Conditions: Developmental and/or Epileptic Encephalopathies
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 18
Healthy volunteers: no

Brief summary:
The purpose of this study is to characterize the multiple-dose safety and tolerability profile of TAK-935 in adult participants with developmental and/or epileptic encephalopathies.

Detailed description:
The drug being tested in this study is called TAK-935. TAK-935 is being tested to treat people who have developmental and/or epileptic encephalopathies. This study will look at safety, tolerability and pharmacokinetics of people who take TAK-935. Study drug will be administered in a double-blind manner in Part 1 and in an open-label manner in Part 2.

The study will enroll approximately 20 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in Part 1-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* TAK-935
* Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

Participants will receive placebo or 100 milligram (mg) TAK-935 tablets, orally or through stable G-tube/PEG tube, BID, in Part 1 (Day 1) and dose will be increased to 200 mg (Day 11) BID and to 300 mg (Day 21) BID in dose titration period. All participants who complete the Double-Blind Treatment Period in Part 1 will have the option to continue directly into the Open-Label Treatment Period in Part 2 where they will receive TAK-935 as two 100 mg tablets (total dose is 200 mg TAK-935) orally or through G-tube/PEG tube, BID and dose will be increased to three 100 mg tablets (total dose is 300 mg TAK-935), orally, BID (Day 41). This dose level will be maintained until the final visit (Day 85) for the dose de-escalation phase.

This multi-center trial will be conducted in North America. The overall time to participate in this study is 121 days excluding screening period of 30-41 days. Participants will make multiple visits to the clinic, and a follow-up phone call will be conducted on Day 91 and at the end of the 30-day follow-up period (Day 121), participants will return to the clinic for a follow-up assessment.

Arms:
arm 1: TAK-935 matching-placebo tablets, orally or through gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, twice daily (BID) from Days 1 to 30 in dose titration period. arm 2: TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID from Days 1 to 10 followed by TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID from Days 11 to 20 followed by TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID from Days 21 to 30 in dose titration period. The dose of TAK-935 was escalated or de-escalated during Part 1 as per investigator's discretion. arm 3: TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID from Days 31 to 40 followed by TAK-935 100 mg tablets x1, x2 or x3, orally or through G-tube/PEG tube, BID from Days 31 to Day 85 as per investigator's discretion in the maintenance period. At the end of Part 2, the dose of TAK-935 was de-escalated until discontinuation.

Interventions: intervention 1: TAK-935 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-935 tablets. intervention 2: TAK-935 placebo-matching tablets.

Protocol document:
Prot_000.pdf: 


•
Title: A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group, Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in Subjects 
With Developmental and/or Epileptic Encephalopathies
NCT Number: NCT03166215
Protocol Approve Date: 21 March 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAG
E
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in Subjects 
With Developmental and/or Epileptic Encephalopathies
Study of TAK-935 as an Adjunctive Therapy in Subjects With Developmental and/or Epileptic 
Encephalopathies
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Study Number:
TAK-935-2001
IND Number:
121234
EudraCT Number:
Not applicable
Compound:
TAK-935
Date:
21 March 2018
Amendment Number:
03
Amendment History:
Date
Amendment Number
Region
05 April 2017
Initial version
North America
24 August 2017
01
North America
16 January 2018
02
North America
21 March 2018
03
North America
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
PPD


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1.2
Approval
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation E6 Good Clinical Practice Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.


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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating Amendment 
No. 03. The primary reason for this amendment is to allow administration of TAK-935 or placebo 
via stable gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube after 
finalization of chemistry, manufacturing, and controls (CMC) in vitro studies demonstrating 100% 
drug delivery through a G-tube when crushed and suspended in water.
Minor grammatical, editorial, and formatting changes are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment 03:
1. Clarified that TAK-935 or placebo can be administered either orally or via stable G-tube/ PEG 
tube.
2. Clarified that a separate consent form will be obtained for subjects with G-tube/PEG tubes.
3. Added inclusion criteria related to subjects with G-tube/PEG tubes.
4. Modified exclusion criteria to allow the use of medical marijuana.
5. Modified secondary endpoints to remove estimation of additional parameters.
6. Removed body weight/body mass index (BMI) from secondary and exploratory endpoints.
7. Modified study drug dosing and regimen sections to clarify how study drug will be 
administered via G-tube/ PEG tube.
8. Modified study drug dispensing procedures to clarify how the investigative product (IP) will 
be prepared for administration via G-tube/PEG tube.
9. Clarified when open-label extension study is expected to be initiated.
10. Updated the medical monitor contact information.


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Coordinating Investigator.........................................................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective ..............................................................................................21
5.1.2
Secondary Objective ..........................................................................................21
5.1.3
Exploratory Objectives.......................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoint...............................................................................................21
5.2.2
Secondary Endpoints..........................................................................................21
5.2.3
Exploratory Endpoints .......................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.2
Justification for Study Design, Dose, and Endpoints ................................................28
6.2.1
Study Design......................................................................................................28
6.2.2
Dose ..................................................................................................................28
6.2.2.1
Dose Selection Rationale .........................................................................28
6.2.2.2
Dose Selection Procedures.......................................................................29
6.2.3
Endpoints...........................................................................................................30
6.2.3.1
Safety Endpoints......................................................................................30
6.2.3.2
PK Endpoints...........................................................................................30
6.2.3.3
................................................................................30
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6.2.3.4
Seizure Assessment by Daily Seizure Diary.............................................30
6.3
Premature Termination or Suspension of Study or Study Site...................................31
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................31
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................31
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ................................................................................31
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............32
7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................33
7.3
Excluded Medications, Procedures, and Treatments.................................................35
7.4
Diet, Fluid, and Activity Control..............................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................35
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................37
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................38
8.1
Study Drug and Materials ........................................................................................38
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................38
8.1.1.1
Study Drug ..............................................................................................38
8.1.1.2
Rescue Medication ..................................................................................38
8.1.1.3
Sponsor-Supplied Drug............................................................................38
8.1.2
Storage...............................................................................................................38
8.1.3
Dose and Regimen .............................................................................................39
8.1.4
Overdose............................................................................................................39
8.2
Study Drug Assignment and Dispensing Procedures ................................................40
8.3
Randomization Code Creation and Storage..............................................................40
8.4
Unblinding Procedure..............................................................................................41
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................41
9.0
STUDY PLAN ..............................................................................................................43
9.1
Study Procedures.....................................................................................................43
9.1.1
Informed Consent Procedure..............................................................................43
9.1.1.1
Study Informed Consent Procedure..........................................................43
9.1.1.2
PGx Informed Consent Procedure............................................................43
9.1.2
Demographics, Medical History, and Medication History Procedure..................43
9.1.3
Physical Examination Procedure ........................................................................44
9.1.4
Neurological Examination Procedure.................................................................44
9.1.5
Weight, Height, and BMI...................................................................................44


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9.1.6
Vital Sign Procedure..........................................................................................44
9.1.7
Seizure Diary Procedure.....................................................................................45
9.1.8
Documentation of Study Drug............................................................................45
9.1.9
Documentation of Concomitant Medications......................................................45
9.1.10 Documentation of Concurrent Medical Conditions.............................................45
9.1.11 Procedures for Clinical Laboratory Samples.......................................................46
9.1.12 Contraception and Pregnancy Avoidance Procedure...........................................48
9.1.13 Pregnancy ..........................................................................................................49
9.1.14 ECG Procedure..................................................................................................50
9.1.15 Clinical Assessment of Suicidal Ideation and Behavior ......................................50
9.1.16 Aberrant Behavior Checklist ..............................................................................50
9.1.17 Collection of Blood Samples for PGx Evaluation...............................................51
9.1.18 PK Sample Collection and Analysis...................................................................52
9.1.18.1
Collection of Plasma Samples for TAK-935 and M-I PK Evaluation .......52
9.1.18.2
Bioanalytical Methods for TAK-935 and M-I ..........................................52
9.1.18.3
PK Parameters.........................................................................................53
9.1.19 PD Sample Collection and Analysis...................................................................53
9.1.19.1
Collection of Plasma Samples for PD Evaluation.....................................53
9.1.19.2
.............................................................53
9.1.19.3
PD Parameters.........................................................................................53
9.1.20 Concomitant AEDs Sample Collection and Analysis..........................................54
9.1.20.1
Collection of Plasma Samples for Concomitant AED PK Evaluation.......54
9.1.20.2
Analytical Methods for Concomitant AEDs.............................................54
9.1.21 Documentation of Screen Failure .......................................................................54
9.1.22 Documentation of Study Entrance......................................................................55
9.2
Monitoring Subject Treatment Compliance..............................................................55
9.3
Schedule of Observations and Procedures................................................................55
9.3.1
Screening/Baseline Period..................................................................................56
9.3.2
Randomization...................................................................................................56
9.3.3
Part 1 .................................................................................................................56
9.3.4
Part 2 .................................................................................................................56
9.3.5
Final Visit ..........................................................................................................57
9.3.6
Follow-up Phone Call ........................................................................................57
9.3.7
Follow-up Visit..................................................................................................57
9.3.8
Poststudy Care ...................................................................................................58
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9.4
Biological Sample Retention and Destruction ..........................................................58
10.0
ADVERSE EVENTS ....................................................................................................59
10.1
Definitions...............................................................................................................59
10.1.1 AEs....................................................................................................................59
10.1.2 Additional Points to Consider for AEs................................................................59
10.1.3 SAEs..................................................................................................................61
10.1.4 Intensity of AEs .................................................................................................62
10.1.5 Causality of AEs ................................................................................................62
10.1.6 Relationship to Study Procedures.......................................................................62
10.1.7 Start Date...........................................................................................................63
10.1.8 Stop Date...........................................................................................................63
10.1.9 Frequency ..........................................................................................................63
10.1.10
Action Concerning Study Drug ....................................................................63
10.1.11
Outcome.......................................................................................................63
10.2
Procedures...............................................................................................................64
10.2.1 Collection and Reporting of AEs........................................................................64
10.2.1.1
AE Collection Period...............................................................................64
10.2.1.2
AE Reporting...........................................................................................64
10.2.2 Collection and Reporting of SAEs......................................................................65
10.2.3 Reporting of Abnormal LFTs.............................................................................65
10.3
Follow-up of SAEs ..................................................................................................66
10.3.1 Safety Reporting to Investigators, IRBs or Independent Ethics Committee, and 
Regulatory Authorities.......................................................................................66
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................67
12.0
DATA HANDLING AND RECORDKEEPING............................................................68
12.1
eCRFs......................................................................................................................68
12.2
Record Retention .....................................................................................................68
13.0
STATISTICAL METHODS..........................................................................................70
13.1
Statistical and Analytical Plans ................................................................................70
13.1.1 Analysis Sets......................................................................................................70
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................70
13.1.3 Safety Analysis ..................................................................................................71
13.1.3.1
AEs .........................................................................................................71
13.1.3.2
Other Safety Endpoints............................................................................71
13.1.4 PK and PD Analysis...........................................................................................71


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13.1.5 Secondary and Exploratory Analyses .................................................................71
13.2
Interim Analysis and Criteria for Early Termination ................................................72
13.3
Determination of Sample Size..................................................................................72
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................73
14.1
Study-Site Monitoring Visits ...................................................................................73
14.2
Protocol Deviations..................................................................................................73
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
15.1
IRB Approval ..........................................................................................................75
15.2
Subject Information, Informed Consent, and Subject Authorization .........................76
15.3
Subject Confidentiality ............................................................................................77
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
15.4.1 Publication and Disclosure.................................................................................77
15.4.2 Clinical Trial Registration..................................................................................78
15.4.3 Clinical Trial Results Disclosure ........................................................................78
15.5
Insurance and Compensation for Injury....................................................................78
16.0
REFERENCES..............................................................................................................79
LIST OF IN-TEXT TABLES
Table 6.a
Planned TAK-935 BID Doses and Associated Estimated EO Levels ..................29
Table 8.a
Planned Dose and Regimen................................................................................39
Table 9.a
Approximate Blood Volume ..............................................................................46
Table 9.b
Clinical Laboratory Tests...................................................................................47
Table 9.c
Collection of Plasma Samples for Measurement of TAK-935 and M-I in Plasma
..........................................................................................................................52
Table 9.d
Collection of Blood Samples for Measurement of 
.........53
Table 9.e
Collection of Blood Samples for Measurement of Concomitant AEDs in 
Plasma ...............................................................................................................54
Table 10.a
Takeda Medically Significant AE List................................................................62
Table 14.a
Windows for PK and PD Blood Sample Collection............................................74
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................27
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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................84
Appendix C
Elements of the Subject Informed Consent.........................................................86
Appendix D
Investigator Consent to Use of Personal Information..........................................89
Appendix E
Detailed Description of Amendments to Text.....................................................90


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Compound:
TAK-935
Title of Protocol: A Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group, 
Dose-Escalation Study With an Open-Label Part to Examine 
the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-935 as an Adjunctive Therapy 
in Subjects With Developmental and/or Epileptic 
Encephalopathies
IND No.: 121234
EudraCT No.:
Not applicable.
Study Number: TAK-935-2001
Phase: 1b/2a
Study Design:
Adult subjects (aged ≥18 and ≤65 years) with a diagnosis of developmental and/or epileptic encephalopathies 
demonstrating bilateral motor seizures (ie, drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, 
myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor features) (average of ≥2 
per month during the past 3 months) based on the investigator’s assessment will be enrolled. Drop seizures are defined 
as a seizure involving the entire body, trunk or head that leads to a fall, injury, slumping in a chair, or head hitting the 
surface, or could have led to a fall or injury, depending on the position of the subject at the time of the attack or spell. 
Drop seizures will be captured separately (eg, tonic seizures leading to a drop will be captured as a drop).
The study will screen a sufficient number of subjects to ensure approximately 20 randomized subjects.
At the Screening Visit (Visit 1), informed consent and/or assent (if applicable) is obtained from the subjects and/or 
subjects’ legally acceptable representative. Subjects will then undergo screening procedures to assess study eligibility 
in accordance with the study entry criteria. At this Screening Visit and at subsequent visits, subjects and/or subjects’ 
caregivers will be provided with a seizure diary and will be instructed to record seizure data on a daily basis starting at 
Baseline and throughout the study.
 
 
. The 4-week Baseline Period 
 can begin as soon as informed consent is signed. At the end of the 4-week Baseline Period and 
after confirmation of eligibility, subjects will return to the clinic on Day 1 in Part 1 (Visit 2) for randomization. If a 
subject does not meet the eligibility criteria during the Screening/Baseline Period, the subject will be discontinued 
from the study (screen failure).
The study will consist of 2 parts:
Part 1 is a randomized double-blind part consisting of 3 periods: a screening/baseline period (4-6 weeks), titration 
period (20 days), and maintenance period (10 days). The target final dose of 300 mg twice daily (BID) will be reached 
after a 20-day titration period.
Part 2 is an open-label continuation part consisting of 4 periods: a titration period (10 days), maintenance period 
(44 days), de-escalation period (3-6 days) and follow-up period (30 days).
Part 1 of the study is designed to investigate the safety, tolerability, pharmacokinetics (PK), and PD in adult subjects 
with developmental and/or epileptic encephalopathies in a double-blind manner. 
 
 exploratory manner.
Approximately 20 adult subjects who demonstrate ≥1 bilateral motor seizure during the 4-week Baseline Period will 
be randomly assigned on Day 1 (Visit 2) to receive TAK-935 (n=16) or matching placebo (n=4 BID orally or via 
gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube for 30 days during the Double-Blind 
Treatment Period. Subjects will initiate the investigative product (IP) (TAK-935 or placebo) at 100 mg BID from Days 
1 through 10. Subjects who cannot tolerate the 100 mg BID dosing will be withdrawn from the study. On Day 11 (Visit 
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3), subjects will return to the clinic and the IP dose will be increased to 200 mg BID; this dose level will be maintained 
from Days 11 through 20 but may be reduced to 100 mg BID in subjects who cannot tolerate the 200 mg BID dose or 
demonstrate safety concerns, based on the investigator’s judgment and in consultation with the subject’s caregiver, 
when applicable. On Day 21 (Visit 4), subjects will return to the clinic; at this visit, the investigator will review the 
subject’s safety and will discuss the benefit-risk with the subject or the subject’s legally acceptable representative 
before increasing the dose from 200 mg BID to 300 mg BID, and this dose level will be maintained from Days 21 
through 30. The dose may be reduced to 200 mg BID in subjects who cannot tolerate the 300 mg BID dose or 
demonstrate safety concerns, as described above. Subjects for whom the dose was reduced to a lower dose level will 
stay on that dose level until the end of Double-Blind Treatment Period. Three days after each dose up-titration or 
de-escalation, subjects will be contacted by phone to monitor study drug compliance, concomitant medication use, and 
adverse events (AEs). Any change in dose will be documented in the subject’s clinic chart and the subject’s caregiver 
will be advised to note the same in the dosing card.
Part 2 of the study is designed to investigate the safety, tolerability, PK, and PD of TAK-935 in adult subjects with 
developmental and/or epileptic encephalopathies in an open-label manner. Efficacy of TAK-935 on 
 
exploratory manner. All subjects who complete the Double-Blind Treatment Period in Part 1 
will have the option to continue directly into the Open-Label Treatment Period in Part 2. Because some subjects may 
enter Part 2 after receiving placebo and others on TAK-935 up to 300 mg BID, to maintain the study blind, all subjects 
will start on TAK-935 200 mg BID at the start of Part 2. On Day 31 (Visit 5), subjects will return to the clinic and 
receive TAK-935 200 mg BID from Days 31 to 40 but may be reduced to 100 mg BID in subjects who cannot tolerate 
the 200 mg BID dose or demonstrate safety concerns, based on the investigator’s judgment and in consultation with 
the subject’s caregiver, when applicable. Subjects who cannot tolerate the 100 mg BID dose or demonstrate safety 
concerns, based on the investigator’s judgment and in consultation with the subject’s caregiver, will be discontinued 
from the study. On Day 41 (Visit 6), subjects will return to the clinic; at this visit, the investigator will review the 
subject’s safety and will discuss the benefit-risk with the subject or the subject’s legally acceptable representative 
before increasing the dose from 200 mg BID to 300 mg BID, and this dose level will be maintained until the Final 
Visit (Visit 7) for the dose de-escalation phase. Subjects’ dose may be increased or decreased before Day 41 (Visit 6) 
based on clinical condition (ie, increasing seizures) and investigator judgment. This dose may be reduced to 200 mg 
BID in subjects who cannot tolerate the 300 mg BID dose or demonstrate safety concerns, as described above. 
Subjects for whom the dose was reduced to a lower dose level will stay on that dose level until the Final Visit (Visit 7) 
for the dose de-escalation phase. Three days after each dose up-titration or de-escalation, subjects will be contacted by 
phone to monitor study drug compliance, concomitant medication use, and AEs. Any change in dose will be 
documented in the subject’s clinic chart and the subject’s caregiver will be advised to note the same in the dosing card.
On Day 85 (Visit 7), subjects will return to the clinic for the Final Visit and enter the 3- or 6-day de-escalation phase. 
Immediately after the last dose is the 30-day Follow-up Period comprised of a Follow-up Phone Call (Visit 8) on 
Day 91 and a Follow-up Visit (Visit 9) on Day 121. At the Follow-up Visit, subjects will return to the clinic for study 
procedures including PD and antiepileptic drug (AED) blood sample collection.
Any subject who prematurely withdraws from the study should proceed directly to the Final Visit (at time of 
withdrawal), including dose de-escalation, as appropriate, followed by the 30-day Follow-up Period.
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Study Schematic:
Primary Objective:

To characterize the multiple-dose safety and tolerability profile of TAK-935 in adult subjects with developmental 
and/or epileptic encephalopathies.
Secondary Objective:

To characterize the multiple-dose PK profile of TAK-935 in adult subjects with developmental and/or epileptic 
encephalopathies on concomitant AEDs.
Subject Population: Adult subjects aged ≥18 and ≤65 years with developmental and/or epileptic encephalopathies 
and on background AED therapy and continued seizure activity.
Number of Subjects:

Approximately 20 subjects (n=16 for TAK-935 and n=4 
for placebo) for Part 1.

