker/non-smoker, if smoker, number of cigarettes per day) will also 
be collected. 
Information on recreational drug use, alcohol use, and smoking obtained as part of substance use 
history will be summarized based on the safety analysis set. 
Each participant’s drug use history for recreational/non-medicinal purposes will also be listed as 
recorded on the CRF including the drug name and class, drug of choice, route of administration, 
number of times used in the past 12 weeks and number of times used in the past two years. The 
listing will be done using the safety analysis set. 
6.7 
PD Analysis 
6.7.1 
PD Endpoints 
PD measures will be administered electronically. This section describes the measures and the 
study endpoints derived from them. 
6.7.1.1 
Subjective Effects 
Subjective drug effects are assessed using standardized questionnaires, each administered as a 
100-point VAS at multiple postdose timepoints. For some questionnaires a predose assessment is 
also done. The VAS may be administered as bipolar or unipolar scales, as appropriate, and the 
choice is determined by the nature of the subjective effect being measured. When VAS are 
administered as bipolar scales, the neutral point equals 50 (Drug Liking, Overall Drug Liking, 
Take Drug Again, Alertness/Drowsiness VAS). The neutral point will also be labeled with an 
anchor, such as “neither like nor dislike.” When VAS are administered as unipolar scales, the 
neutral point equals 0, and anchors will be presented using text such as “Not at all” (score = 0) 
to “Extremely” (score = 100; eg, Good, Bad, High, and Any Effects VASs). Scales that refer 
specifically to drug (eg, Drug Liking, Good Effects VAS, Bad Effects VAS, and Any Effects VAS) 
are not administered predose. 
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


TAK-935-1012 
Page 20 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
variances will be considered heterogeneous. Otherwise, variances will be considered 
homogeneous. 
If the variances are homogeneous, the model will constrain variances to be equal across 
treatment groups. This is implemented using the SAS procedure MIXED with the option 
“RANDOM SUBJECT” included. If variances are heterogeneous, the model will allow unequal 
variances across treatment groups. This will be implemented by adding the option 
“REPEATED/SUBJECT=SUBJECT GROUP=TREATMENT” to the “RANDOM SUBJECT” 
option. 
After determining whether the treatment variance is homogeneous or heterogeneous, the 
residuals from the model will be investigated for normality using the Shapiro-Wilk W-test. If the 
test has p-value <0.05, the residuals will be considered not normally distributed. Otherwise, the 
residuals will be considered normally distributed. 
If the residuals are normally distributed, it will be determined whether the carryover effects 
should be included in the model. Carryover effects are defined as the effect of the treatment 
administered in the previous treatment period. As there are no carryover effects in treatment 
period 1, placebo will be used in this period. If the carryover effect has p-value <0.25, the term 
will be included in the model. Otherwise, the term will be dropped. 
If the residuals are not normally distributed, the distribution of the paired difference for each 
contrast will be examined in terms of normality and skewness. Each paired difference will be 
investigated for normality using the Shapiro-Wilk W-test. If the test has p-value ≥0.05, the 
paired difference will be considered normally distributed, and a paired t-test will be used for 
analysis. If the paired difference is not normally distributed, that is, the W-test has p-value <0.05, 
the following criteria on skewness will be used to determine whether the paired t-test or sign test 
is used for testing: 
a) If the alternative hypothesis is upper-tailed, and skewness is [0, 0.5], the paired t-test 
will be used. 
b) If the alternative hypothesis is upper-tailed, and skewness <0 or skewness >0.5, the 
sign test will be used. 
c) If the alternative hypothesis is lower-tailed, and skewness is [-0.5, 0], the paired t-test 
will be used. 
d) If the alternative hypothesis is lower-tailed, and skewness <-0.5 or skewness >0, the 
sign test will be used. 
e) If the alternative hypothesis is two-tailed, and skewness is [-0.5, 0.5], the paired t-test 
will be used. 
f) If the alternative hypothesis is two-tailed, and skewness <-0.5 or skewness >0.5, the 
sign test will be used. 
If the sign test is used for analysis, the median of the paired difference, first quartile (Q1), third 
quartile (Q3), 1-sided 95% CI, and p-value from the sign test will be displayed (Hollander and 
For non-commercial use only