Up to 20 subjects (all TAK-935) for Part 2. 
Number of Sites: 
~11 sites in North America
Dose Levels:

TAK-935 100, 200, and 300 mg BID.

Matching placebo BID.
Route of Administration:
Oral or via G-tube/PEG-tube
Duration of Treatment:
Part 1: 30 days
Part 2: ~60 days
Period of Evaluation:
~20 weeks (includes 4 to 6-week Screening/Baseline 
and 30-day Follow-up Periods)
Main Criteria for Inclusion:

The subject is a male or female aged ≥18 and ≤65 years at the time of informed consent and the first dose of study 
drug.

The subject has a documented clinical diagnosis of developmental and/or epileptic encephalopathies with 
bilateral motor seizures, defined as an average of ≥2 per month during the past 3 months, based on the 
investigator’s assessment, and a monthly average of ≥1 per month during the 4-week Baseline Period based on the 
seizure diary record.

The subject is taking 1 to 4 AEDs at a stable dose for ≥4 weeks before Screening (Visit 1), and the subject or 
subject’s legally acceptable representative is willing to keep the regimen(s) stable throughout the study.

The subject has an average of ≥1 bilateral motor seizure per month during the 4-week Baseline Period (ie, drop 
seizures, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures 
with bilateral hyperkinetic motor features). If the subject has <1 bilateral motor seizure per month during the 
Baseline Period, the subject will be considered a screen failure.


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Main Criteria for Exclusion:

The subject was admitted to a medical facility for treatment of status epilepticus requiring mechanical respiration 
within 3 months before Screening (Visit 1).

The subject had a vagal nerve stimulator implanted within 6 months before Screening (Visit 1) and settings have 
been changed within 1 month of the Screening Visit (Visit 1) and/or are anticipated to change during the study.

The subject has unstable, clinically significant neurologic (other than the disease being studied), psychiatric, 
cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, or 
endocrine disease or other abnormality, which may impact the ability of the subject to participate or potentially 
confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, 
consultation with the Medical Monitor may be warranted.

The subject has a history of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Screening (Visit 1). If the subject is unable to comply with the C-SSRS due to 
developmental status, a parent proxy may be used for the completion of the C-SSRS. The Investigator may also 
use clinical judgment, which must then be documented in the source document.
Main Criteria for Evaluation and Analyses:
Primary Endpoint

Percentage of subjects with at least 1 treatment-emergent adverse event (TEAE), as reported by the subjects or 
subjects’ caregivers or observed by the investigator, after TAK-935 treatment.
Secondary Endpoints

Population mean estimates of drug clearance (CL), volume of distribution of the central compartment (Vc), 
absorption rate constant (Ka), volume of distribution of the peripheral compartment (Vp), intercompartmental 
clearance (Q), the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve 
over a dosing interval (AUC0-tau), the average concentration during a dosing interval at steady-state (Cav,ss), and 
the plasma concentration immediately prior to dosing (Ctrough) for TAK-935.

Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory evaluations, vital signs, and 
electrocardiogram (ECG) parameters after TAK-935 treatment.
Statistical Considerations:
TEAEs will be a primary endpoint for each part of the study. TEAEs will be summarized using descriptive statistics 
(number and percentage of subjects) for the safety analysis set. No statistical testing will be performed or inferential 
statistics will be generated.
The PK of TAK-935 and other safety endpoints will be analyzed as the secondary endpoints in each part of the study. 
The number and percentage of subjects with clinical laboratory test, vital sign, weight/BMI, and ECG parameter 
values that meet Takeda’s predefined criteria for markedly abnormal values at least once postdose will be summarized 
by treatment and part of the study. Plasma concentrations of TAK-935 will be listed for each subject and summarized 
by each time point for each dose and part of the study. A population PK/PD analysis approach will be used to 
determine the population estimates for TAK-935.
After all subjects have completed the Double-Blind Treatment Period or have discontinued from the study (and prior 
to completion of the Open-Label Period), an unblinded safety summary may be generated (Section 13.2). 
Sample Size Justification: Approximately 20 adult subjects are planned to be randomized. A formal sample size 
calculation was not performed for this study. The current sample size is deemed appropriate to evaluate the safety and 
tolerability of TAK-935 before dosing in pediatric epilepsy subjects <18 years of age. Subjects who fail to complete 
Part 1 may be replaced and will receive the same treatment as the replaced subject.


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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 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research, 
as well as study participation. The Signatory Coordinating Investigator will be required to review 
and sign the clinical study report and by doing so agrees that it accurately describes the results of 
the study.


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3.3
List of Abbreviations
24HC
24S-hydroxycholesterol
ABC-C
Aberrant Behavior Checklist-Community Edition
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BA
bioavailability
BID
twice daily
BMI
body mass index
Cav,ss
average concentration during a dosing interval at steady-state
CFR
Code of Federal Regulations
CH24H
24S-hydroxylase
CNS
central nervous system
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
EEG
electroencephalogram
EO
enzyme occupancy
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
-glutamyl transferase
G-tube
gastrostomy tube
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ID
identification
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IVRS
interactive voice response system
IWRS
interactive web response system


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LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
M-I
metabolite of TAK-935
MRD
multiple-rising dose
PD
pharmacodynamic(s)
PDR
posterior dominant rhythm
PEG
percutaneous endoscopic gastrostomy
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PPS
per-protocol set
PTZ
pentylenetetrazol
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
TAK-935 is a potent and selective cholesterol 24S-hydroxylase (CH24H) inhibitor currently in 
development for adjunct treatment for epileptic disorders.
In the brain, cholesterol is metabolized by CH24H, which is specifically and constitutively 
expressed in neurons, to 24S-hydroxycholesterol (24HC). This cholesterol metabolite, 24HC, 
leaves the brain via lipoproteins and is excreted in bile. Aberrant cholesterol metabolism is 
implicated in epilepsy disorders/syndromes.
Under normal conditions, extracellular glutamate is sequestered by glutamate transporters on 
neighboring astrocytes that require adequate cholesterol levels to efficiently maintain lipid raft 
structures in the astrocyte plasma membrane. Upon central nervous system (CNS) injury, CH24H 
is induced in reactive astrocytes and microglia. This leads to disruption in astrocytic glutamate 
homeostasis and a large increase in extracellular glutamate levels. As the CH24H enzyme converts 
cholesterol essential for the integrity of plasma membrane lipid rafts to 24HC, the circulating 
levels of 24HC increase and may further contribute to underlying pathophysiological processes. 
Excessive extracellular glutamate and 24HC levels are thought to play major roles in 
excitotoxicity either through a sustained activation of the N-methyl-D-aspartate (NMDA) receptor 
channel or as a positive allosteric modulator of the receptor [1]. The processes may be equally 
important in contributing to the enhanced glutamatergic activity observed in epilepsy disorders.
To date, TAK-935 has been studied in 4 clinical studies including a single-rising dose (SRD) 
first-in-human study (TAK-935-101), a single-dose positron emission tomography (PET) target 
occupancy study (TAK-935-1003), a multiple-rising dose (MRD) study (TAK-935-1002), and a 
single-dose relative bioavailability (BA) and food-effect study (TAK-935-1005). The 
pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-935 administered as an oral solution 
or tablet in healthy subjects were characterized in these studies. In addition, the PET study 
provided clinical evidence of dose-dependent decreases in plasma 24HC concentrations and PET 
occupancy measurements that were dose- and time-dependent and correlated with circulating 
levels of 24HC.
For further information, refer to the TAK-935 Investigator’s Brochure.
4.2
Rationale for the Proposed Study
The term epileptic encephalopathies describes a heterogeneous group of epilepsy syndromes in 
which the epileptic activity itself may contribute to severe cognitive and behavioral impairments 
above and beyond what might be expected from the underlying pathology alone (eg, cortical 
malformation) and that can worsen over time [2]. These disorders are generally diagnosed in 
childhood and adolescence, varying in their etiologies, seizure types, electroencephalographic 
patterns, cognitive deficits, and prognosis, while sharing a consistent and significant impact on 
neurological development.


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The International League against Epilepsy (ILAE) recently expanded this definition to include 
disorders that may result in developmental delay before epilepsy onset and used the term of 
Developmental and/or Epileptic Encephalopathy to encompass this broader population [3].
The current study is designed to further characterize the safety, tolerability, PK, and PD of 
multiple-dose TAK-935 administration in adult subjects with developmental and/or epileptic 
encephalopathies. An additional aim is to explore the effects of TAK-935 on seizure frequency 
using a seizure diary. In addition, this study will use a dose-escalation design, which will help 
guide dosing recommendations for future studies.
Pharmacogenomic (PGx) analysis may be conducted to investigate the contribution of genetic 
variance on drug response, for example, its efficacy and safety. As PGx is an evolving science, 
currently many genes and their functions are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response and safety that may lead to additional 
hypothesis-generating exploratory research on stored samples. Participation of study subjects in 
PGx sample collection is optional.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
!
To characterize the multiple-dose safety and tolerability profile of TAK-935 in adult subjects 
with developmental and/or epileptic encephalopathies.
5.1.2
Secondary Objective
!
To characterize the multiple-dose PK profile of TAK-935 in adult subjects with developmental 
and/or epileptic encephalopathies on concomitant antiepileptic drugs (AEDs).
5.1.3
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoint
!
Percentage of subjects with at least 1 treatment-emergent adverse event (TEAE), as reported 
by the subjects or subjects’ caregivers or observed by the investigator, after TAK-935 
treatment.
5.2.2
Secondary Endpoints
!
Population mean estimates of drug clearance (CL), volume of distribution of the central 
compartment (Vc), absorption rate constant (Ka), volume of distribution of the peripheral 
compartment (Vp), intercompartmental clearance (Q), the maximum plasma concentration 
(Cmax), the area under the plasma concentration-time curve over a dosing interval (AUC0-tau), 
the average concentration during a dosing interval at steady-state (Cav,ss), and the plasma 
concentration immediately prior to dosing (Ctrough) for TAK-935.
!
Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory 
evaluations, vital signs, and electrocardiogram (ECG) parameters after TAK-935 treatment.
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5.2.3
Exploratory Endpoints
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This phase 1b/2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-escalation study with an open-label part is designed to examine the safety, tolerability, PK, 
and PD of TAK-935 as adjunctive therapy in adult subjects with a diagnosis of developmental 
and/or epileptic encephalopathies. This study will be conducted at approximately 11 sites in North 
America with experience in conducting clinical studies in patients with rare epilepsies.
Adult subjects (aged ≥18 and ≤65 years) with a diagnosis of developmental and/or epileptic 
encephalopathies demonstrating bilateral motor seizures (ie, drop seizures, tonic-clonic, tonic, 
bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral 
hyperkinetic motor features) (average of ≥2 per month during the past 3 months) based on the 
investigator’s assessment will be enrolled. The study will screen a sufficient number of subjects to 
ensure approximately 20 randomized subjects.
At the Screening Visit (Visit 1), informed consent and/or assent (if applicable) is obtained from the 
subjects and/or subjects’ legally acceptable representative. Subjects will then undergo screening 
procedures to assess study eligibility in accordance with the study entry criteria (see Appendix A
and Sections 7.1 and 7.2). 
 
 
 
 
The 4-week Baseline Period 
 can begin as soon as 
informed consent has been signed. At the end of the 4-week Baseline Period and after confirmation 
of eligibility, subjects will return to the clinic on Day 1 in Part 1 (Visit 2) for randomization. If a 
subject does not meet the eligibility criteria during the Screening/Baseline Period, the subject will 
be discontinued from the study (screen failure).
The study will consist of 2 parts:
!
Part 1 is a randomized double-blind part consisting of 3 periods: a screening/baseline period 
(4-6 weeks), titration period (20 days), and maintenance period (10 days). The target final dose 
of 300 mg BID will be reached after a 20-day titration period.
!
Part 2 is an open-label continuation part consisting of 4 periods: a titration period (10 days), 
maintenance period (44 days), de-escalation period (3-6 days) and follow-up period (30 days).
Part 1 of the study is designed to investigate the safety, tolerability, PK, and PD in adult subjects 
with developmental and/or epileptic encephalopathies in a double-blind manner. Efficacy
 
 
 
 
during the 4-week Baseline Period will be randomly assigned on 
C
CI
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Day 1 (Visit 2) to receive TAK-935 (n=16) or matching placebo (n=4) twice daily (BID) orally or 
via stable gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube for 30
days during the Double-Blind Treatment Period. Subjects will initiate IP (investigational product; 
TAK-935 or placebo) at 100 mg BID from Days 1 through 10. Subjects who cannot tolerate the 
100 mg BID dosing will be withdrawn from the study. On Day 11 (Visit 3), subjects will return to 
the clinic and the IP dose will be increased to 200 mg BID; this dose level will be maintained from 
Days 11 through 20 but may be reduced to 100 mg BID in subjects who cannot tolerate the 200 mg 
BID dose or demonstrate safety concerns, based on the investigator’s judgment and in consultation 
with the subject’s caregiver, when applicable. On Day 21 (Visit 4), subjects will return to the 
clinic; at this visit, the investigator will review the subject’s safety data and will discuss the 
benefit-risk with the subject or subject’s legally acceptable representative before proceeding to 
increase the dose from 200 mg BID to 300 mg BID, and this dose level will be maintained from 
Days 21 through 30. The dose may be reduced to 200 mg BID in subjects who cannot tolerate the 
300 mg BID dose or demonstrate safety concerns, as described above. Subjects for whom the dose 
was reduced to a lower dose level will stay on that dose level until the end of the Double-Blind 
Treatment Period. Three days after each dose up-titration or de-escalation, subjects will be 
contacted by phone to monitor study drug compliance, concomitant medication use, and AEs. Any 
change in dose will be documented in the subject’s clinic chart and the subject’s caregiver will be 
advised to note the same in the dosing card.
On Day 1 (Visit 2), PK, PD, AED, and optional PGx blood samples will be collected before the 
morning dose of study drug. PK and PD blood samples also will be collected at 1, 3, and 5 hours 
after the morning dose on Day 1. On Day 11 (Visit 3) and Day 21 (Visit 4), PK and PD blood 
samples (before and approximately 1 hour after morning dose), an AED blood sample (before 
morning dose), and seizure diary data will be collected.
Subjects who are unwilling to continue into Part 2 of the study will proceed directly to the Final 
Visit (at Day 31), including dose de-escalation, as appropriate, followed by the 30-day Follow-up 
Period.
Part 2 of the study is designed to investigate the safety, tolerability, PK, and PD of TAK-935 in 
adult subjects with developmental and/or epileptic encephalopathies in an open-label manner. All 
subjects who complete the Double-Blind Treatment Period in Part 1 will have the option to 
continue directly into the Open-Label Treatment Period in Part 2. Because some subjects may 
enter Part 2 after receiving placebo and others TAK-935 up to 300 mg BID and to maintain the 
study blind, all subjects will start on TAK-935 200 mg BID at the start of Part 2. On Day 31 
(Visit 5), subjects will return to the clinic and receive TAK-935 200 mg BID from Days 31 to 40 
but may be reduced to 100 mg BID in subjects who cannot tolerate the 200 mg BID dose or 
demonstrate safety concerns, based on the investigator’s judgment and in consultation with the 
subject’s caregiver, when applicable. Subjects who cannot tolerate the 100 mg BID dose or 
demonstrate safety concerns, based on the investigator’s judgment and in consultation with the 
subject’s caregiver, will be discontinued from the study. On Day 41 (Visit 6), subjects will return 
to the clinic; at this visit, the investigator will review the subject’s safety data and will discuss the 
benefit-risk with the subject or subject’s legally acceptable representative before proceeding to 


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increase the dose from 200 mg BID to 300 mg BID, and this dose level will be maintained until the 
Final Visit (Visit 7) for the dose de-escalation phase. Subjects’ dose may be increased or decreased 
before Day 41 (Visit 6) based on clinical condition (ie, increasing seizures) and investigator 
judgment. This dose may be reduced to 200 mg BID in subjects who cannot tolerate the 300 mg 
BID dose or demonstrate safety concerns, as described above. Subjects for whom the dose was 
reduced to a lower dose level will stay on that dose level until the Final Visit (Visit 7) for the dose 
de-escalation phase. Three days after each dose up-titration or de-escalation, subjects will be 
contacted by phone to monitor study drug compliance, concomitant medication use, and AEs. Any 
change in dose will be documented in the subject’s clinic chart and the subject’s caregiver will be 
advised to note the same in the dosing card.
On Day 31 (Visit 5), PK, PD, AED, and PGx (if collected on Day 1) blood samples will be 
collected before the morning dose of study drug and seizure data will also be collected. On Day 41 
(Visit 6), PK, PD, and AED blood samples will be collected before the morning dose of study drug 
and seizure data will also be collected.
On Day 85 (Visit 7), subjects will return to the clinic for the Final Visit and enter the 3- or 6-day 
de-escalation phase. At this visit, PK, PD, and AED blood samples will be collected before the 
morning dose of study drug and seizure data will also be collected. Subjects will then enter the 
dose de-escalation phase and will be instructed to follow the applicable de-escalation dosing 
schedule outlined below:

For subjects on 300 mg BID during the maintenance phase, the dose will be de-escalated to 
200 mg BID for 3 days (Days 85-87) and subsequently to 100 mg BID for 3 days 
(Days 88-90).

For subjects on 200 mg BID during the maintenance phase, the dose will be de-escalated to 
100 mg BID for 3 days (Days 85-87).

For subjects on 100 mg BID during the maintenance phase, there is no de-escalation and the 
dose is discontinued on Day 85.
Immediately after the last dose is the 30-day Follow-up Period comprised of a Follow-up Phone 
Call (Visit 8) on Day 91 and a Follow-up Visit (Visit 9) on Day 121. At the Follow-up Visit, 
subjects will return to the clinic for study procedures including PD and AED blood sample 
collection.
In Parts 1 and 2, subjects will be instructed to not take their morning dose of study drug or 
concomitant AEDs on the days of scheduled study visits to facilitate collection of the predose PK, 
PD, AED, and optional PGx blood samples. The morning dose of study drug and concomitant 
AEDs will be administered in the clinic on these study days after laboratory samples are collected. 
For subjects who are not able to come for the visit during the morning hours, they should be 
instructed to take their morning dose, as usual, and come to the study site during the afternoon 
hours, as feasible for the subject. While in the clinic, the site should attempt to obtain 2 PK 
samples, separated by 1-2 hours, if possible. Hours since the last dose of the study medication must 
be recorded in the eCRF upon collection of the PK sample(s).


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Seizure data will be recorded daily in the seizure diary by each subject and/or subjects’ caregiver 
throughout the Screening/Baseline Period up until the Follow-up Visit (Visit 9) on Day 121 and 
will be collected from the diary at each visit.
The investigator, in consultation with the sponsor, may decide to reduce the TAK-935 dose at any 
time during the study in the event of any safety or tolerability concerns.
Any subject who prematurely withdraws from the study should proceed directly to the Final Visit 
(at time of withdrawal), including dose de-escalation, as appropriate, followed by the 30-day 
Follow-up Period.
A schematic of the study design is shown in Figure 6.a. A schedule of study procedures is listed in 
Appendix A.


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Figure 6.a
Schematic of Study Design
Note 1: Circled numbers denote study visits.
Note 2: Subjects will remain on stable background AED therapy throughout the study.
Note 3: Starting doses for Parts 1 and 2 are shown; individual subject doses may be reduced to the previous dose level if there are safety and tolerability concerns at 
new dose level.
Note 4: Maintenance dose levels (ie, 100, 200, or 300 mg BID) will be de-escalated at the end of the maintenance phase of Part 2, depending on the dose subjects are 
taking at that time (ie, if at TAK-935 300 mg BID level, reduce to 200 mg BID for 3 days followed by 100 mg BID for 3 days; if at the 200 mg BID level, reduce to 
100 mg BID for 3 days; if at the 100 mg BID level, there is no de-escalation).


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6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-escalation study with an open-label part to examine the safety, tolerability, PK and PD, and 
preliminary efficacy of TAK-935 as adjunctive therapy in the treatment of subjects with a 
diagnosis of developmental and/or epileptic encephalopathies demonstrating bilateral motor 
seizures (ie, drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, 
myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor features) (average of ≥2 
per month during the past 3 months) based on the investigator’s assessment.
The safety, tolerability, PK, and 
 of TAK-935 after multiple-dose 
administration either orally or via G-Tube/PEG tube is first assessed (in Part 1), and then the 
longer-term safety, tolerability, and PK/PD of TAK-935 is assessed (in Part 2), with a seamless 
transition between Parts 1 and 2. The main goal of this study is to identify the safe and tolerable 
dose of TAK-935 to assess the efficacy of TAK-935 in subjects with developmental and/or 
epileptic encephalopathies.
6.2.2
Dose
6.2.2.1
Dose Selection Rationale
In the current study, dose selection was mainly based on the safety and tolerability data from the 
single- and multiple-dose phase 1 studies in healthy subjects administered TAK-935 as an oral 
solution. The selection of BID doses was also supported by the PK/PD/enzyme occupancy (EO) 
modeling and simulations using available phase 1 data. In addition, nonclinical data from rodent 
epilepsy models were used to define efficacious doses.
The safety results from the phase 1 studies show that TAK 935 (up to a single dose of 1350 mg) is 
generally safe and well tolerated in healthy male and female subjects. TAK-935 has been 
evaluated at doses up to 600 mg once daily (QD) as well as 300 mg BID in healthy adult subjects in 
the MRD study. Multiple rising doses of TAK-935 up to 400 mg QD for 14 days without 
up-titration was generally safe and well tolerated in healthy subjects. When administered in a 
nontitrating fashion, AEs considered by the investigator to be nonserious were seen in individual 
subjects at 300 mg BID (mental confusion of mild intensity) and 600 mg QD (acute psychosis of 
severe intensity) dose levels. This TAK-935-2001 study will continue to investigate safety, 
tolerability, PK, and PD of TAK-935 by studying a dose range of 100 mg BID to 300 mg BID in an 
epilepsy adult patient population. In this study, a titration scheme will be used to ensure safety and 
tolerability before moving to higher doses.
In pentylenetetrazol (PTZ)-induced kindling in mice, TAK-935 at a dose of 1 mg/kg resulted in a 
statistically significant reduction in seizure counts. This dose also resulted in an approximately 
60% reduction in mean brain 24HC levels, which translated to an average EO of approximately 
CCI


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65%. At higher doses, TAK-935 exerted stronger effects on generalized seizures. The 1 mg/kg 
dose was determined to be the minimum effective dose of TAK-935.
A selective PET ligand was developed and used to assess the CNS target engagement of TAK-935 
in healthy adult subjects, and a preliminary PK/PD/EO model was developed. Firstly, an empirical 
PK model was developed to characterize complex and nonlinear PK data in healthy adult subjects 
from the SRD and MRD studies as well as the relative BA study comparing the exposure between 
oral dosing with solution and tablet formulations. Subsequently, the predicted TAK-935 plasma 
concentrations were modeled with PD (24HC and PET occupancy) data to assess target 
engagement. The relationship between TAK-935 plasma concentrations and the observed brain 
occupancy values was characterized by a sigmoidal maximum effect model using an effect-site 
compartment to account for the temporal lag observed between PK and PD measurements. The 
relationship between TAK-935 plasma concentrations and plasma 24HC levels was characterized 
by an inhibitory indirect response model. This PK/PD/EO model was used to select the doses for 
the current study. The model-based simulations were performed for both QD and BID dosing 
regimens with the same daily dose in adult subjects, and the BID regimen was selected over QD 
regimen due to its lower variability on the expected EO, PK, and PD parameters and a more 
sustained period during a dosing interval with EO above 65%.
6.2.2.2
Dose Selection Procedures
The planned doses are based on predictions from the available PK/PD/EO model. A TAK-935 
100 mg tablet, administered as 1, 2, or 3 tablets corresponding to the different dose levels, will be 
used for dosing in adult subjects.
The EO levels and planned TAK-935 doses are shown for each part of the study in Table 6.a.
Table 6.a
Planned TAK-935 BID Doses and Associated Estimated EO Levels
TAK-935 BID Dose
(mg)
Average EO
Level (%) (a)
300
85-95
200
80-90
100
70-80
(a) Average EO% at steady state during a dosing interval.
The investigator, in consultation with the sponsor, may decide to reduce the IP (TAK-935 or 
placebo) during Part 1 and TAK-935 during Part 2 dose at any time during the study, in the event 
of any safety or tolerability concerns. In Part 1, the planned starting dose of TAK-935 for adult 
subjects is 100 mg BID to achieve an average steady-state EO of approximately 70% to 80%. If 
well tolerated, this dose will be increased to 200 mg BID on Day 11 and subsequently to 300 mg 
BID on Day 21; the average steady-state EO at these doses are expected to be approximately 80% 
to 90% and 85% to 95%, respectively (Table 6.a).


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In Part 2, the planned starting dose of TAK-935 for all subjects, including those who received 
placebo in Part 1, is 200 mg BID to be increased to 300 mg BID. The dose may be decreased at any 
time due to safety or tolerability concerns.
6.2.3
Endpoints
6.2.3.1
Safety Endpoints
The safety-related endpoints of TEAEs, clinical laboratory test results, vital sign measurements, 
C-SSRS, and ECG parameters selected for this study are standard methods for assessing safety and 
tolerability in clinical studies. The ABC-C is a standard tool for measuring the severity of a range 
of problem behaviors commonly observed in individuals with intellectual and developmental 
disabilities.
6.2.3.2
PK Endpoints
The secondary PK endpoints selected for this study, Cmax, AUC0-tau, Cav,ss, and Ctrough are common 
PK parameters used to describe the steady-state exposure of a study drug following multiple doses 
in clinical studies. Additional population PK parameters will be included in the population PK 
model used to characterize the TAK-935 concentration-time profile and will be reported in the 
population PK report.
6.2.3.3
6.2.3.4
CCI
CCI
CCI
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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 of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for TAK-935, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the 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.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
In the event that the sponsor, an Institutional Review Board (IRB), or a regulatory authority elects 
to terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before the first dose of study drug.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
1. In the opinion of the investigator, the subject or subject’s legally acceptable representative is 
capable of understanding and complying with protocol requirements.
2. The subject or the subject’s legally acceptable representative signs and dates a written, 
informed consent form and any required privacy authorization before the initiation of any 
study procedures, including requesting that a subject fast for any clinical laboratory 
evaluations. An assent should be obtained from the subject, if possible. If the subject cannot 
provide assent (ie, due to developmental status), the investigator should document why assent 
was not obtained. For subjects with G-tube/PEG tube, a separate supplemental consent form 
will be signed by the subject/caregiver and attached to the general consent.
3. The subject is a male or female aged ≥18 and ≤65 years at the time of informed consent and the 
first dose of study drug.
4. The subject has a documented clinical diagnosis of developmental and/or epileptic 
encephalopathies with bilateral motor seizures, defined as an average of ≥2 per month during 
the past 3 months, based on the investigator’s assessment, and a monthly average of ≥1 per 
month during the 4-week Baseline Period, based on the seizure diary record.
Developmental and/or epileptic encephalopathy will be defined as:

Subjects with an established diagnosis of the following: for example, Lennox-Gastaut 
Syndrome, Dravet Syndrome, Tuberous Sclerosis Complex, OR

Retrospectively including:

History of special education classes, OR

Formal IQ <70, OR

Generalized background slowing (posterior dominant rhythm [PDR] persistently 
<8 Hz) on interictal EEG,
AND

Epilepsy not due to a brain injury acquired after age 3 years.
5. The subject is taking 1 to 4 AEDs at a stable dose for ≥4 weeks before Screening (Visit 1), and 
the subject or subject’s legally acceptable representative is willing to keep the regimen(s) 
stable throughout the study. For the purposes of this study ketogenic diet and vagus nerve 
stimulation will not be considered AEDs.


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6. The subject has an average of ≥1 bilateral motor seizure per month during the 4-week 
Baseline Period (ie, drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, 
myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor 
features). Drop seizures are defined as a seizure involving the entire body, trunk or head that 
leads to a fall, injury, slumping in a chair, or head hitting the surface, or could have led to a fall 
or injury, depending on the position of the subject at the time of the attack or spell. Drop 
seizures will be captured separately (eg, tonic seizures leading to a drop will be captured as a 
drop). If the subject has <1 bilateral motor seizure per month during the Baseline Period, the 
subject will be considered a screen failure.
7. A female subject of childbearing potential* must have a negative serum pregnancy (human 
chorionic gonadotropin [hCG]) test at Screening (Visit 1) and a negative urine pregnancy test 
before Randomization (Visit 2). If urine cannot be collected, the results of the serum 
pregnancy test obtained at Visit 1 must be confirmed to be negative by the investigator prior to 
randomization.
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely an adequate method of contraception* from signing of informed 
consent throughout the duration of the study and for 30 days after last dose.
9. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 30 days after last dose.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.12 and reporting responsibilities are defined in Section 9.1.13.
10. Subjects and/or subjects’ caregivers must agree to not post any subject’s personal medical data 
related to the study or information related to the study on any web site or social media site (eg, 
Facebook, Twitter) until the study has been completed.
11. For subjects with G-tube/PEG tube, G-tubes/PEG tubes should have been placed and been 
functioning for at least 3 months prior to screening. Naso-gastric tubes are not allowed.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has been part of a clinical study involving another investigational product in the 
previous 3 months or subject is currently receiving an investigational product.
2. The subject has received TAK-935 in a previous clinical study or as a therapeutic agent.
3. The subject was admitted to a medical facility for treatment of status epilepticus requiring 
mechanical respiration within 3 months before Screening (Visit 1).
4. The subject had a vagal nerve stimulator implanted within 6 months before Screening (Visit 1) 
and settings have been changed within 1 month of the Screening Visit (Visit 1) and/or are 
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5. The subject is on a ketogenic diet that has been started within 6 months of the Screening Visit 
(Visit1), has been changed within 1 month of the Screening Visit (Visit 1), or is anticipated to 
change during the study.
6. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.
7. The subject has unstable, clinically significant neurologic (other than the disease being 
studied), psychiatric, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal,
urologic, immunologic, hematopoietic, or endocrine disease or other abnormality, which may 
impact the ability of the subject to participate or potentially confound the study results. It is the 
responsibility of the investigator to assess the clinical significance; however, consultation with 
the Medical Monitor may be warranted.
8. The subject has degenerative eye disease.
9. The subject has a history of suicidal behavior or any suicidal ideation of type 4 or 5 on the 
C-SSRS at Screening (Visit 1). If the subject is unable to comply with the C-SSRS due to 
developmental status, a parent proxy may be used for the completion of the C-SSRS. The 
Investigator may also use clinical judgment, which must then be documented in the source 
document.
10. Positive for human immunodeficiency virus, hepatitis B, or hepatitis C infections. (Note that 
subjects who have been vaccinated against hepatitis B [hepatitis B surface antibody 
{Ab}-positive] who are negative for other markers of prior hepatitis B infection [eg, negative 
for hepatitis B core Ab] are eligible. Also note that subjects who are positive for hepatitis C Ab 
are eligible as long as they have a negative hepatitis C viral load by quantitative polymerase 
chain reaction [qPCR]). 
11. The subject has an abnormal and clinically significant ECG at Screening (Visit 1), in the 
opinion of the investigator, for example, second or third-degree heart block or a corrected QT 
interval (QTc) >450 msec. Entry of any subject with an abnormal but not clinically significant 
ECG must be approved and documented by signature by the principal investigator or 
appropriately qualified delegate.
12. The subject has abnormal clinical laboratory test results at Screening (Visit 1) that suggest a 
clinically significant underlying disease. If the subject has alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) >2.5 × the upper limit of normal (ULN), the Medical 
Monitor should be consulted.
13. The subject has a known hypersensitivity to any component of the formulation of TAK-935.
14. The subject has received any excluded medications, procedures, or treatments during the time 
periods listed in Section 7.3.


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15. The subject has a history of alcohol, opioid, or other drug use disorder, as per the Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition, within the previous 2 years before 
Screening (Visit 1). Medical marijuana use is allowed.
16. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 30 days after participating in this study; or intending to donate ova during such time 
period.
17. If male, the subject intends to donate sperm during the course of this study or within 30 days 
after the last dose of study drug.
7.3
Excluded Medications, Procedures, and Treatments
The following medications and products are excluded from the Screening Visit (Visit 1) until the 
end of the Follow-up Visit (Visit 9):

Intermittent use of benzodiazepines as rescue medication ≥3 times a week. Chronic 
benzodiazepine use is not exclusionary.

Stiripentol
Subjects should be advised to not consume alcohol or drugs such as cannabis (medical marijuana is 
allowed) during the study. Subjects must be instructed not to take any medications, including 
over-the-counter products, without first consulting with the investigator.
7.4
Diet, Fluid, and Activity Control
TAK-935 tablets should be administered at approximately the same time on each dosing day with 
or without food. The time of the last meal relative to dosing must be recorded in the electronic case 
report form (eCRF) at each PK/PD sampling visit. Subjects and/or subjects’ caregivers should be 
instructed to maintain the same dose administration time for the concomitant AEDs throughout the 
study, if possible. It is recommended that subjects remain upright (seated, standing, or ambulatory) 
for approximately 1 hour after study drug dosing on the PK sampling days, if possible. For 
subjects receiving study drug via G-tube/PEG tube, other medications or enteral feeds should not 
be given concurrently.
Subjects who are on a ketogenic diet must maintain stable dietary habits throughout the study. The 
ketogenic diet should not be altered during the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Subjects who cannot tolerate the 100 mg BID dosing will be withdrawn from the study and should 
undergo all procedures scheduled for the Final Visit at the time of withdrawal.
The primary reason for discontinuation or withdrawal of the subject from the study or of study 
drug should be recorded in the eCRF using the categories listed below. For screen failure subjects, 
refer to Section 9.1.21.


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1. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.

Liver Function Test (LFT) Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.11), if the following circumstances occur at any 
time during study drug treatment:
ALT or AST >8 × ULN, or
ALT or AST >5 × ULN and persists for >2 weeks, or
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
2. Significant Protocol Deviation. The discovery after the first dose of study drug that the subject 
failed to meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to Follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
4. Withdrawal by Subject. The subject wishes to withdraw (or subject’s legally acceptable 
representative wishes to withdraw the subject) from the study.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded. Withdrawal due to an AE 
should not be recorded in the “voluntary withdrawal” category. Similarly, lack of efficacy 
should not be recorded in the “voluntary withdrawal” category.
5. Progressive Disease. Clinically significant worsening in seizure frequency as judged by the 
investigator in either Part 1 or Part 2.
6. Symptomatic Deterioration. The subject has an episode of clinically symptomatic status 
epilepticus that requires mechanical respiration.
7. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
8. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.13.
9. Other.


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Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’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 
Final Visit (at time of withdrawal), including dose de-escalation, as appropriate, followed by the 
30-day Follow-up Period. Up to 6 discontinued or withdrawn subjects may be replaced at the 
discretion of the sponsor. For the subjects who discontinue or are withdrawn from the study, 
whenever possible, the seizure activity monitoring will continue for 30 days following study exit 
to assess possible rebound in seizure activity.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to all or any of the drugs defined below.
8.1.1.1
Study Drug
The sponsor will supply the study sites with TAK-935 100 mg tablets and matching placebo 
tablets. TAK-935 100 mg tablets and matching placebo tablets are manufactured by Spera Pharm 
Inc, Osaka Japan. 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. The label text will be in English. The bottles to be used will be 
identifiable by a unique identification number and managed by the interactive voice response 
system (IVRS)/interactive web response system (IWRS).
For subjects receiving study drug via G-tube/PEG tube, tablets will be crushed, suspended in 
water, and the suspension will be administered via the G-tube/PEG tube using a syringe. Complete 
instructions will be provided to subjects/caregivers in a document provided outside of the protocol.
8.1.1.2
Rescue Medication
Rescue medication will be used in case of major seizures, according with the judgment of the 
investigator and based on evidence of prior positive responses of each subject. Rescue medication 
will not be supplied by the sponsor.
8.1.1.3
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol are the following:

TAK-935 100 mg tablets.

Matching placebo tablets.
8.1.2
Storage
TAK-935 100 mg tablets and matching placebo tablets must be stored at 20°C to 25°C 
(68°F-77°F). Excursions are permitted between 15°C and 30°C (59°F-86°F).
Study drug, must be kept in an appropriate, limited-access, secure place until it is used 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 working day.


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8.1.3
Dose and Regimen
Each subject and/or subject’s caregiver will be instructed to administer study drug, orally or via 
G-tube/PEG tube, at the same time each day with or without food. The study site personnel will 
indicate how many tablets should be taken per day on the bottle label, per information provided by 
the IVRS/IWRS. For each visit with scheduled PK blood sampling, the morning dose of study 
drug will be administered in the clinic. The time of the last meal relative to dosing must be 
recorded in the eCRF at each PK/PD sampling visit.
For G-tube/PEG-tube administration, the required number of tablets will be ground into a powder, 
suspended in water, and the suspension will be administered via G-tube/PEG-tube using a syringe. 
Complete instructions for administering the drug via G-tube/PEG-tube will be provided to 
subjects/caregivers in a document provided outside of the protocol.
The investigator or designee will instruct the subject and/or subject’s caregiver on the dosing 
procedures and study drug storage requirements. Subjects and/or subjects’ caregivers should 
return unused study drug at each study visit to allow the investigator or designee to evaluate 
subjects’ compliance with the dosing instructions.
The planned daily dose and tablet count to be administered to subjects in each part of the study is 
shown in Table 8.a.
Table 8.a
Planned Dose and Regimen
Study Part
Planned Doses
Treatment Description
Part 1
(double-blind dose 
escalation)
TAK-935 200 mg/day (100 mg BID)
Matching Placebo BID
TAK-935 400 mg/day (200 mg BID)
Matching Placebo BID
TAK-935 600 mg/day (300 mg BID)
Matching Placebo BID
1 TAK-935 100 mg tablet BID for 10 days
1 placebo tablet BID for 10 days
2 TAK-935 100 mg tablets BID for 10 days
2 placebo tablets BID for 10 days
3 TAK-935 100 mg tablets BID for 10 days
3 placebo tablets BID for 10 days
Part 2 (open-label
dose escalation)
TAK-935 400 mg/day (200 mg BID)
TAK-935 600 mg/day (300 mg BID)
2 TAK-935 100 mg tablets BID for 10 days
3 TAK-935 100 mg tablets BID for 44 days
Note 1: The dose of IP will be gradually escalated during Parts 1 and 2, provided there are no safety or tolerability 
concerns. At the end of Part 2, the dose of TAK-935 will be de-escalated before dosing is discontinued. See Section 
6.1 for details of the dose escalation and de-escalation procedures.
Note 2: The investigator, in consultation with the sponsor, may reduce the IP (Part 1) or TAK-935 (Part 2) dose at any 
time in the event of any safety or tolerability concerns, including to the 100 mg BID dose in Part 2.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.


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All cases of overdose (with or without associated AEs) will be documented in the eCRF. Cases of 
overdose without manifested signs or symptoms are not considered AEs. AEs associated with an 
overdose will be documented on the AE eCRF page according to Section 10.2.1.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive their treatment according to the randomization schedule. The 
investigator or investigator’s designee will access the IVRS/IWRS at the Screening Visit (Visit 1) 
to obtain the subject number. At Randomization (Visit 2), the investigator or the investigator’s 
designee will use the IVRS/IWRS to randomize eligible subjects into the study. During this 
contact, the investigator or designee will provide the necessary subject-identifying information, 
including the subject number assigned at Screening. The medication identification (ID) number of 
the study drug to be dispensed will then be provided by the IVRS/IWRS. At subsequent 
drug-dispensing visits, the investigator or designee will again contact the IVRS/IWRS to request 
additional study drug for a subject. The medication ID number of the study drug to be dispensed 
will again be provided by the IVRS/IWRS. The medication ID number will be entered onto the 
eCRF. If sponsor-supplied drug (TAK-935 100 mg or matching placebo tablets) is lost or 
damaged, the site can request a replacement from the IVRS/IWRS (refer to the IVRS/IWRS 
manual provided separately).
Each subject and/or subject’s caregiver should be instructed as follows:

Keep sponsor-supplied drugs in original containers until the time of dosing.