TAK-935-1012 
Page 21 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
Wolfe 1999). Note that the calculation of the p-value of the sign test excludes paired differences 
in scores that are equal to zero after subtracting the margin from the differences. The calculation 
of CI does not exclude any paired difference (Hollander and Wolfe 1999). The conclusions will 
be based on p-values. 
If the paired t-test is used for analysis, the mean difference, SE, 1-sided 95% CI, and p-value 
from the t-test will be displayed. 
If a mixed effects model is used for analysis, the least squares mean difference, SE, 1-sided 95%, 
and p-value from the contrast test will be displayed. 
6.7.3.3 
Supplementary Analyses 
Regardless of the main analytic approach taken per section 6.7.3.2, results of the mixed model 
(including/excluding carryover effects) and paired t-test will be displayed as a supplementary 
analysis. 
If the modified completer analysis set differs from the completer analysis set by more than 
5 participants, a supplementary analysis will be conducted using the Completer Analysis Set and 
following the main analytic approach described in Section 6.7.3.2. 
If a mixed effects model is used for the main analysis and the carryover effect has p-value <0.05, 
a supplementary first-period analysis will be conducted using an ANOVA model containing 
treatment group as the fixed effect. The difference in least squares means, 1-sided 95% CIs of the 
difference, and p-values will be provided for each treatment comparison. 
6.7.4 
PD Analysis: Secondary Endpoints 
6.7.4.1 
Secondary Endpoints Analysis 
The key secondary endpoints are Emax of Overall Drug Liking and Emax of Take Drug Again. The 
other secondary endpoints are Emax of Bad Drug Effects, Emax of Good Drug Effects, and Emax of 
High. Refer to Section 6.7.1.1 for derivations and descriptions of these endpoints. 
The following hypotheses will be evaluated for key and other secondary endpoints. Comparisons 
among treatments will be evaluated at 1-sided significance level 0.05 for hypotheses 1 and 2, 
and 2-sided significance level 0.10 for hypothesis 3 as stated below. 
1. Positive control (alprazolam) (C) vs placebo (P): 
H0: µC - µP ≤ 0 vs Ha: µC - µP >0 
2. Positive control (alprazolam) (C) vs each dose of soticlestat (T): 
H0: µC - µT ≤ 0 vs Ha: µC - µT >0 
3. Each dose of soticlestat (T) vs placebo (P): 
H0: μT - μP = 0 vs Ha: μT - μP ≠ 0 
For non-commercial use only


For non-commercial use only


TAK-935-1012 
Page 23 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
severity is missing, the AE will be counted under the highest severity in summary tables, and if 
relationship is missing, the AE will be counted as related in summary tables. Any medical 
condition starting or worsening after the ICF but before the first dose of study drug in the 
qualification phase will be classified as pre-treatment event. 
Summary of TEAEs will be presented separately for each study phase. Summary tables will 
include number and percent of participants reporting the TEAE and number of events by 
treatment and overall. The denominators for percent calculations will be the number of 
participants dosed for each treatment. 
Summary tables will also be generated for: SAEs, SAEs related to study drug, TEAEs leading to 
study drug discontinuation, TEAEs related to study drug, the most commonly reported non-
serious TEAEs (ie, those events reported by >2 participants excluding SAEs), TEAEs by 
severity, and TEAEs by relationship to study drug. If a participant has multiple TEAEs with 
different severity levels within the same PT, the participant will be counted in the most severe 
category only. If a participant has both related and unrelated TEAEs with the same term, the 
participant will be counted as having related TEAEs. 
An overview summary of TEAEs table, including number of participants with TEAEs, SAEs, 
treatment-related TEAEs, treatment-related SAEs, TEAEs by severity, and TEAEs leading to 
discontinuation of study drug will be provided. 
Data listings will be provided for pre-treatment AEs, TEAEs, TEAEs leading to study drug 
discontinuation, SAEs, and TEAEs that resulted in death. 
AE monitoring begins at signing of ICF and ends at the follow-up visit or at the time of early 
termination/discontinuation procedures. 
6.8.2 
Other Safety Analysis 
6.8.2.1 
Vital Signs 
Vital signs parameters include temperature, pulse rate, respiration rate, systolic and diastolic 
blood pressures. In the qualification phase, vital signs will be obtained at screening, Day -1, 
predose and 2 hours postdose on Day 1, predose and 2 hours postdose on Day 2, and on Day 3 at 
least 24 hours after Day 2 dose (or at early termination if applicable). In the treatment phase, 
vital signs will be obtained at Day -1, Day 30 (or at early termination if applicable), and at the 
following timepoints in all 5 periods: Day 1 predose, Day 1 hour 2, and Day 2 at 24 hours post 
Day 1 dose. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be presented for vital 
sign results and change from baseline by treatment and timepoint of collection for each study 
phase. Baseline is defined as the last assessment including rechecks taken prior to dosing in each 
period. Postdose unscheduled or recheck assessments will not be used in summaries. Vital sign 
data will be listed by study phase and participant. 
For non-commercial use only