Administer study drug as instructed. If the subject misses a dose, he or she should not be given 
twice the dose the next day. 

Store sponsor-supplied drugs according to the label and keep them out of the reach of children.

Return sponsor-supplied drugs at each clinic visit.

On the dosing card provided with each supply of drug, record the AM and PM daily doses and 
days/times the drug has been down-titrated, including during the de-escalation portion of the 
study. 
In addition to the above, subjects/caregivers will be provided complete instructions on preparing 
the study drug for administration via G-tube/PEG-tube in a document provided outside of the 
protocol. They should follow these instructions carefully.
8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.


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Study drug will be administered in a double-blind manner in Part 1 and in an open-label manner in 
Part 2. The study drug blind will be maintained using the IVRS/IWRS. The principal investigator 
at each study site will receive instructions for obtaining the study drug assignment through the 
IWRS. During regularly scheduled monitoring visits, a study monitor from the sponsor or a 
designee will perform an inventory of assigned and unassigned bottles of study drug. All 
assigned/unassigned study drug bottles will be reconciled and returned to the sponsor or a designee 
before study closure.
8.4
Unblinding Procedure
The study drug blind in Part 1 shall not be broken by the investigator unless information 
concerning the study drug is necessary for the medical treatment of the subject. If possible, the 
sponsor/designee should be notified before the study drug blind is broken. If a medical emergency 
requiring unblinding occurs, the investigator (or designee) at the site will contact the sponsor or 
designee (see Takeda Medical Monitor contact information listed in Section 1.1) to assess the 
necessity to break the study drug blind.
For unblinding a subject, the investigator can obtain the study drug blind information by accessing 
the IVRS/IWRS. The sponsor/designee must be notified immediately if the study drug blind is 
broken. The date, time, and reason the blind was broken must be recorded in the source documents 
and on the appropriate eCRF.
If any site personnel is unblinded, study drug must be de-escalated in consultation with the 
Medical Monitor and the subject must be withdrawn from the study. The reason for withdrawal 
should be recorded as “Protocol Deviation.” Subjects who are withdrawn early from the study 
should undergo all procedures scheduled for the Final Visit at the time of withdrawal.
8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (TAK-935 100 mg and matching placebo tablets), the investigator or 
designee must maintain records of all sponsor-supplied drug delivery to the site, site inventory, 
dispensation and use by each subject, 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 
study drug is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by recording in IVRS/IWRS. 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.


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The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to the following:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or medication ID number) used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IVRS/IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(TAK-935 100 mg and matching placebo tablets) on a sponsor-approved drug accountability log. 
The following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, expiry date, date 
and amount dispensed including initials or signature of the person dispensing the drug, and the 
date and amount returned to the site by the subject, including the initials or signature of the person 
receiving the sponsor-supplied drug. The log should include all required information as a separate 
entry for each subject to whom sponsor-supplied drug is dispensed.
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Before 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. 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 retest date extension of sponsor-supplied drug during the 
study conduct. On expiry date notification from the sponsor or designee, the 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 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 sites.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures to be performed and data to be collected. For 
each procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
9.1.1.1
Study Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for clinical 
laboratory evaluations.
The informed consent form must be signed by the subject or the subject’s legally acceptable 
representative. A verbal or written subject assent should be obtained from the subject in the event 
the subject is not capable of providing an informed consent. If the subject is not capable of 
providing an assent, the reason should be documented by the investigator.
In addition, a separate supplemental informed consent form (ICF) providing information on 
G-tube/PEG-tube administration of study drug will be signed.
A unique subject identification (ID) number (subject number) will be assigned to each subject at 
the time that informed consent is obtained; this subject number will be used throughout the study.
9.1.1.2
PGx Informed Consent Procedure
A separate informed consent form pertaining to collection, storage, and analysis of the PGx blood 
samples must be obtained before collecting these samples in this study. The provision of consent to 
collect and analyze the PGx sample is independent of consent to the other aspects of the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject. Height and weight will be collected at Screening (Visit 1).
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.10).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and the efficacy or safety evaluations stopped at or within 28 days before signing of 
informed consent. AED history will be collected as part of the medication history information.


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9.1.3
Physical Examination Procedure
The physical examination will consist of the following body systems: (1) ears, nose, throat; 
(2) cardiovascular system; (3) respiratory system; (4) gastrointestinal system; (5) dermatologic 
system; (6) extremities; (7) musculoskeletal system; (8) lymph nodes; (9) psychiatric status; and 
(10) other. All examinations are to be performed by the investigator. The physical examination 
must be captured in the source document and eCRF.
9.1.4
Neurological Examination Procedure
A separate neurological examination will be performed and collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, motor function (including 
strength and reflexes), and sensation.
As part of the neurological exam, vision testing is recommended to include fundoscopy and best 
corrected visual acuity using a pocket vision screening card, if possible.
9.1.5
Weight, Height, and BMI
Weight and height are to be measured while the subject 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 or the subject’s caretaker). The investigator must document in the source document the 
reason for not obtaining height or weight (eg, the subject is in a wheelchair). The BMI is calculated 
using metric units with the formula provided below. The Takeda standard for collecting height is 
centimeters without decimal places and for weight is kilograms (kg) with 1 decimal place. BMI 
should be derived as follows:
Note that although height is reported in centimeters, the formula uses meters, which can be 
determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2.
9.1.6
Vital Sign Procedure
Vital signs to be measured are oral body temperature, sitting (after resting for 5 minutes) blood 
pressure, heart rate (beats per minute), and sitting respiratory rate. Heart rate and blood pressure 
will also be measured after 5 minutes supine and after 1 and 3 minutes standing, if possible. The 
investigator must document in the source document the reason for not obtaining a standing or 
supine blood pressure (eg, the subject is in a wheelchair).
Vital signs should be measured at the same time of day across visits, if possible. 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 0.25 hour before or after the scheduled blood draw, if possible.


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All vital sign data collected at study visits will be recorded on the source documents and in the 
eCRF. 
9.1.7
9.1.8
Documentation of Study Drug
A dosing card will be provided to the subject and/or caregiver at each clinic visit to record daily 
AM and PM study drug administration throughout the study, including changes in dosing regimen 
(de-escalation) that may occur between visits and during the de-escalation period of the study.
9.1.9
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by Takeda. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed 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 source document and eCRF. Documentation will include 
generic medication name, dose, unit, frequency, route of administration, start and end dates, and 
reason for use.
9.1.10 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. These include clinically significant laboratory, ECG, or physical 
examination abnormalities noted at Screening (Visit 1), according the judgment of the 
CCI
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investigator. The condition (ie, diagnosis) should be described and recorded on the Medical 
History form.
9.1.11 Procedures for Clinical Laboratory Samples
Blood and urine samples are to be collected at the time points stipulated in the Schedule of Study 
Procedures (Appendix A). Blood samples for hematology and serum chemistry tests are to be 
collected after an overnight fast of ≥8 hours, if possible. Samples will be collected in accordance 
with acceptable laboratory procedures. Details of these procedures and required safety monitoring 
will be given in the laboratory manual.
For an individual subject, the maximum volume of blood collected at any single visit will be 
approximately 71 mL, and the approximate total volume of blood collected over the course of the 
study will be 230 mL (Table 9.a).
Table 9.a
Approximate Blood Volume
Sample Type
Sample
Volume
(mL)
Number of Samples (a)
Total 
Volume
(mL)
Screening 
Visit
Part 1
Part 2
Follow-up
Visit
HIV, HBsAg, HCV (b)
6
1
---
---
---
6
HCV RNA detection by qPCR (c)
6
1
---
---
---
6
FSH (d)
(d)
1
1
(d)
Estradiol (e)
2
1
1
4
Serum chemistry (f)
6
1
1
2
---
24
Hematology
2
1
1
2
---
8
Plasma sample for TAK-935 PK analysis
4
---
8
3
---
44
Plasma sample for AED analysis
4
---
3
3
1
28
Plasma sample for PD analysis (g)
4
2
16
6
2
104
Blood sample for DNA PGx
6
---
1
---
---
6
Blood sample for RNA PGx (g)
2.5
---
2
2
---
10
Total Blood Volume (mL)
240
--- =not applicable.
(a) Does not include blood draws at any unscheduled visits.
(b) One 2-mL blood sample for each test.
(c) Subjects who are positive for hepatitis C Ab should return to the clinic for an unscheduled visit to provide a blood 
sample for HCV qPCR.
(d) For diagnostic purposes in female subjects only; sample will be run from serum chemistry volume (no extra 
volume required).
(e) In female subjects only.
(f) Includes serum pregnancy test for female subjects of childbearing potential.
(g) Two blood samples per scheduled time.


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The clinical laboratory tests to be performed are listed in Table 9.b.
Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis (a)
Study Specific
RBC
WBC with differential 
(% and absolute)
Hemoglobin
Hematocrit
Platelets
PT/INR
aPTT
ALT
Albumin
Alpha-1-acid glycoprotein
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
FSH (c)
Estradiol (d)
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Microscopic Analysis: (b)
RBC/high power field
WBC/high power field
Epithelial cells, casts etc
Plasma
Plasma (Concomitant AEDs)
Carbamazepine 
Clobazam 
Valproic acid
Phenytoin
Topiramate
Lamotrigine
Rufinamide
Zonizamide
Phenobarbital
Levetiracetam
Lacosamide
10-hydroxycabazepine (metabolite 
of oxcarbazepine)
Felbamate
Diagnostic Screening
Serum
Urine (a)
HIV
Drug screen including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, alcohol, and 
cotinine
hCG (for pregnancy) (f)
HBsAg and anti-HCV
HCV RNA detection by qPCR (e)
hCG (for pregnancy) (f)
aPTT= activated partial thromboplastin time, FSH=follicle-stimulating hormone, GGT=γ-glutamyl transferase, 
HDL=high-density lipoprotein, LDL=low-density lipoprotein, PT=prothrombin time, RBC=red blood cell; 
WBC=white blood cell.
(a) If urine cannot be collected at the time of the Screening Visit or other Visits due to the subject’s cooperation or 
because the subject is wearing a diaper, it is acceptable for the subject to continue in the study and the reason should be 
documented in the source document.
(b) Only if dipstick results are positive.
(c) For diagnostic purposes in female subjects only.
(d) In female patients only
(e) Subjects who are positive for hepatitis C Ab should return to the clinic for an unscheduled visit to provide a blood 
sample for HCV qPCR.
(f) Only for female subjects of childbearing potential. If urine cannot be collected at Visit 2, the reason should be 
documented in the source document and the results of the serum pregnancy test obtained at Visit 1 must be confirmed 
to be negative by the investigator prior to randomization. An additional serum hCG pregnancy test will be performed 
at the Final Visit.
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The central laboratory will perform laboratory tests for hematology, serum chemistry, and 
urinalysis. The results of clinical laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. The investigator will maintain a copy of the 
laboratory accreditation and the reference ranges for the laboratory used.
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed preferably 
within 48 to 72 hours and no later than 5 days after the abnormality was noted.
(Please refer to Section 7.5 for discontinuation criteria and Section 10.2.3 for reporting 
requirements related to ALT or AST >3×ULN in conjunction with total bilirubin >2×ULN.)
If the ALT or AST remains elevated >3×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, and discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3
for reporting requirements).
If urine cannot be collected due to the subject’s cooperation or because the subject is wearing a 
diaper, the reason should be documented in the source document and, for female subjects, the 
results of the serum pregnancy test obtained at Visit 1 must be confirmed to be negative by the 
investigator prior to randomization.
9.1.12 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for up to 30 days after 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. Females 
of childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list of adequate contraception below.
From signing of informed consent, throughout the duration of the study, and for 30 days after the 
last dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition, they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal (eg, defined 
as ≥1 year since last regular menses with an FSH >40 IU/L or ≥5 years since last regular menses, 
confirmed before any study drug is administered).
**Sterilized males should be ≥1 year postvasectomy and have confirmed that they have obtained 
documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate 
per year when used consistently and correctly. In this study, where medications and devices 
containing hormones are excluded, the only acceptable methods of contraception are as follows:


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Barrier methods (each time the subject has intercourse):

Male condom PLUS spermicide.

Cap (plus spermicidal cream or jelly) PLUS male condom and spermicide.

Diaphragm (plus spermicidal cream or jelly) PLUS male condom and spermicide.
Intrauterine devices:

Copper T PLUS condom or spermicide.
Sterilization:

Bilateral tubal occlusion.

Vasectomized partner (provided that the partner is the sole sexual partner of the study 
participant and the absence of sperm in the ejaculate has been confirmed).
Abstinence:

Sexual abstinence, if it is the preferred and usual lifestyle of the subject, will be considered an 
acceptable method of contraception on a case-by-case basis upon prior approval by the 
Medical Monitor. Subjects practicing abstinence as a method of contraception must refrain 
from heterosexual intercourse throughout the duration of the study and for 30 days after last 
dose of study drug.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study and for 30 days after the last dose of study drug. This may be signed 
by the legal representative of the subject.
All female subjects of childbearing potential must have a negative serum hCG pregnancy test at 
Screening (Visit 1) and a negative urine hCG pregnancy test on Day 1 (Visit 2), before receiving 
any dose of study drug. During the course of the study, subjects will receive continued guidance 
with respect to the avoidance of pregnancy and sperm donation as part of the study procedures. An 
additional serum hCG pregnancy test will be performed at the Final Visit.
9.1.13 Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 30 days after the last dose should also be recorded 
following authorization from the subject’s partner.
If the pregnancy occurs during administration of active study drug, for example, after Visit 2 or 
within 30 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.


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Should the pregnancy occur during or after administration of blinded study drug, the investigator 
must inform the subject of their right to receive treatment information. If the subject chooses to 
receive unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable).
All reported pregnancies, including those in female partners of male subjects, will be followed up 
to final outcome, using the pregnancy form. 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 ECG Procedure
A 12-lead ECG will be recorded. If the subject cannot tolerate being supine, a sitting ECG may be 
obtained. The investigator (or a qualified observer at the study site) will interpret the ECG using 1 
of the following categories: within normal limits, abnormal but not clinically significant, or 
abnormal and clinically significant. The interpretation of the ECG will be recorded in the source 
documents and in the eCRF. The time that the ECG was performed will be recorded. The 
following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, RR 
interval, PR interval, QT interval, QRS interval with QTcF, and corrected QT interval. ECG traces 
recorded on thermal paper will be photocopied to avoid degradation of trace over time.
9.1.15 Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed using the C-SSRS. The C-SSRS is a 3-part scale 
that measures suicidal ideation (eg, subject endorses thoughts about a wish to be dead or has other 
thoughts of suicide), intensity of ideation (frequency, duration, controllability, deterrents, and 
reasons for ideation), and suicidal behavior (actually, interrupted, and aborted attempts at suicide) 
[8].
Two versions of the C-SSRS will be used in this study: The Screening/Baseline C-SSRS Lifetime 
and the Since-Last-Visit C-SSRS.
If the subject is unable to comply with the C-SSRS due to developmental status, a parent proxy 
may be used for the completion of the C-SSRS. The investigator may also use clinical judgment to 
assess for suicidal ideation and behavior.
9.1.16 Aberrant Behavior Checklist
Behavior will be assessed by the use of the Community (ABC-C) questionnaire, which is a rating 
scale that measures the severity of a range of problem behaviors commonly observed in 
individuals with intellectual and developmental disabilities [9]. It is completed by the caregiver. It 
is an empirically developed scale designed to measure psychiatric symptoms and behavioral 
disturbance exhibited by individuals across 5 domains with 58 items: irritability, agitation, and 


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crying (15 items); lethargy, social withdrawal (16 items); stereotypy (7 items); 
hyperactivity/noncompliance (16 items); and inappropriate speech (4 items).
9.1.17 Collection of Blood Samples for PGx Evaluation
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters, or drug targets, and may be evaluated for the genetic contribution to how the drug is 
broken down, or how the drug affects the body. This is called a “PGx research study.” Specific 
purposes of this study include the following:

Identifying genetic reasons why certain people respond differently to TAK-935.

Finding out more information about how TAK-935 works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to TAK-935.

Identifying variations in genes related to the biological target of TAK-935.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of TAK-935 and other study drugs, to increase understanding of the disease/condition 
being studied, and to improve the efficiency, design, and methods of future research studies.
In the current study, collection of PGx blood samples is optional for each subject. A separate 
informed consent form pertaining to collection, storage, and analysis of the samples must be 
signed before the PGx blood samples can be collected. The provision of consent to collect and 
analyze the PGx sample is independent of consent to the other aspects of the study.
One 6-mL whole blood sample for DNA isolation is to be collected before the morning dose of 
study drug on Day 1 from each subject in the study, into a plastic K2EDTA spray-coated tube. If 
necessary and feasible, a second aliquot of blood may be collected if isolation of DNA from the 
first sample was not successful or possible.
Two 2.5-mL whole blood samples for RNA isolation are to be collected before the morning dose 
of study drug on Days 1 and 31 from each subject in the study, into a PaxGene tube.
Each PGx sample should be identifiable on the requisition form with an 8-digit subject ID number 
(the 5-digit site number plus the 3-digit subject number). Detailed instructions for the handling and 
shipping of samples are provided in the laboratory manual.
A portion of the DNA sample will be analyzed for the presence of allelic variants in drug 
metabolizing enzymes, drug transporters, or putative drug targets of relevance to epileptic 
disorders. Additional PGx analyses may be performed.
The samples will be stored for no longer than 15 years after completion of the TAK-935 study 
and/or until the drug development of TAK-935 is no longer actively pursued by Takeda or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Takeda. “Stored samples” are defined as samples 
that are coded (the samples are stripped of all personal identifying information but a key links the 


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samples to the clinical data collected from the sample donor) and are used in the analysis of study 
drug or related drugs. Subjects can request that their stored samples be destroyed at any time.
9.1.18 PK Sample Collection and Analysis
9.1.18.1 Collection of Plasma Samples for TAK-935 and M-I PK Evaluation
Blood samples (one 4-mL sample per scheduled time) for the measurement of plasma 
concentrations of TAK-935 and its metabolite M-I will be collected into chilled vacutainers 
containing the K2EDTA according to the sparse sampling schedule shown in Table 9.c. 
Table 9.c
Collection of Plasma Samples for Measurement of TAK-935 and M-I in 
Plasma 
Study Part
Study Day/Visit
Scheduled Time
Part 1
Day 1
Days 11 and 21
Before and 1, 3, 5 hours after morning dose
Before and ~1 hour after morning dose
Part 2
Day 31, 41, and 85
Before morning dose
Subjects and/or subjects’ caregivers will be instructed to not administer the morning dose of study 
drug on Days 11, 21, 31, 41, and 85. On these days, the predose (ie, within 30 minutes prior to 
dosing) blood sample will be collected at the same time point as the blood samples for clinical 
laboratory tests. The morning dose of study drug will be administered immediately after the 
predose PK blood samples have been collected. The exact date and time of last morning and 
evening study drug doses before each scheduled visit, the exact time of study drug dose taken in 
the clinic, the exact time of the last meal relative to dosing, and exact time of the PK blood draws 
will be recorded on the source document and eCRF.
For subjects who are not able to come for the visit during the morning hours, they should be 
instructed to take their morning dose, as usual, and come to the study site during the afternoon 
hours, as feasible for the subject. While in the clinic, the site should attempt to obtain 2 PK 
samples, separated by 1-2 hours, if possible. Hours since the last dose of the study medication and 
the exact time of the last meal relative to dosing must be recorded in the eCRF upon collection of 
the PK sample(s).
Instructions for the collection, handling, and shipping of plasma PK samples are provided in the 
Laboratory Manual.
9.1.18.2 Bioanalytical Methods for TAK-935 and M-I
Plasma concentrations of TAK-935 and M-I will be measured by high-performance liquid 
chromatography with tandem mass spectrometry.


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9.1.18.3 PK Parameters
The PK parameters of TAK-935 will be determined from the concentration-time profiles for all 
evaluable subjects using a population PK approach. Actual sampling times, rather than scheduled 
sampling times, will be used in all PK computations involving sampling times. 
The population PK/PD/EO model developed for TAK-935 based on the data from single- and 
multiple-dose phase 1 studies in healthy subjects will be updated using data from this study. The 
detailed population analysis approach will be described in a separate Data Analysis Plan before 
database lock. The results will be described in more detail in a Population PK Analysis Report.
9.1.19 PD Sample Collection and Analysis
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9.1.20
Concomitant AEDs Sample Collection and Analysis
9.1.21 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
ineligible for the study at this visit, the investigator should complete the eCRF screen failure form. 
The IVRS/IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is to be recorded in the eCRF using the following categories:
!
AE.
!
Did not meet entrance criteria (specify reason).
CCI
CCI


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
Significant protocol deviation.

Lost to follow-up.

Withdrawal by subject.

Study terminated by sponsor.

Other (specify reason).
Subjects may be re-screened after consultation with the Medical Monitor.
Subject ID numbers assigned to subjects who fail screening should not be reused. If a subject fails 
screening, but is later successfully rescreened, the data for the subject will be entered as if these 
were 2 separate subjects. Therefore, the data should be entered as follows:
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject ID number and treated as a stand-alone 
subject.
9.1.22 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the Part 1 Double-Blind Treatment Period.
If the subject is found to be not eligible, the investigator should record the primary reason for 
failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
On in-clinic dosing days, after administration of study drug orally, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
For those subjects receiving study drug via G-tube/PEG-tube, the site monitor, the caregiver’s 
preparation as provided in the instruction document and monitor that the caregiver has given the 
dose. If a site visit is not possible during the morning hours, the subject should take their morning 
dose prior to attending the visit during the afternoon hours. The date and time of each dose will be 
recorded in the source documents and on the eCRFs.
Subjects and/or subjects’ caregivers will be required to bring study drug containers/unused study 
drug and the daily recording in the dosing card to each dispensing site visit. All subjects and/or 
subjects’ caregivers should be reinstructed about the dosing requirements during study contacts. 
The authorized study personnel conducting the re-education must document the process in the 
subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures is shown in Appendix A. Assessments should be 
completed at the designated visit/time point(s).


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9.3.1
Screening/Baseline Period
Eligibility of subjects will be assessed in accordance with predefined inclusion and exclusion 
criteria as described in Section 7.0 at the Screening Visit (Visit 1). See Section 9.1.21 for 
procedures for documenting screening failures. At the Screening Visit, subjects will be given a 
seizure diary. Subjects and/or subjects’ caregivers will be instructed to record seizure activity on a 
daily basis during the Screening/Baseline Period and throughout the study after the consent has 
been signed. Diary data can begin at the Screening Visit and record 4 weeks of Baseline Period.
Eligible subjects will be notified by phone of their study entry, after completing the Baseline 
Period, including the Baseline seizure diary.
9.3.2
Randomization 
Randomization for eligible subjects will take place on Day 1 in Part 1 (Visit 2).
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IVRS/IWRS, as described in 
Section 8.2.
9.3.3
Part 1
In Part 1, subjects will receive the first dose of double-blind IP (double-blind TAK-935 or placebo) 
on the morning of Day 1 (Visit 2) in the clinic after randomization and after collection of predose 
PK, PD, AED and optional PGx blood samples. Subjects will remain in the clinic until completion 
of all study procedures on Day 1, including collection of the PK and PD blood samples at 1, 3, and 
5 hours after the morning dose. Subjects will return to the clinic on Day 11 (Visit 3) and Day 21 
(Visit 4) for the collection of blood samples for PK (before and approximately 1 hour after the 
morning dose), PD (before and approximately 1 hour after the morning dose), and AED (before the 
morning dose); study drug dosing; and collection of the seizure diary data. For subjects who are 
not able to come for the visit during the morning hours, they should be instructed to take their 
morning dose, as usual, and come to the study site during the afternoon hours, as feasible for the 
subject. While in the clinic, the site should attempt to obtain 2 PK samples, separated by 1-2 hours, 
if possible. Hours since the last dose of the study medication must be recorded in the eCRF upon 
collection of the PK sample(s).
Subjects and/or subjects’ caregivers will administer the evening dose of IP to the subjects on study 
visit days and BID on all other days during the 30-day Double-Blind Treatment Period. Three days 
after each dose up-titration or de-escalation, subjects will be contacted by phone to monitor study 
drug compliance, concomitant medication use, and AEs. Seizure data will be recorded by diary 
throughout Part 1 and collected and reviewed by the investigator with the subject and/or subject’s 
caregiver at each clinic visit.
9.3.4
Part 2
In Part 2, subjects will receive the first dose of study drug (open-label TAK-935) on the morning of 
Day 31 (Visit 5) in the clinic. Subjects will remain in the clinic until completion of all study 


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procedures during this Visit 5, including the collection of PK, PD, AED, and PGx blood samples. 
Subjects will return to the clinic on Day 41 (Visit 6) for the collection of PK, PD, and AED blood 
samples (all before the morning dose), study drug dosing, and collection of the seizure diary data. 
For subjects who are not able to come for the visit during the morning hours, they should be 
instructed to take their morning dose, as usual, and come to the study site during the afternoon 
hours, as feasible for the subject. While in the clinic, the site should attempt to obtain 2 PK 
samples, separated by 1-2 hours, if possible. Hours since the last dose of the study medication must 
be recorded in the eCRF upon collection of the PK sample(s).
Subjects and/or subjects’ caregivers will administer the evening dose of study drug to the subjects 
on study visit days and BID on all other days during the approximately 60-day Open-Label 
Treatment Period. Three days after each dose up-titration or de-escalation, subjects will be 
contacted by phone to monitor study drug compliance, concomitant medication use, and AEs. 
Seizure diary data will be collected and reviewed by the investigator with the subject and/or 
subject’s caregiver at each clinic visit.
9.3.5
Final Visit
The Final Visit (Visit 7) is on Day 85, at which time, the appropriate dose de-escalation schedule 
begins (ie, if at TAK-935 300 mg BID level, reduce to 200 mg BID for 3 days followed by 100 mg 
BID for 3 days; if at the 200 mg BID level, reduce to 100 mg BID for 3 days; if at the 100 mg BID 
level, there is no de-escalation). PK, PD, and AED blood samples (all before the morning dose) 
will be collected at this visit. For subjects who are not able to come for the visit during the morning 
hours, they should be instructed to take their morning dose, as usual, and come to the study site 
during the afternoon hours, as feasible for the subject. While in the clinic, the site should attempt to 
obtain 2 PK samples, separated by 1-2 hours, if possible. Hours since the last dose of the study 
medication must be recorded in the eCRF upon collection of the PK sample(s).
Subjects who do not enter Part 2 or withdraw early from the study should complete all procedures 
scheduled for the Final Visit (Visit 7) at time of withdrawal, including dose de-escalation as 
appropriate, followed by the Follow-up Period (Visits 8 and 9).
For all subjects receiving study drug, the investigator must complete the End-of-Study eCRF page.
Subjects who are withdrawn early from the study should undergo all procedures scheduled for the 
Final Visit at the time of withdrawal.
9.3.6
Follow-up Phone Call
A Follow-up Phone Call will be conducted on Day 91 (Visit 8). All subjects, including those who 
withdraw early from the study, must complete this Follow-up Phone Call.
9.3.7
Follow-up Visit
At the end of the 30-day Follow-up Period, subjects will return to the clinic for a Follow-up Visit 
on Day 121 (Visit 9). PD and AED blood samples will be collected at this visit. All subjects, 
including those who withdraw early from the study, must complete this Follow-up Visit.


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9.3.8
Poststudy Care
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required. Subjects 
may be eligible to enroll in an open-label extension study expected to be initiated in 2018.
9.4
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.17. 
The genetic material will be preserved and retained at Covance for up to but not longer than 
15 years or as required by applicable law. The sponsor has put into place a system to protect the 
subjects’ personal information to ensure optimal confidentiality and defined standard processes for 
sample and data collection, storage, analysis, and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The samples will be initially stored at PPD Central Laboratory. The 
sponsor and researchers working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the study will be stored securely with limited access 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
Subjects who consented and provided PGx samples for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time before analysis. Notify sponsor of 
consent withdrawal.


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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has
signed informed consent to participate in the study; it does not necessarily have to have a causal 
relationship with study participation or treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with study participation or use of a 
drug whether or not it is considered related to study participation or the drug.
10.1.2 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.

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 an AE.
Diagnoses vs 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 is not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation, or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
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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. Baseline evaluations (eg, 
laboratory tests, ECG, X-rays) should NOT be recorded as AEs unless related to study 
procedures. However, if the subject 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 subject 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 subject 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 the purpose of this study, seizures will not be considered (S)AEs unless: 1) there is a clear 
increase in frequency of seizures compared to the subject’s baseline, 2) there is an emergence 
of a new seizure type, or 3) the subject experiences status epilepticus, and any other time the 
investigator feels the seizure should be captured as an (S)AE in which case the investigator 
should document her/his reasoning.
Worsening of AEs:

If the subject 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 subject 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 prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as an AE. Complications resulting from any planned surgery 
should be reported as AEs.


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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented in the eCRF. Any manifested side effects will be 
considered AEs and will be recorded on the AE page of the eCRF.
10.1.3 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 subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements. 
10.1.4 Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.5 Causality of AEs
The relationship of each AE to study drug 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.
10.1.6 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. 


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10.1.7 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.1.8 Stop Date
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.9 Frequency
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events either occur once or are continuous.
10.1.10 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 subject died, or dosing with study drug was already stopped 
before the onset of the AE.

Dose Reduced – the dose was reduced due to the particular AE.

Dose Interrupted – the dose was interrupted due to the particular AE.

Dose Increased – the dose was increased due to the particular AE.
10.1.11 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject 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 or signs/symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “not recovered/not 
resolved”.


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
Resolved with Sequelae – the subject 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 AEs which are considered as the cause of death. 

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’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 the time informed consent is provided at Screening
(Visit 1) and continue until screen failure or until the Follow-up Visit (Visit 9). For subjects who 
discontinue prior to study drug administration, AEs are collected until the subject discontinues 
study participation.
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. 
Subjects may report AEs occurring at any other time during the study.
All subjects 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 there is a satisfactory explanation for the
changes 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 (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.


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9. Seriousness.
The seizure diary will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information recorded in the diary, proper 
follow-up with the subject for medical evaluation should be undertaken. Through this follow-up, if 
it is determined that an AE not previously reported has been identified, normal reporting 
requirements should be applied (see Section 10.1.2).
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:
An SAE should be completed in EDC with all mandatory information. If EDC is not available, a 
Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject ID number.

Investigator’s name.

Name of the study drug.

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
10.2.3 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, as 
specified in Section 9.1.11, the abnormality should be recorded as an AE.
If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.11 must also be performed. In addition, relevant eCRFs must be 
completed and transmitted with the Takeda SAE form (as per Section 10.2.2).


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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 the follow-up information with additions or changes to the SAE in 
EDC. A paper SAE form should only be used if EDC is not available. Paper SAE forms or other 
written documentation should be faxed immediately within 24 hours of receipt to the attention of 
the contact listed in Section 1.1. 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 or Independent Ethics Committee, 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, including the European 
Medicines Agency, investigators, and IRBs or Independent Ethics Committees (IECs), as 
applicable, in accordance with national regulations in the countries where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited reports 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 study. The study site 
also will forward a copy of all expedited reports to his or her IRB or IEC in accordance with local
regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent form.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate 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 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 of, 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 principal 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 of, modification of, or addition to the data on the 
eCRFs should be made by the investigator with the approval from the sponsor. The principal 
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 subject’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 subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 


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enable evaluations or audits from regulatory authorities, the sponsor, or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’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.
The investigator and the head of the study site are required to retain essential relevant documents 
until the day specified as (1) or (2) below, whichever comes later. However, if the sponsor requests 
a longer time period for retention, the head of the study site should discuss how long and how to 
retain those documents with the sponsor. 
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the 
date of notification in the case that the investigation is discontinued.)
2. The day 3 years after the date of early termination or completion of the study. 
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A blinded data review will be conducted before database lock. This review will assess the accuracy 
and completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
13.1.1 Analysis Sets
The randomized set will include all subjects who were randomly assigned to treatment through the 
IVRS/IWRS.
The PK analysis set for Parts 1 and 2 will include all subjects who received at least 1 dose of study 
drug and have at least 1 measurable TAK-935 or M-I plasma concentration.
The full analysis set (FAS) for Parts 1 and 2 will include all subjects who were randomized, 
received at least 1 dose of study drug, and have at least 1 valid postbaseline value for assessment of 
the efficacy endpoint(s). In FAS efficacy summaries, subjects will be analyzed according to the 
treatment to which they were randomized. To adjust for treatment noncompliance or insufficient 
treatment exposure, one or more modified FAS populations may be defined in the SAP.
The per-protocol set (PPS) for Parts 1 and 2 will include all subjects in the FAS who had no major 
protocol violations. Subjects to be excluded from the PPS, whether due to protocol violations or 
noncompliance to the dosing schedule, will be identified via a subject evaluability assessment 
performed before unblinding.
The safety analysis set for Parts 1 and 2 will include all subjects who received at least 1 dose of 
study drug. In safety summaries, subjects will be analyzed according to the treatment they 
received.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized and listed for enrolled 
subjects by treatment group and overall. Descriptive statistics will be used to summarize data for 
continuous variables such as age and weight (eg, number of subjects, mean, median, SD, and 
range) and for categorical variables such as sex, ethnicity, and race (number and percentage of 
subjects within each category). Medical history and medication history will be listed by subject.
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13.1.3 Safety Analysis
13.1.3.1 AEs
AEs will be reported throughout the study. TEAEs will be a primary endpoint for each part of the 
study. TEAEs will be summarized using descriptive statistics (number and percentage of subjects) 
for the safety analysis set. No statistical testing will be performed or inferential statistics will be 
generated.
The definition of TEAEs will be provided in the SAP. AEs will be coded using MedDRA and will 
be summarized by system organ class and preferred term and by treatment group separately for 
each part of the study.
AEs that were reported more than once by a subject during a part of the study will be counted only 
once for that subject at the maximum severity.
13.1.3.2 Other Safety Endpoints
Absolute values and changes from Screening/Baseline for clinical laboratory tests, vital signs, and 
ECGs will be summarized by treatment group for each part of the study using descriptive statistics. 
Clinical laboratory test, vital sign, 
 and ECG results that are outside the normal 
ranges and potentially clinically significant will be flagged and tabulated. The number and 
percentage of subjects with clinical laboratory test, vital sign, weight/BMI, and ECG parameter 
values that meet Takeda’s predefined criteria for markedly abnormal values at least once postdose 
will be summarized by treatment and part of the study. Physical examination findings will be listed 
by subject and treatment group for each part of the study.
13.1.4 PK and PD Analysis
Plasma concentrations of TAK-935, its metabolite M-I, and 
will be listed for each subject 
and summarized by each time point for each dose and part of the study.
A population PK/PD analysis approach will be used to determine the population estimates for 
TAK-935. The PK and PD parameters for TAK-935 will be summarized in a separate population 
PK/PD report.
13.1.5 Secondary and Exploratory Analyses
Safety (clinical laboratory evaluations, vital signs, weight/BMI, and ECGs) and PK (TAK-935) 
endpoints will be analyzed as the secondary endpoints in the study.
 
 
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13.2
Interim Analysis and Criteria for Early Termination
After all subjects have completed the Double-Blind Treatment Period or have discontinued from 
the study (and prior to completion of the Open-Label Period), an unblinded safety summary may 
be generated. There will be no early stopping for efficacy or futility.
13.3
Determination of Sample Size
Approximately 20 adult subjects are planned to be randomized. A formal sample size calculation 
was not performed for this study. The current sample size is deemed appropriate to evaluate the 
safety and tolerability of TAK-935 before dosing in pediatric subjects <18 years of age. Subjects 
who fail to complete Part 1 may be replaced and will receive the same treatment as the replaced 
subject.
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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 and the study site guarantee 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 subject to review by the sponsor or sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), 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.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. 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 site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the 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 subject, or confound interpretation of primary study assessment. A 
Protocol Deviation Form should be completed by the site and signed by the sponsor or designee for 
any significant deviation from the protocol.
Every attempt will be made to collect each PK and PD blood sample at the designated time point, 
and the actual time of each blood sample will be recorded on the source document and eCRF. 
Table 14.a defines the target windows for sample collections. Samples collected outside of these 
collection windows will not be considered a protocol deviation after Day 1 if the time and date of 
the sample collection is recorded in the eCRF AND the time and date of the dose prior to the 
sample collection is recorded in the eCRF. The only exception is the Day 1 predose sample, which 
must be collected prior to dosing on Day 1.


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Table 14.a
Windows for PK and PD Blood Sample Collection
Study Part and Day
Nominal/Target Sampling Time
Window
Part 1, Day 1
Predose (0 hour)
No more than 30 minutes predose
Part 1, Day 1
1, 3 and 5 hours postdose
±15 minutes of nominal time
Part 1, Days 11 and 21
Predose and 1 hour postdose
No more than 30 minutes predose, 
and ±15 minutes of nominal time, 
respectively
Part 2, Days 31, 41, and 85
Predose
No more than 30 minutes predose
Part 1, Day 1
Predose (0 hour)
No more than 30 minutes predose
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and study site guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
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 consent and investigator responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable 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. Those 
Americas sites unwilling to provide names and titles of all members due to privacy and conflict of 
interest concerns should instead provide a Federal Wide Assurance Number or comparable 
number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject 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 subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. The 
sponsor will notify the site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from competent 
authority to begin the study.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, 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.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, subject 
authorization form (if applicable), and subject information sheet (if applicable) must be approved 
by both the IRB and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. 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 subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’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 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA (and RNA) analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify sponsor 
of consent withdrawal.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject ID number. As permitted by all 
applicable laws and regulations, limited subject attributes, such as sex, age or date of birth, and 
subject initials may be used to verify the subject and accuracy of the subject’s unique ID 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 subject’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 subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
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.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 


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this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
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. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. Any 
investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
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 subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject 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 subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.


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16.0
REFERENCES
1. Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, et al. The major 
brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of 
N-methyl-D-aspartate receptors. J Neurosci 2013;33(44):17290-300.
2. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised 
terminology and concepts for organization of seizures and epilepsies: report of the ILAE 
Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51(4):676-85.
3. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE 
classification of the epilepsies: Position paper of the ILAE Commission for Classification and 
Terminology. Epilepsia 2017;58(4):512-21.
4. Bretillon L, Lutjohann D, Stahle L, Widhe T, Bindl L, Eggertsen G, et al. Plasma levels of 
24S-hydroxycholesterol reflect the balance between cerebral production and hepatic 
metabolism and are inversely related to body surface. J Lipid Res 2000;41(5):840-5.
5. Cartagena CM, Ahmed F, Burns MP, Pajoohesh-Ganji A, Pak DT, Faden AI, et al. Cortical 
injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J Neurotrauma 
2008;25(9):1087-98.
6. Tian G, Kong Q, Lai L, Ray-Chaudhury A, Lin CG. Increased expression of cholesterol 
24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with 
lipid rafts: a potential role in Alzheimer's disease. J Neurochem 2010;113(4):978-89.
7. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational 
classification of seizure types by the International League Against Epilepsy: Position Paper of 
the ILAE Commission for Classification and Terminology. Epilepsia 2017.
8. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
9. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior 
rating scale for the assessment of treatment effects. Am J Ment Defic 1985;89(5):485-91.