For non-commercial use only


TAK-935-1012 
Page 25 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
7.0 
REFERENCES 
Chen, L, and K R Bonson. 2013. "An Equivalence Test for the Comparison Between a Test Drug 
and Placebo in Human Abuse Potential Studies." J Biopham Stat 23 (2): 294-306. 
Daniel, W W. 1990. Applied nonparametric statistics. Pacific Grove, CA: Duxbury. 
Hollander, Myles, and Douglas A Wolfe. 1999. Nonparametric Statistical Methods. Wiley. 
Levy-Cooperman, N, K A Schoedel, B Charkraborty, D Blum, and H Cheng. 2016. "Abuse 
liability assessment of eslicarbazepine acetate in healthy male and female recreational 
sedative users: A Phase I randomized controlled trial." Epilepsy Behav. 61: 63-71. 
Schoedel, K A, A Stockis, and E M Sellers. 2018. "Human abuse potential of brivaracetam in 
healthy recreational central nervous system depressant users." Epilepsy Behav. 78: 194-
201. 
 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
There are no changes to protocol planned analyses. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
The primary purpose of this SAP amendment is to clarify the methodology of the sign test and to 
add supplementary analyses for the primary and key secondary endpoints. The table below 
outlines changes pertinent to statistical analyses. 
SAP Section  
Impacted Text (shown 
in bold) 
Change  
Rationale for Change 
6.7.3.2 Main Analytical 
Approach 
The calculation of the 
sign test, and the CI for 
the median of the paired 
difference based on the 
sign test will exclude 
participants who have 
zero difference in scores 
between the 2 
treatments (Daniel 1990) 
 
Text and reference to 
Daniel 1990 was deleted. 
 
New text and reference 
were added: 
Note that the calculation 
of the p-value of the sign 
test excludes paired 
differences in scores that 
are equal to zero after 
subtracting the margin 
from the differences. 
The calculation of CI 
does not exclude any 
paired difference 
Clarify the analytic 
method and update the 
source. 
For non-commercial use only


TAK-935-1012 
Page 26 of 26
Statistical Analysis Plan Amendment 2 
10-AUG-2023
 
CONFIDENTIAL 
(Hollander and Wolfe 
1999). The conclusions 
will be based on p-
values. 
6.7.3.3 Supplementary 
Analyses 
NA 
New text added: 
Regardless of the main 
analytic approach taken 
per section 6.7.3.2, 
results of the mixed 
model 
(including/excluding 
carryover effects) and 
paired t-test will be 
displayed as a 
supplementary analysis. 
Added supplementary 
analysis  
6.7.4.3 Sensitivity and 
Supplementary Analyses 
No sensitivity or 
supplementary analyses 
are planned. 
New text added: 
For key secondary 
endpoints, regardless of 
the main analytic 
approach taken per 
section 6.7.4.2, results of 
the mixed model 
(including/excluding 
carryover effects) and 
the paired t-test will be 
displayed as a 
supplementary analysis. 
Added supplementary 
analysis 
 
9.1.1 
Definition of Visit Windows 
By-timepoint analyses are generally based on nominal timepoints as recorded in the eCRF. 
Analysis windows will not be used. Results obtained at unscheduled visits will not be included in 
statistical summaries by timepoint but are included in data listings. 
9.2 
Analysis Software 
SAS® Version 9.4 or higher will be used for all statistical analyses provided in the CSR. 
 
For non-commercial use only


Signature Page for Statistical Analysis Plan Amendment 2
Title: TAK-935-1012 16-1-9-2 Statistical Analysis Plan Amendment 1 - 2023-07-20
Document Number: TDN-000196973 v1.0
Approval
Statistics
14-Aug-2023 15:39:55 GMT+0000
For non-commercial use only