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Appendix A
Schedule of Study Procedures 
Screening/
Baseline Period (a)
Part 1: Double-Blind
Treatment Period (b)
Part 2: Open-Label
Treatment Period (b)
Follow-up Period (c)
Study Day
Days -41 to 0
Day 1
Day 11
Day 21
Day 31
Day 41
Day 85 (c,d)
Day 91
Day 121
Visit Window (days)
±2
±2
±2
±2
±2
±2
±2
Visit Number
1
Screening 
Visit
2
3
4
5
6
7
Final 
Visit
8
Follow-up 
Phone Call
9
Follow-up 
Visit
Informed consent and assent, if 
appropriate
X
Optional PGx informed consent
X
Inclusion/exclusion criteria
X
X
Randomization
X
Demographics, medical history, 
medication history
X
Height, weight, BMI 
X
Concurrent medical conditions
X
Concomitant medications, including 
AED 
X
X
X
X
X
X
X
X
X
Urine drug and alcohol screen (e)
X
HIV, HBsAg, HCV tests (f)
X
C-SSRS, if appropriate (g)
X
X
X
Aberrant behavior checklist
X
X
X
X
X
X
X
FSH and estradiol (h)
X
X
Serum/urine pregnancy test (i)
X(serum)
X(urine)
X(serum)
Pregnancy avoidance counseling
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
Physical examination (j)
X
X
X
(Footnotes follow table.)


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Appendix A
Schedule of Study Procedures (continued)
Screening/
Baseline Period (a)
Part 1: Double-Blind
Treatment Period (b)
Part 2: Open-Label
Treatment Period (b)
Follow-up Period (c)
Study Day
Days -41 to 0
Day 1
Day 11
Day 21
Day 31
Day 41
Day 85 (c,d)
Day 91
Day 121
Visit Window (days)
±2
±2
±2
±2
±2
±2
±2
Visit Number
1
Screening 
Visit
2
3
4
5
6
7
Final 
Visit
8
Follow-up 
Phone Call
9
Follow-up 
Visit
Neurological exam, including 
fundoscopy and visual acuity (if 
possible) (k)
X
X
X
12-lead ECG 
X
X
X
X
Clinical laboratory tests (l)
X
X
X
X
Plasma sample for TAK-935 PK (m,n)
X
X
X
X
X
X
Plasma sample for AED analysis (n,o)
X
X
X
X
X
X
X
Plasma sample for PD (n,p)
X
X
X
X
X
X
X
X
Blood sample for DNA PGx (q)
X
Blood sample for RNA PGx (n,r)
X
X
Access IVRS/IWRS for subject 
ID/medication ID/subject status (s)
X
X
X
X
X
X
X
Assess benefit-risk analysis with subject 
and caregiver before increasing dose to 
300 mg BID
X
Dispense study drug with dosing card (t)
X
X
X
X
X
X
In-clinic administration of morning dose 
of study drug (u)
X
X
X
X
X
X
(Footnotes follow table.)
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Appendix A
Schedule of Study Procedures (continued)
Screening/
Baseline Period (a)
Part 1: Double-Blind
Treatment Period (b)
Part 2: Open-Label
Treatment Period (b)
Follow-up Period (c)
Study Day
Days -41 to 0
Day 1
Day 11
Day 21
Day 31
Day 41
Day 85 (c,d)
Day 91
Day 121
Visit Window (days)
±2
±2
±2
±2
±2
±2
±2
Visit Number
1
Screening 
Visit
2
3
4
5
6
7
Final 
Visit
8
Follow-up 
Phone Call
9
Follow-up 
Visit
Study drug return/
accountability/compliance
X
X
X
X
X
X
Assess AEs (v)
X
X
X
X
X
X
X
X
X
Footnotes for Appendix A
(a) The 4-week baseline seizure diary recording can begin as soon as the ICF has been signed. Randomization can occur once the 4-week baseline seizure count of ≥1 has been 
obtained and the subject meets all of the inclusion and none of the exclusion criteria.
(b) Three days after each dose up-titration or de-escalation, subjects will be contacted by phone to monitor study drug compliance, concomitant medication use, and AEs.
(c) Subjects who do not enter Part 2 or withdraw early from the study should complete all procedures scheduled for the Final Visit (Visit 7) at time of withdrawal, including dose 
de-escalation as appropriate, followed by the Follow-up Period (Visits 8 and 9). See Section 6.1 for details.
(d) Dose de-escalation, as appropriate, begins at the Final Visit (ie, if at TAK-935 300 mg BID level, reduce to 200 mg BID for 3 days followed by 100 mg BID for 3 days; if at the 
200 mg BID level, reduce to 100 mg BID for 3 days; if at the 100 mg BID level, there is no de-escalation). See Section 6.1 for details.
(e) If urine cannot be collected, the reason should be documented in the source document.
(f) Subjects who are positive for hepatitis C Ab should return to the clinic for an unscheduled visit to provide a blood sample for HCV qPCR
(g) If the subject is unable to comply with the C-SSRS due to developmental status, a parent proxy may be used for the completion of the C-SSRS. The investigator may also use 
clinical judgment to assess for suicidal ideation and behavior.
(h) For female subjects only at the Screening and Final Visits.
(i) For female subjects of childbearing potential, a serum pregnancy (hCG) test will be performed at the Screening and Final Visits and a urine pregnancy test will be performed before 
the morning dose on Day 1 in Part 1 (Visit 2). If urine cannot be collected, the reason should be documented in the source document and the serum pregnancy test obtained at Visit 1 
must be confirmed to be negative by the investigator prior to randomization. Additional pregnancy tests may be performed throughout the study at the investigator’s discretion.
(j) PE must be captured in the source document. Any clinically significant abnormalities noted prior to administration of study drug should be described and captured on the Medical 
History form. Any clinically significant changes in PE noted after administration of study drug should be captured on the AE page of the eCRF.
(k) Any clinically significant abnormalities noted prior to administration of study drug should be described and recorded on the Medical History form. Any clinically significant 
changes in the neurological examination noted after administration of study drug should be captured on the AE page of the eCRF.
(l) Hematology, serum chemistry, and urinalysis tests. If urine cannot be collected due to the subject’s cooperation or because the subject is wearing a diaper, it is acceptable for the 
subject to continue in the study and the reason should be documented in the source document.
(m) PK plasma samples for measurement of TAK-935 and M-I concentrations will be collected before and 1, 3, and 5 hours after the morning dose on Day 1; before and 
approximately 1 hour after the morning dose on Days 11 and 21; and before the morning dose on Days 31, 41, and 85.
(n) On Days 11, 21, 31, 41, and 85, subjects should visit the clinic in the morning prior to taking their morning dose. For subjects who are not able to come for the visit during the 


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morning hours, they should be instructed to take their morning dose, as usual, and come to the study site during the afternoon hours, as feasible for the subject. While in the clinic, the 
site should attempt to obtain 2 PK samples, separated by 1-2 hours, if possible. Hours since the last dose of the study medication must be recorded in the eCRF upon collection of the 
PK sample(s).
(o) Plasma samples for measurement of concomitant AED concentrations will be collected before the morning dose on Days 1, 11, 21, 31, 41, and 85; and at the Follow-up Visit 
(Day 121).
 
(q) One PGx blood sample for DNA isolation will be collected before the morning dose on Day 1.
(r) Two PGx blood samples for RNA isolation will be collected before the morning dose on Days 1 and 31.
(s) The dose of IP will be increased on Days 11 and 21 in Part 1 and on Day 41 in Part 2, provided there are no safety or tolerability concerns. Subjects’ dose may be increased or 
decreased before Day 41 (Visit 6) based on clinical condition (ie, increasing seizures) and investigator judgment. At the end of Part 2, the dose of TAK-935 will be de-escalated before 
dosing is discontinued. See Section 6.1 for details.
(t) A dosing card will be provided to record daily AM and PM study drug administration throughout the study, including changes in dosing regimen (de-escalation) that may occur 
between visits and during the de-escalation period of the study.
(u) On in-clinic dosing days, after administration of study drug, appropriate mouth and/or hand checks will be performed to ensure that the dose is swallowed and noted in the source 
document. If a site visit is not possible during the morning hours, the subject should take their morning dose prior to attending the visit during the afternoon hours. The date and time 
of each dose will be recorded in the source documents and on the eCRFs.
(v) Collection of AEs will commence from the time informed consent is provided (Screening Visit) and continue until screen failure or the Follow-up Visit.
CCI


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff 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 (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’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 


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that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’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 subjects involved in the study.
7. A description of the subject’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 subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’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 subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.


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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx 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 subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects 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 subjects 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


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e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening throughout the duration of the study, and for 30 days after last dose. 
Regular pregnancy tests will be performed throughout the study for all female subjects of 
childbearing potential. If a subject is found to be pregnant during study, study drug will be 
discontinued and the investigator will offer the subject the choice to receive unblinded 
treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for 30 days after 
last dose. If the partner or wife of the subject is found to be pregnant during the study, the 
investigator will offer the subject the choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details, and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 03 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Clarified that TAK-935 or placebo can be administered either orally or via stable 
G-tube/ PEG tube.
The primary change occurs in Section 6.1 Study Design
Added text: or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) 
tube
Rationale for Change: To allow administration of TAK-935 or placebo via G-tube/PEG tube 
after finalization of CMC in vitro studies demonstrating nearly 100% drug delivery through a 
G-tube when crushed and suspended in water.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 4.1 Background

Section 6.1 Study Design

Section 6.2 Justification for Study Design, Dose, and Endpoints

Section 8.1.3 Dose and Regimen

Section 9.2 Monitoring Subject Treatment Compliance
Change 2: Clarified that a separate consent form will be obtained for subjects with G-tube/PEG 
tubes.
The primary change occurs in Section 9.1.1 Informed Consent Procedure
Added text: In addition, a separate supplemental informed consent form (ICF) providing 
information on G-tube/PEG-tube administration of study drug will be signed.
Rationale for Change: To provide detail on separate consent form for subjects with G-tube/PEG 
tubes.


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The following sections also contain this change:

Section 7.1 Inclusion Criteria
Change 3: Added inclusion criteria related to subjects with G-tube/PEG tubes.
The primary change occurs in Section 7.1 Inclusion Criteria
Added text: For subjects with G-tube/PEG tube, G-tubes/PEG tubes should have been placed 
and been functioning for at least 3 months prior to screening. Naso-gastric tubes 
are not allowed.
Rationale for Change: To clarify the subject population with G-tube/PEG tubes.
The following sections also contain this change:

Section 7.4 Diet, Fluid, and Activity Control
Change 4: Modified exclusion criteria to allow the use of medical marijuana.
The primary change occurs in Section 7.2 Exclusion Criteria
Initial 
wording:
The subject has a history of alcohol, opioid, or other drug use disorder, as per the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within the 
previous 2 years before Screening (Visit 1). Previous sporadic cannabis use is not 
exclusionary provided the subject is requested and agrees to not use cannabis during 
the study.
Amended 
or new 
wording:
The subject has a history of alcohol, opioid, or other drug use disorder, as per the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within the 
previous 2 years before Screening (Visit 1). Previous sporadic cannabis use is not 
exclusionary provided the subject is requested and agrees to not use cannabis during 
the study. Medical marijuana use is allowed.
Rationale for Change: To allow enrollment of subjects in states where use of medical marijuana 
is legal.
The following sections also contain this change:

Section 7.3 Excluded Medications, Procedures, and Treatments


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Change 5: Modified secondary endpoints to remove estimation of additional parameters.
The primary change occurs in Section 5.2.2 Secondary Endpoints
Deleted 
text:

Population mean estimates of drug clearance (CL), volume of distribution of the 
central compartment (Vc), absorption rate constant (Ka), volume of distribution of 
the peripheral compartment (Vp), intercompartmental clearance (Q), the 
maximum plasma concentration (Cmax), the area under the plasma 
concentration-time curve over a dosing interval (AUC0-tau), the average 
concentration during a dosing interval at steady-state (Cav,ss), and the plasma 
concentration immediately prior to dosing (Ctrough) for TAK-935. Additional 
parameters may be estimated, if appropriate.
Rationale for Change: To keep endpoints specific and consistent guidelines for disclosure of 
study details.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
Change 6: Removed body weight/body mass index (BMI) from secondary and exploratory 
endpoints.
The primary change occurs in Section 5.2.2 Secondary Endpoints
Deleted 
text:

Percentage of subjects with at least 1 markedly abnormal value for clinical 
laboratory evaluations, vital signs, body weight/body mass index (BMI), and 
electrocardiogram (ECG) parameters after TAK-935 treatment.
Rationale for Change: These parameters are only measured at screening and therefore change 
cannot be monitored.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 5.2.3 Exploratory Endpoints
Change 7: Modified study drug dosing and regimen sections to clarify how study drug will be 
administered via G-tube/ PEG tube.
The primary change occurs in Section 8.1.1 Dosage Form, Manufacturing, Packaging, and 
Labeling
Added text: For subjects receiving study drug via G-tube/PEG tube, tablets will be crushed, 
suspended in water, and the suspension will be administered via the G-tube/PEG 
tube using a syringe. Complete instructions will be provided to 
subjects/caregivers in a document provided outside of the protocol.


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Study No. TAK-935-2001
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Rationale for Change: To provide clarification on study dosing and regimen for subjects with 
G-tube/PEG tubes.
The following sections also contain this change:
!
Section 8.1.3 Dose and Regimen
Change 8: Modified study drug dispensing procedures to clarify how the investigative product 
(IP) will be prepared for administration via G-tube/PEG tube.
The primary change occurs in
Added text: In addition to the above, subjects/caregivers will be provided complete 
instructions on preparing the study drug for administration via 
G-tube/PEG-tube in a document provided outside of the protocol. They should 
follow these instructions carefully.
Rationale for Change: To provide clarification on study dosing and regimen for subjects with 
G-tube/PEG tubes.
Change 9: Clarified when open-label extension study is expected to be initiated.
The primary change occurs in Section 9.3.8 Poststudy Care
Initial 
wording:
Study drug will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies 
as required. Subjects may be eligible to enroll in an open-label extension study if and 
when available.
Amended 
or new 
wording:
Study drug will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies 
as required. Subjects may be eligible to enroll in an open-label extension study if and 
when availableexpected to be initiated in 2018.
Rationale for Change: To provide information to sites/subjects as to when the open-label 
extension study will be initiated.
Change 10: Updated the medical monitor contact information.
The primary change occurs in Section 1.1 Contacts
Description 
of change:
The contact information for the medical monitor was changed from 
 
.
Rationale for Change: Due to a change in medical monitor at the Clinical Research Organization.
PPD


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group, Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in Subjects 
With Developmental and/or Epileptic Encephalopathies
NCT Number: NCT03166215
SAP Approve Date: 26 October 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-935-2001
A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group,
Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability,
Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in Subjects
With Developmental and/or Epileptic Encephalopathies
Study of TAK-935 as an Adjunctive Therapy in Subjects With Developmental and/or Epileptic 
Encephalopathies
PHASE 1b/2a
Version: Final
Date: 26 October 2018
Prepared by:
Based on:
Protocol Version: Amendment 03
Protocol Date: 21 March 2018
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.
PPD


PPD


TAK-935-2001
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CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objective......................................................................................................8
4.2
Secondary Objective..................................................................................................8
4.3
Exploratory Objectives ..............................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................13
5.1
Primary Endpoint.....................................................................................................13
5.2
Secondary Endpoints ...............................................................................................13
5.3
Exploratory Endpoints .............................................................................................13
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................15
7.1
General Principles....................................................................................................15
7.1.1
Definition of Study Day and Baseline ................................................................15
7.1.2
Definitions of Study Visit Windows...................................................................15
7.1.3
Conventions for Missing Adverse Event Dates...................................................17
7.1.3.1 Imputation of missing or partial dates of AE start dates................................17
7.1.3.2 Imputation of missing or partial dates of AE end dates .................................18
7.1.4
Conventions for Missing Concomitant Medication Dates...................................19
7.1.4.1 Imputation of missing or partial dates of concomitant medication start 
dates.............................................................................................................19
7.1.4.2 Imputation of missing or partial dates of concomitant medication end dates .19
7.1.5
Conventions for Missing Data............................................................................19
7.2
Analysis Sets ...........................................................................................................19
7.3
Disposition of Subjects ............................................................................................20
7.4
Demographic and Other Baseline Characteristics.....................................................20
7.5
Medical History and Concurrent Medical Conditions...............................................21
7.6
Medication History and Concomitant Medications...................................................21
7.7
Study Drug Exposure and Compliance.....................................................................22
7.8
Efficacy Analysis.....................................................................................................23
7.8.1
Primary Efficacy Endpoint(s).............................................................................23


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CONFIDENTIAL
7.8.2
Secondary Efficacy Endpoint(s).........................................................................23
7.8.3
Exploratory Efficacy Endpoint(s).......................................................................23
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................25
7.9.1
Pharmacokinetic Analysis ..................................................................................25
7.9.1.1 Pharmacokinetic Concentrations...................................................................25
7.9.1.2 Pharmacokinetic Parameters (Secondary Endpoints) ....................................25
7.9.2
Pharmacodynamic Analysis ...............................................................................25
7.9.2.1 Pharmacodynamic Concentrations................................................................25
7.9.3
Concomitant AEDs Analysis..............................................................................26
7.9.3.1 Sample Concentrations.................................................................................26
7.9.3.2 Parameter and Analysis ................................................................................27
7.10
Other Outcomes.......................................................................................................27
7.11
Safety Analysis........................................................................................................27
7.11.1 Adverse Events ..................................................................................................27
7.11.2 Clinical Laboratory Evaluations .........................................................................29
7.11.3 Vital Signs .........................................................................................................31
7.11.4 12-Lead ECGs ...................................................................................................31
7.12
Changes in the Statistical Analysis Plan...................................................................32
8.0
REFERENCES..............................................................................................................33
LIST OF IN-TEXT TABLES
Table 7.a
Visit Analysis Windows for Part 1 .....................................................................16
Table 7.b
Visit Analysis Windows for Part 2 .....................................................................17
Table 7.c
Collection of Plasma Samples for Measurement of TAK-935 and M-I in 
Plasma ...............................................................................................................25
Table 7.d
.........26
Table 7.e
..26
Table 7.f
Clinical Laboratory Tests...................................................................................30
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................12
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LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................34
Appendix B
Criteria for Markedly Abnormal Vital Signs.......................................................36
Appendix C
Criteria for Markedly Abnormal 12-Lead ECG Parameters ................................37


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3.0
LIST OF ABBREVIATIONS
24HC
24S-hydroxycholesterol
ABC-C
Aberrant Behavior Checklist-Community Edition
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BA
bioavailability
BID
twice daily
BMI
body mass index
Cav,ss
average concentration during a dosing interval at steady-state
CFR
Code of Federal Regulations
CH24H
24S-hydroxylase
CNS
central nervous system
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form 
EEG
electroencephalogram
EO
enzyme occupancy
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
-glutamyl transferase
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
ID
identification
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IVRS
interactive voice response system
IWRS
interactive web response system
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
M-I
metabolite of TAK-935


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MRD
multiple-rising dose
PD
pharmacodynamic(s)
PDR
posterior dominant rhythm
PEG
Percutaneous endoscopic gastrostomy
PET
positron emission tomography
PGx
pharmacogenomic(s)
PK
pharmacokinetic(s)
PPS
per-protocol set
PTZ
pentylenetetrazol
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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4.0
OBJECTIVES
4.1
Primary Objective
∀
To characterize the multiple-dose safety and tolerability profile of TAK-935 in adult subjects 
with developmental and/or epileptic encephalopathies.
4.2
Secondary Objective
∀
To characterize the multiple-dose PK profile of TAK-935 in adult subjects with 
developmental and/or epileptic encephalopathies on concomitant antiepileptic drugs (AEDs).
4.3
Exploratory Objectives
4.4
Study Design
This phase 1b/2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-escalation study with an open-label part is designed to examine the safety, tolerability, PK, 
and PD of TAK-935 as adjunctive therapy in adult subjects with a diagnosis of developmental 
and/or epileptic encephalopathies. This study will be conducted at approximately 11 sites in 
North America with experience in conducting clinical studies in patients with rare epilepsies.
Adult subjects (aged ≥18 and ≤65 years) with a diagnosis of developmental and/or epileptic 
encephalopathies demonstrating bilateral motor seizures (ie, drop seizures, tonic-clonic, tonic, 
bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral 
hyperkinetic motor features) (average of ≥2 per month during the past 3 months) based on the 
investigator’s assessment will be enrolled. The study will screen a sufficient number of subjects 
to ensure approximately 20 randomized subjects. 
At the Screening Visit (Visit 1), informed consent and/or assent (if applicable) is obtained from 
the subjects and/or subjects’ legally acceptable representative. Subjects will then undergo 
screening procedures to assess study eligibility in accordance with the study entry criteria (see 
Appendix A and Sections 71 and 7.2. in the Protocol). At this Screening Visit and at subsequent 
visits, subjects and/or subjects’ caregivers will be provided with a seizure diary and will be 
instructed to record seizure data on a daily basis starting at Baseline and throughout the study. 
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 The 4-week Baseline 
Period 
 can begin as soon as informed consent has been signed. At the end 
of the 4-week Baseline Period and after confirmation of eligibility, subjects will return to the 
clinic on Day 1 in Part 1 (Visit 2) for randomization. If a subject does not meet the eligibility 
criteria during the Screening/Baseline Period, the subject will be discontinued from the study 
(screen failure).
The study will consist of 2 parts: 
Part 1 is a randomized double-blind part consisting of 3 periods: a screening/baseline period (4-
6 weeks), titration period (20 days), and maintenance period (10 days). The target final dose of 
300 mg BID will be reached after a 20-day titration period.
Part 2 is an open-label continuation part consisting of 4 periods: a titration period (10 days), 
maintenance period (44 days), de-escalation period (3-6 days) and follow-up period (30 days).
Part 1 of the study is designed to investigate the safety, tolerability, PK, and PD in adult subjects 
with developmental and/or epileptic encephalopathies in a double-blind manner. 
 
 will be investigated in an exploratory manner. Approximately 20 
adult subjects who 
 
 
during the 4-week Baseline Period will be randomly assigned on 
Day 1 (Visit 2) to receive TAK-935 (n=16) or matching placebo (n=4) twice daily (BID) orally 
or via stable gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube for 30 
days during the Double-Blind Treatment Period. Subjects will initiate IP (investigational 
product; TAK-935 or placebo) at 100 mg BID from Days 1 through 10. Subjects who cannot 
tolerate the 100 mg BID dosing will be withdrawn from the study. On Day 11 (Visit 3), subjects 
will return to the clinic and the IP dose will be increased to 200 mg BID; this dose level will be 
maintained from Days 11 through 20 but may be reduced to 100 mg BID in subjects who cannot 
tolerate the 200 mg BID dose or demonstrate safety concerns, based on the investigator’s 
judgment and in consultation with the subject’s caregiver, when applicable. On Day 21 (Visit 4), 
subjects will return to the clinic; at this visit, the investigator will review the subject’s safety data 
and will discuss the benefit-risk with the subject or subject’s legally acceptable representative 
before proceeding to increase the dose from 200 mg BID to 300 mg BID, and this dose level will 
be maintained from Days 21 through 30. The dose may be reduced to 200 mg BID in subjects 
who cannot tolerate the 300 mg BID dose or demonstrate safety concerns, as described above. 
Subjects for whom the dose was reduced to a lower dose level will stay on that dose level until 
the end of the Double-Blind Treatment Period. Three days after each dose up-titration or de-
escalation, subjects will be contacted by phone to monitor study drug compliance, concomitant 
medication use, and AEs. Any change in dose will be documented in the subject’s clinic chart 
and the subject’s caregiver will be advised to note the same in the dosing card. 
On Day 1 (Visit 2), PK, PD, AED, and optional PGx blood samples will be collected before the 
morning dose of study drug. PK and PD blood samples also will be collected at 1, 3, and 5 hours 
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after the morning dose on Day 1. On Day 11 (Visit 3) and Day 21 (Visit 4), PK and PD blood 
samples (before and approximately 1 hour after morning dose), an AED blood sample (before 
morning dose), and seizure diary data will be collected.
Subjects who are unwilling to continue into Part 2 of the study will proceed directly to the Final 
Visit (at Day 31), including dose de-escalation, as appropriate, followed by the 30-day Follow-up 
Period. 
Part 2 of the study is designed to investigate the safety, tolerability, PK, and PD of TAK-935 in 
adult subjects with developmental and/or epileptic encephalopathies in an open-label manner. All 
subjects who complete the Double-Blind Treatment Period in Part 1 will have the option to 
continue directly into the Open-Label Treatment Period in Part 2. Because some subjects may 
enter Part 2 after receiving placebo and others TAK-935 up to 300 mg BID and to maintain the 
study blind, all subjects will start on TAK-935 200 mg BID at the start of Part 2. On Day 31 
(Visit 5), subjects will return to the clinic and receive TAK-935 200 mg BID from Days 31 to 40 
but may be reduced to 100 mg BID in subjects who cannot tolerate the 200 mg BID dose or 
demonstrate safety concerns, based on the investigator’s judgment and in consultation with the 
subject’s caregiver, when applicable. Subjects who cannot tolerate the 100 mg BID dose or 
demonstrate safety concerns, based on the investigator’s judgment and in consultation with the 
subject’s caregiver, will be discontinued from the study. On Day 41 (Visit 6), subjects will return 
to the clinic; at this visit, the investigator will review the subject’s safety data and will discuss 
the benefit-risk with the subject or subject’s legally acceptable representative before proceeding 
to increase the dose from 200 mg BID to 300 mg BID, and this dose level will be maintained 
until the Final Visit (Visit 7) for the dose de-escalation phase. Subjects’ dose may be increased 
or decreased before Day 41 (Visit 6) based on clinical condition (ie, increasing seizures) and 
investigator judgment. This dose may be reduced to 200 mg BID in subjects who cannot tolerate 
the 300 mg BID dose or demonstrate safety concerns, as described above. Subjects for whom the 
dose was reduced to a lower dose level will stay on that dose level until the Final Visit (Visit 7) 
for the dose de-escalation phase. Three days after each dose up-titration or de-escalation, 
subjects will be contacted by phone to monitor study drug compliance, concomitant medication 
use, and AEs. Any change in dose will be documented in the subject’s clinic chart and the 
subject’s caregiver will be advised to note the same in the dosing card.
On Day 31 (Visit 5), PK, PD, AED, and PGx (if collected on Day 1) blood samples will be 
collected before the morning dose of study drug and seizure data will also be collected. On 
Day 41 (Visit 6), PK, PD, and AED blood samples will be collected before the morning dose of 
study drug and seizure data will also be collected. 
On Day 85 (Visit 7), subjects will return to the clinic for the Final Visit and enter the 3- or 6-day 
de-escalation phase. At this visit, PK, PD, and AED blood samples will be collected before the 
morning dose of study drug and seizure data will also be collected. Subjects will then enter the 
dose de-escalation phase and will be instructed to follow the applicable de-escalation dosing 
schedule outlined below: 
For subjects on 300 mg BID during the maintenance phase, the dose will be de-escalated to 
200 mg BID for 3 days (Days 85-87) and subsequently to 100 mg BID for 3 days (Days 88-90).


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For subjects on 200 mg BID during the maintenance phase, the dose will be de-escalated to 100 
mg BID for 3 days (Days 85-87). 
For subjects on 100 mg BID during the maintenance phase, there is no de-escalation and the dose 
is discontinued on Day 85. 
Immediately after the last dose is the 30-day Follow-up Period comprised of a Follow-up Phone 
Call (Visit 8) on Day 91 and a Follow-up Visit (Visit 9) on Day 121. At the Follow-up Visit,
subjects will return to the clinic for study procedures including PD and AED blood sample 
collection. 
In Parts 1 and 2, subjects will be instructed to not take their morning dose of study drug or 
concomitant AEDs on the days of scheduled study visits to facilitate collection of the predose 
PK, PD, AED, and optional PGx blood samples. The morning dose of study drug and 
concomitant AEDs will be administered in the clinic on these study days after laboratory samples 
are collected. For subjects who are not able to come for the visit during the morning hours, they 
should be instructed to take their morning dose, as usual, and come to the study site during the 
afternoon hours, as feasible for the subject. While in the clinic, the site should attempt to obtain 2 
PK samples, separated by 1-2 hours, if possible. Hours since the last dose of the study 
medication must be recorded in the eCRF upon collection of the PK sample(s). 
Seizure data will be recorded daily in the seizure diary by each subject and/or subjects’ caregiver 
throughout the Screening/Baseline Period up until the Follow-up Visit (Visit 9) on Day 121 and 
will be collected from the diary at each visit.
The investigator, in consultation with the sponsor, may decide to reduce the TAK-935 dose at 
any time during the study in the event of any safety or tolerability concerns. 
Any subject who prematurely withdraws from the study should proceed directly to the Final Visit 
(at time of withdrawal), including dose de-escalation, as appropriate, followed by the 30-day 
Follow-up Period. 
A schematic of the study design is shown in Figure 4.a. Refer to Appendix A in the Protocol for 
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Figure 4.a
Schematic of Study Design
Note 1: Circled numbers denote study visits. 
Note 2: Subjects will remain on stable background AED therapy throughout the study.
Note 3: Starting doses for Parts 1 and 2 are shown; individual subject doses may be reduced to the previous dose 
level if there are safety and tolerability concerns at new dose level.
Note 4: Maintenance dose levels (ie, 100, 200, or 300 mg BID) will be de-escalated at the end of the maintenance 
phase of Part 2, depending on the dose subjects are taking at that time (ie, if at TAK-935 300 mg BID level, reduce 
to 200 mg BID for 3 days followed by 100 mg BID for 3 days; if at the 200 mg BID level, reduce to 100 mg BID for 
3 days; if at the 100 mg BID level, there is no de-escalation). 


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
Percentage of subjects with at least 1 treatment-emergent adverse event (TEAE), as reported by 
the subjects or subjects’ caregivers or observed by the investigator, after TAK-935 treatment.
5.2
Secondary Endpoints
∀
Population mean estimates of drug clearance (CL), volume of distribution of the central 
compartment (Vc), absorption rate constant (Ka), volume of distribution of the peripheral 
compartment (Vp), intercompartmental clearance (Q), the maximum plasma concentration 
(Cmax), the area under the plasma concentration-time curve over a dosing interval (AUC0-tau), 
the average concentration during a dosing interval at steady-state (Cav,ss), and the plasma 
concentration immediately prior to dosing (Ctrough) for TAK-935. 
∀
Percentage of subjects with at least 1 markedly abnormal value for clinical laboratory 
evaluations, vital signs, and electrocardiogram (ECG) parameters after TAK-935 treatment.
5.3
Exploratory Endpoints
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6.0
DETERMINATION OF SAMPLE SIZE
Approximately 20 adult subjects are planned to be randomized. A formal sample size calculation 
was not performed for this study. The current sample size is deemed appropriate to evaluate the 
safety and tolerability of TAK-935 before dosing in pediatric subjects <18 years of age. Subjects 
who fail to complete Part 1 may be replaced and will receive the same treatment as the replaced 
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All confidence intervals (CI), statistical tests, and resulting P-values will be reported as 2-sided 
and will be assessed at α=0.05 significance level unless otherwise stated. P-values will be 
rounded to 3 decimal places prior to assessment of statistical significance. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the counts and percentages of subjects will be tabulated. The denominator for the 
percentages will be based on the number of subjects who provide non-missing responses to the 
categorical variable. For continuous variables, the number of subjects with non-missing values, 
mean, median, SD, minimum, and maximum values will be tabulated. 
All data analyses and figures will be generated using SAS System® Version 9.2 or higher.
7.1.1
Definition of Study Day and Baseline 
Study day will be calculated relative to the date of the first dosing. Study day prior to the first 
dose of treatment will be calculated as: date of assessment/event – date of treatment; study day 
on or after the date of first dose of treatment will be calculated as: date of assessment/event –
date of treatment + 1.
Baseline for Part 1 is defined as the last non-missing measurement prior to first dose of study 
drug in Part 1. Baseline for Part 2 is defined as the last non-missing measurement prior to first 
dose of study drug. 
Baselines for Part 1 and Part 2 (when needed for the analysis) are defined as the last observation 
prior to the first dose in Part 1 and 2, respectively. Both date and time of the measurement and 
the dosing date and time should be used when determining the baseline if possible. For Part 1, in 
the case where the last non-missing measurement (except AE and concomitant medications) and 
the first dose on Day 1 coincide at the same time, or the same date if time of the measurement is 
not collected, that measurement will be considered as baseline value for Part 1. For Part 2, in the 
case where the last non-missing measurement (except AE and concomitant medications) and the 
first dose on Day 31 coincide at the same time, or the same date if time of the measurement is 
not collected, that measurement will be considered as baseline value for Part 2.
7.1.2
Definitions of Study Visit Windows
For each visit, a window will be defined; this window will establish a time interval around which 
data will be considered for the analysis of the scheduled visit pertaining to that window. The 
lower and upper bounds of each window are the approximate midpoints between the scheduled 
days for the current visit and its adjacent scheduled visits. The value used in analysis for by-visit 


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summaries is the value within the specified window that is closest to the scheduled study day. If 
two observations are equidistant from the scheduled visit date, the observation with a later date 
will be used. The visit windows and applicable study day ranges are presented below in Table 7.a
and Table 7.b. Cut-off days for inclusion in the window (number of days following the date of 
the last dose of open-label study drug) are provided.
Table 7.a
Visit Analysis Windows for Part 1
Visit
Scheduled 
Visit Day
Visit Window (Days)
Vital Signs, 
, 
PK, 
 Plasma 
Sample for 
AED, 
Concomitant 
Medications
ECG, Clinical 
Laboratory 
Tests
, 
Serum/urine 
Pregnancy 
Test
Physical Exam, 
Neurological 
Exam
Baseline I
1
≤1
≤1
≤1
≤1
≤1
Visit 3
11
2-16
2-16
2-16
2-43
Visit 4
21
17-26
17-26
2-33
Visit 5
31
27-36
27-36
17-58
Visit 6
41
37-53
37-53
Visit 7
85
54-Last Dose+7
54-Last 
Dose+7
59-Last 
Dose+7
44-Last 
Dose+7
34-Last Dose+7
Note: Any value collected after the administration of first dose on Day 1 will be grouped under Day 2, except for 
PK, 
 and plasma sample for AED.
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Table 7.b
Visit Analysis Windows for Part 2 
Visit
Scheduled 
Visit Day
Visit Window (Days)
Vital Signs, 
 
PK, 
, Plasma 
Sample for AED, 
Concomitant 
Medications
ECG, 
Clinical 
Laboratory 
Tests
, 
Serum/urine 
Pregnancy 
Test
Physical 
Exam, 
Neurological 
Exam
Baseline II
≤First Dose in 
Part 2
≤First Dose 
in Part 2
≤First Dose 
in Part 2
≤First Dose in 
Part 2
≤First Dose 
in Part 2
Visit 6
41
Day after First 
Dose in Part 2-53
Day after 
First Dose in 
Part 2-53
Visit 7
85
54-Last Dose+7
54-Last 
Dose+7
Day after 
First Dose in 
Part 2-Last 
Dose+7
Day after First 
Dose in Part 2-
Last Dose+7
Day after 
First Dose in 
Part 2-Last 
Dose+7
Note: Any value collected after the administration of first dose in Part 2 will be grouped under day after first dose in 
Part 2, except for PK, 
 and plasma sample for AED.
7.1.3
Conventions for Missing Adverse Event Dates
Adverse events with completely or partially missing dates will be imputed as follows.
7.1.3.1
Imputation of missing or partial dates of AE start dates
∀
Month/year available and day missing:
–
If the month and year are the same as those in the first dose date in Part 1 and the event is 
not indicated as a pre-treatment event, the first dose date in Part 1 is to be used to impute 
the start date.
–
If the month and year are the same as those in the first dose date in Part 1 and the event is 
indicated as a pre-treatment event, the date prior to the first dose date in Part 1 is to be 
used to impute the AE start date. If the date prior to the first dose date in Part 1 is in 
previous month/year, set the start month/year to the previous month/year. 
–
If the month and year are after the first dose date in Part 1 and the same as or before the 
last dose date in Part 1 plus 30 days for patients who do not continue to Part 2 or before 
the first dose date in Part 2, the first day of the month will be used for the start date.
–
If the month and year are the same as the first dose date in Part 2 and the same as the last 
dose date in Part 1, the first day of the month will be used for the start date.
–
If the month and year are the same as the first dose date in Part 2 and after the last dose 
date in Part 1, then the event is considered as a treatment emergent for Part 2 and the first 
dose date in Part 2 is to be used to impute the start date.
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–
If the month and year are after the first dose date in Part 2, the first day of the month will 
be used for the start date. 

Year available and month/day missing:
–
If the year is the same as the year of the first dose in Part 1 and same as or before the first 
dose in Part 2 and the event is not indicated as a pre-treatment event, the first dose date in 
Part 1 is to be used to impute the AE start date.
–
If the year is the same as the year of the first dose date in Part 1 and same as or before the 
first dose in Part 2 and the event is indicated as a pre-treatment event, the date prior to the 
first dose date in Part 1 is to be used to impute the AE start date. If the date prior to the 
first dose date in Part 1 is in previous month/year, set the start month/year to the previous 
month/year.
–
If the year is the same as the first dose date in Part 2 and after the last dose date in Part 1, 
the first dose date in Part 2 is to be used to impute the AE start date.
–
If the year is not the same as the year of the first dose date in Part 1 or the year of first 
dose date in Part 2, set the start date as January 1.

Year/month/day all missing:
–
If the event is not indicated as a pre-treatment event, the first dose date in Part 1 is to be 
used to impute the AE start date.
–
If the event is indicated as a pre-treatment event, the date prior to the first dose date in 
Part 1 is to be used to impute the AE start date. 
7.1.3.2
Imputation of missing or partial dates of AE end dates
If the event is indicated as ongoing at the end of the study, no imputation is needed.
If the event is not indicated as ongoing:

Month/year available and day missing:
–
Use the last day of the month to impute the AE end date. If the imputed end date is before 
the AE start date, keep the end date same as the start date. If the subject died, use the date 
of death to impute the end date. 

Year available and month/day missing:
–
If the year is the same as or before the year of the last dose in Part 2, set the end date as 
December 31.
–
If the year is after the year of the last dose in Part 2, set the end date as January 1.


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
Year/month/day all missing:
–
Impute the end date as December 31 of the Part 2 last dose year. If the imputed end date 
is before the AE start date, keep the end date same as the start date. If the subject died, 
use the date of death to impute the end date.
7.1.4
Conventions for Missing Concomitant Medication Dates
Concomitant medications with completely or partially missing will be imputed as follows.
7.1.4.1
Imputation of missing or partial dates of concomitant medication start dates 

Month/year available and day missing:
–
The first day of the month will be used for the start date.

Year available and month/day missing:
–
Set the start date as January 1.

Year/month/day all missing:
–
If date of birth is available, use the date of birth as the start date.
–
If date of birth is not available, estimate date of birth using the screening date and age, 
and use the estimated date of birth as the start date.
7.1.4.2
Imputation of missing or partial dates of concomitant medication end dates 
If the concomitant medication is indicated as ongoing, no imputation is needed.
If the concomitant medication is not indicated as ongoing, use the same algorithm in Section 
7.1.3.2 to impute.
7.1.5
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero in 
the summarization of concentration values. These values will be flagged in the data listings and 
deviations from this convention may be considered on a case-by-case basis as deemed
appropriate.
7.2
Analysis Sets
The randomized set will include all subjects who were randomly assigned to planned treatment 
through the IVRS/IWRS.
The PK analysis set for Parts 1 and 2 will include all subjects who received at least 1 dose of 
study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.


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The full analysis set (FAS) for Parts 1 and 2 will include all subjects who were randomized, 
received at least 1 dose of study drug, and have at least 1 valid post-baseline value for 
assessment of the efficacy endpoint(s) in Part 1 or Part 2. In FAS efficacy summaries, subjects 
will be analyzed according to the treatment to which they were randomized. 
The safety analysis set for Parts 1 and 2 will include all subjects who received at least 1 dose of 
study drug. In safety summaries, subjects will be analyzed according to the actual treatment they 
received.
7.3
Disposition of Subjects
Study information will be presented, including date first subject signed the Informed Consent 
Form, date of last subject’s last visit/contact, date of last subject’s last procedure for collection of
data for primary endpoint, Medical Dictionary for Regulatory Activities (MedDRA) Version, 
World Health Organization Drug Dictionary Version (WHODRUG), and SAS Version.
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data.
The number and percentage of subjects who complete study drug and all study visits in Part 1 of 
the study, prematurely discontinue study drug and study visits in Part 1 will be summarized by 
treatment group and overall for all randomized subjects in the double-blind period. For all the 
subjects who continue in Part 2 of the study, the number and percentage of subjects who 
complete study drug and all study visits in Part 2, prematurely discontinue study drug and study 
visits in Part 2 will be summarized. For each of Part 1 and Part 2, the primary reason for 
discontinuation of study drug/visits, as entered on the electronic case report form (eCRF), will be 
tabulated. The date of first dose, date of last dose, duration of treatment and the reason for 
premature discontinuation of study drug/study visit will be presented for each subject in listings.
Disposition of screen failure subjects in Part 1 will be summarized descriptively. Primary reasons 
for failure will be summarized and will be presented in a data listing
The number and percentage of subjects who comprised each analysis set will be summarized by 
treatment group and overall in Part 1, and overall in Part 2, respectively.
Disposition of the study drug dose combination for subjects in Part 1 and 2 will also be 
summarized by sequence of dose. For example, for subjects taking TAK-935 in Part 1, the 
number and percentage of subjects with dose combination of 100 to 200mg BID will be 
summarized. This summary will be based on safety analysis set. Details for important 
(significant) protocol deviations will be provided in a data listing. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics (e.g., date of birth, sex, Hispanic ethnicity, race as
described by the subject, epilepsy diagnosis) will be summarized and listed for subjects by 
treatment group and overall using the safety analysis set in Part 1. Summary statistics (number of 
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subjects, mean, SD, median, minimum, and maximum) will be presented for continuous 
variables (e.g., age, and weight), and the number and percentage of subjects within each category 
will be presented for categorical variables (e.g., sex, ethnicity, race). No inferential statistics will
be presented. Individual subject demographic and baseline characteristic data will be listed.
Demographic variables of screen failure subjects and reasons for screen failure will be 
summarized overall for subjects who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, any available safety data and reason for 
screen failure will also be presented in the data listing. 
7.5
Medical History and Concurrent Medical Conditions
Medical history refers to the significant conditions or diseases relevant to the disease under study 
that resolved at or prior to signing of informed consent. Concurrent medical conditions are those 
significant ongoing conditions or diseases present at signing of informed consent.
Medical history, epilepsy diagnosis, and concurrent medical conditions will be coded using the 
latest version of Medical Dictionary for Regulatory Activities (MedDRA, version 19.0) and will 
be summarized by treatment group and overall in Part 1, using System Organ Class (SOC) and 
MedDRA preferred term. The table will include number and percentages of subjects and will be 
sorted in alphabetical order by system organ class and preferred term. A subject will only be 
counted once within a particular class even if he/she has multiple conditions/symptoms. 
Summaries will be presented for Part 1 only, and will be based on the safety analysis set for Part 
1.
All medical history, epilepsy diagnosis, and concurrent medical condition data will be presented 
in listing.
7.6
Medication History and Concomitant Medications
Medication history information to be obtained includes any medication relevant to eligibility
criteria and the efficacy or safety evaluations stopped at or within 28 days before signing of
informed consent. AED history will be collected as part of the medication history information.
Medications used from signing of informed consent through the end of each study part will be 
considered as concomitant medications for each study part, respectively.
Summaries of medication history will be presented for Part 1 and Part 2, separately, and will be
based on the safety analysis set for Part 1. Concomitant medications that started and stopped 
prior to baseline, started prior to baseline and ongoing at baseline, started after baseline, and 
ongoing at baseline and started after baseline will be summarized using the safety analysis set in 
Part 1. Concomitant medication for Part 1 is defined as the medication that the patient started 
taking before first dose in Part 1 and ongoing in Part 1 of the study, and concomitant for Part 2 is 
defined as the medication that the patient started taking before first dose in Part 2 and ongoing in 
Part 2. No inferential statistics will be presented. 
All prior and concomitant medications data will be presented in listing.


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7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in a data listing based on the 
safety analysis set. Summaries of study drug concentration and exposure data will be provided 
by dose using the safety analysis set in Parts 1 and 2 separately. No inferential statistics will be 
presented.
The duration of exposure (days) to the double-blind study medication in Part 1 is defined as (date 
of last dose of double-blind study drug - date of first dose double-blind study drug + 1). The 
duration of exposure to the open-label study medication in Part 2 is defined as (date of last dose 
of open-label study drug – date of first dose of open-label study drug + 1). For patients who have 
been treated in both Parts 1 and 2 with active drug (TAK-935), the duration of exposure to the 
TAK-935 overall is defined as (date of last dose of open-label study drug – date of first dose of 
double-blind study drug +1). 
The date of last dose of study drug will be obtained from the eCRF. In the event that the date of 
last dose is missing, then for analysis and summary purpose, the last dose date will be estimated 
as the later date between the last drug dispense date plus the number of days in the dosing 
interval (dispense date + (next visit day – last visit day) + 1) and the last study visit day. 
The duration of double-blind treatment in Part 1 will be summarized by treatment group using 
the following categories: 1 to 11 days and 12 to 21 days, 22 to 31 days. The duration of open-
label treatment in Part 2 will be summarized using the following categories: 32 to 41 days, 42 to 
85 days, and 85 days or more. The intervals are calculated using the actual study days according 
to the visit window definitions in Table 7.a and Table 7.b.
In Part 1 of the study, subjects are to take 1-3 tablets for TAK-935 (100mg/200mg/300mg) or 
matching placebo twice each day. In Part 2, subjects are to take 1-3 tablets for TAK-935 
(100mg/200mg/300mg) twice daily. Overall percent study drug compliance for each period (Part 
1 and Part 2) will be calculated as: 
Overall compliance (%) = 100 ×{(number of tablets dispensed – number of tablets returned) / 
(expected number of tablets to be taken)}, 
where expected number of tablets to be taken = [number of tablets to be taken daily*(date of last 
dose of medication – date of first dose of medication + 1)]. 
Compliance will be presented to 1 decimal place in the derived dataset and Table, Figures, and 
Listings (TFLs) outputs.
Overall study drug compliance in Part 1 and Part 2 will each be summarized using descriptive 
statistics and by the number of subjects in each of the following compliance categories: <70%, 
>=70 to <=130%, >130%, and missing, if applicable. 
All study drug administration (double-blind placebo in Part 1, double-blind active (TAK-935) 
drug in Part 1, and open-label study drug in Part 2) and accountability data will be listed by site 
and subject number. The following variables will be listed: subject identifier, treatment, first and 
last double-blind dose dates, first and last open-label dose dates, number of tablets dispensed and 


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returned, overall double-blind percent compliance in Part 1, and overall open-label study drug 
percent compliance in Part 2. 
7.8
Efficacy Analysis
Efficacy analysis will be performed using FAS in Parts 1 and 2 separately.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable.
7.8.2
Secondary Efficacy Endpoint(s)
Not applicable.
7.8.3
Exploratory Efficacy Endpoint(s)
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
7.9.1.1
Pharmacokinetic Concentrations
Blood samples (one 4-mL sample per scheduled time) for the measurement of plasma 
concentrations of TAK-935 and its metabolite M-I will be collected according to Table 7.c.
Table 7.c
Collection of Plasma Samples for Measurement of TAK-935 and M-I in 
Plasma 
Study Part
Study Day/Visit
Scheduled Time
Part 1
Day 1
Days 11 and 21
Before and 1, 3, 5 hours after morning dose
Before and ~1 hour after morning dose
Part 2
Days 31, 41 and 85
Before morning dose
The plasma concentration of TAK-935 and its metabolite M-I will be listed for each subject and 
summarized by each time point for each dose and part of the study (N, mean, SD, median, 
minimum, and maximum).
7.9.1.2
Pharmacokinetic Parameters (Secondary Endpoints)
A population PK analysis approach will be used to determine the population estimates for TAK-
935. The PK analysis will be described in a separate analysis plan, and the PK parameters for 
TAK-935 will be summarized in a separate population PK/PD report.
7.9.2
Pharmacodynamic Analysis
7.9.2.1
Pharmacodynamic Concentrations
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7.9.3
Concomitant AEDs Analysis
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7.9.3.2
Parameter and Analysis
7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory parameters, vital sign parameters, 12-lead ECG 
results, and other safety parameters. The safety analysis set will be used for all summaries of 
safety parameters. The safety endpoints will be presented by placebo TAK-935, and overall in 
Part 1, by placebo, TAK-935 received in Part 1 and overall in Part 2 of the study, and by 
placebo, TAK-935 received in Part 1 and overall for Part 1 and 2 combined.
7.11.1 Adverse Events
A Pre-Treatment Event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. PTE and AE verbatim terms will be coded by SOC and PT using MedDRA (version 
19 or later).
TEAEs for Part 1 will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occur after the first dose of study drug received in Part 1 and up 
to 30 days (onset date – last date of dose + 1 ≤30) after the last dose of study drug in Part 1 or 
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early termination. AEs that occur on the same day as the first dose of study drug in Part 1 but 
with missing time will be considered as TEAEs for Part 1.
TEAEs for Part 2 will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occur after the first dose of study drug received in Part 2 and up 
to 30 days (onset date – last date of dose + 1 ≤30) after the last dose of study drug in Part 2 or 
early termination. AEs that occur on the same day as the first dose of study drug in Part 2 but 
with missing time will be considered as TEAEs for Part 2.
TEAEs for Part 1 and 2 combined will be defined as any sign, symptom, syndrome, or new 
illness, regardless of relationship to study drug, that occur after the first dose of study drug
received in Part 1 and up to 30 days (onset date – last date of dose + 1 ≤30) after the last dose of 
study drug in Part 2 or early termination. AEs that occur on the same day as the first dose of 
study drug in Part 1 but with missing time will be considered as TEAEs for Part 1 and 2.
TEAEs will be presented by severity (mild, moderate, and severe). Serious TEAEs, TEAEs 
leading to study drug discontinuation, and TEAEs leading to death will also be summarized 
using SOC and PT. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
AEs with missing severity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. Similarly, if the relationship of an event is missing, the event will 
be considered as related but in listings it will be presented as missing.
In general, AEs will be tabulated at the following levels: overall summary (subjects with at least 
1 AE in any dose or treatment), the MedDRA SOC, and the MedDRA PT. The tables will 
include the number and percentage (N[%]) of subjects. The following summary tables will be 
generated for each study part (Part 1 and Part 2): 

Overview of Treatment-Emergent Adverse Events 

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Treatment-Emergent Adverse Events by Preferred Term

Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term

Most Frequent (>5% or N>2) Non-Serious Adverse Events by Preferred Term

Most Frequent (>5% or N>2) Non-Serious Adverse Events by System Organ Class and 
Preferred Term

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term


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
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 

Drug-Related Treatment-Emergent Adverse Events by Preferred Term

Severity of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Pretreatment Adverse Events by System Organ Class and Preferred Term
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
SAEs, and AEs that resulted in death.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the safety analysis set and will be evaluated and 
presented using International System of Units (SI) unless otherwise stated. Table 7.f shows a list 
of all clinical laboratory tests. 


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Table 7.f
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis (a)
Study Specific
RBC
WBC with differential 
(% and absolute)
Hemoglobin
Hematocrit
Platelets
PT/INR
aPTT
ALT
Albumin
Alpha-1-acid glycoprotein
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
FSH (c)
Estradiol (d)
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Microscopic Analysis: (b)
RBC/high power field
WBC/high power field
Epithelial cells, casts etc
Plasma
Plasma (Concomitant AEDs)
Carbamazepine 
Clobazam 
Valproic acid
Phenytoin
Topiramate
Lamotrigine
Rufinamide
Zonisamide
Phenobarbital
Levetiracetam
Lacosamide
10-hydroxycabazepine (metabolite 
of oxcarbazepine)
Felbamate
Diagnostic Screening
Serum
Urine (a)
HIV
Drug screen including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, alcohol, and 
cotinine
hCG (for pregnancy) (f)
HBsAg and anti-HCV
HCV RNA detection by qPCR (e)
hCG (for pregnancy) (f)
aPTT= activated partial thromboplastin time, FSH=follicle-stimulating hormone, GGT=γ-glutamyl transferase, 
HDL=high-density lipoprotein, LDL=low-density lipoprotein, PT=prothrombin time, RBC=red blood cell; 
WBC=white blood cell.
(a) If urine cannot be collected at the time of the Screening Visit or other Visits due to the subject’s cooperation or 
because the subject is wearing a diaper, it is acceptable for the subject to continue in the study and the reason should 
be documented in the source document.
(b) Only if dipstick results are positive.
(c) For diagnostic purposes in female subjects only.
(d) In female patients only
(e) Subjects who are positive for hepatitis C Ab should return to the clinic for an unscheduled visit to provide a 
blood sample for HCV qPCR.
(f) Only for female subjects of childbearing potential. If urine cannot be collected at Visit 2, the reason should be 
documented in the source document and the results of the serum pregnancy test obtained at Visit 1 must be 
confirmed to be negative by the investigator prior to randomization. An additional serum hCG pregnancy test will be 
performed at the Final Visit.
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All laboratory test parameters will be displayed in individual subject data listings in both SI units 
and conventional (CV) units. For test results not in SI units, the conversion to SI units will be 
done in derived analysis data sets using the known conversion factors. If necessary, SI units from 
the central laboratory may be converted to Takeda’s preferred SI units in the derived dataset. All 
summaries and analyses will be based on the values using these preferred SI units.
Only observations within 7 days of the last dose of study drug will be included in the tables. No 
inferential statistics will be presented unless otherwise stated.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values will be presented for Parts 1 and 2 separately. Study baseline 
defined in Section 7.1.1 will be used for change from baseline in each part of the study. Note that 
character urinalysis tests will only be listed.
Laboratory Markedly Abnormal Values (MAVs), identified by the criteria defined in Appendix
A, will be tabulated. If a subject has a MAV for a particular laboratory test, all visits for that 
subject for that parameter will be listed. The number and percentage of subjects with at least 1 
post-dose markedly abnormal laboratory test result will be summarized. The mapping of the 
subjects who meet the MAV criteria will be listed as a table. All observations, including ones at 
unscheduled visits, will be included in the MAV evaluation and summaries if MAV criteria are 
satisfied.
All clinical laboratory data will be presented in both SI and conventional units in data listings.
7.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit for both Parts 1 and 2. Study baseline defined in Section 7.1.1 will be 
used. Only observations within 7 days of the study drug will be included in the tables.
Vital sign MAVs, identified by the criteria defined in Appendix B, will be tabulated. If a subject 
has a MAV for a particular vital signs parameter, all visits for that subject for that parameter will 
be listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal 
vital signs measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries if MAV criteria are satisfied.
All vital signs will be listed in a data listing.
7.11.4 12-Lead ECGs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters, 
including heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc interval 
(Fredericia’s and Bazett’s corrections), will be presented for baseline, each post-baseline visit, 
and change from baseline to each post-baseline visit for both Parts 1 and 2. Study baseline 
defined in Section 7.1.1 will be used. Only the scheduled measurements will be included in the 


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summary. Only observations within 7 days of the study drug will be included in the tables. No 
inferential statistics will be presented.
ECG MAVs, identified by the criteria defined in Appendix C, will be tabulated. If a subject has a 
MAV for a particular 12-lead ECG parameter, all visits for that subject for that parameter will be 
listed. The number and percentage of subjects with at least 1 post-dose markedly abnormal 12-
lead ECG measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant, not evaluable) is collected by eCRF at baseline and at each scheduled post-
baseline visit. Shifts in ECG interpretation will be presented as cross-tabulations (baseline versus 
each post-baseline visit) of numbers of subjects with normal, abnormal not clinically significant, 
and abnormal clinically significant interpretations, not evaluable, with missing, if applicable, and 
total categories by each treatment (placebo, TAK-935).
All ECG parameters will be listed in a data listing.
7.12
Changes in the Statistical Analysis Plan 
No additional/modified FAS or per-protocol populations will be defined. No interim analysis for 
Part 1 will be performed.


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8.0
REFERENCES
1. A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in 
Subjects With Developmental and/or Epileptic Encephalopathies, Takeda, Protocol
Amendment No.03 for TAK-935-2001, dated 21 March 2018.
2. Aman, M.; Singh, N. The Aberrant Behavior Checklist-Community. East Aurora, NY: 
Slosson Education Publications, Inc.; 1994.
3. Carpenter, JR, Kenward, MG, Vansteelandt, S.A comparison of multiple imputation and 
doubly robust estimation for analyses with missing data. Journal of the Royal Statistical 
Society: Series A (Statistics in Society) 2006: 169: 571–584.
4. Gringras P, Green D, Wright B, Rush C, Sparrowhawk M, Pratt K, Allgar V, Hooke N, 
Moore D, Zaiwalla Z, Wiggs L. Weighted Blankets and Sleep in Autistic Children—A 
Randomized Controlled Trial. Pediatrics 2014; 134 (2): :298–306.
5. Schmidt JD, Huete JM, Fodstad JC, Chin MD, Kurtz PF. An evaluation of the aberrant 
behavior checklist for children under age 5. Res Dev Disabil 2013; 34: 1190–1197.


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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 × LLN
>1.5 × ULN
Platelet count
Conventional
<75 × 103/L
>600 × 103/L
SI
<75 × 109/L
>600 × 109/L
Prothrombin 
time/international 
normalized ratio
Both
--
>1.5 × ULN
Activated partial 
thromboplastin time
Both
--
>1.5 × ULN
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3 × ULN
AST
Both
--
>3 × ULN
GGT
Both
--
>3 × ULN
Alkaline phosphatase
Both
--
>3 × ULN
Calcium
Conventional
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8 × LLN
>1.2 × ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 mol/L
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L


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Serum Chemistry – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit 
Low Abnormal
High Abnormal
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
Bicarbonate
Conventional
<8.0 mEq/L
--
SI
<8.0 mmol/L
--
Creatine kinase
Conventional
--
>5 × ULN
SI
--
>5 × ULN
Total Cholesterol
Conventional
--
>300 mg/dL
SI
--
>7.72 mmol/L
Triglycerides
Both
--
>2.5 × ULN
LDL Cholesterol
Conventional
< 50 mg/dL
>160 mg/dL
SI
<1.30 mmol/L
>4.14 mmol/L
HDL Cholesterol
Conventional
<40 mg/DL
>60mg/DL
SI
<1.04 mmol/L
>1.55 mmol/L
Alpha-1-Acid 
Glycoprotein
Conventional
<47mg/DL
>125 mg/DL
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


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Appendix B
Criteria for Markedly Abnormal Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
< 35.6
>37.7


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Appendix C
Criteria for Markedly Abnormal 12-Lead ECG Parameters
Parameter
Unit
Lower Criteria 
Upper Criteria
Heart Rate
bpm
< 50
> 120
PR 
msec
≤ 80
≥ 200
RR 
msec
≤ 600
≥ 1440
QRS 
msec
≤ 80
≥ 180
QT Interval
msec
≤ 50
≥ 460
QTcF Interval
msec
≤ 50
≥ 500 
OR 
≥ 30 change from baseline and ≥ 450


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䣖䣃䣍䢻䢵䢷䢯䢴䢲䢲䢳䢢䣕䣃䣒䢢䣈䣫䣰䣣䣮䢢䢴䢷䣑䣥䣶䣱䣤䣧䣴䢴䢲䢳䢺
%LRVWDWLVWLFV$SSURYDO
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&OLQLFDO$SSURYDO
2FW87&
%LRVWDWLVWLFV$SSURYDO
1RY87&
PPD