Conditions: Depressive Disorder
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess the safety, tolerability and pharmacokinetics (PK) of TAK-653 when administered as single and multiple oral doses at escalating dose levels in healthy participants.

Detailed description:
The drug being tested in this study is called TAK-653. TAK-653 is being tested to treat people who have depression. This study will look at the tolerability and PK of TAK-653 in healthy participants.

The study may enroll up to 112 participants and each cohort will enroll 8 participants. This study consists of 2 parts: Part 1- single rising dose (SRD) consisting of at least 6 cohorts and Part 2- single rising dose and multiple rising dose (SRD/MRD) consisting of at least 5 cohorts. Additional cohorts may be added depending on the emerging safety and PK data. Participants will be randomly assigned (by chance, like flipping a coin) within each cohort to receive TAK-653 or placebo which will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need). Participants enrolled in Cohort 1 to 5 of Part 1 will receive TAK-653 0.3 mg, 1.0 mg, 3.0 mg, 5.0 mg and 9.0 mg or TAK-653 placebo-matching tablet. Subsequent dose escalation in Part-1, from Cohort 6 onward will occur after the full availability of safety, tolerability, PK, and PD data from preceding cohorts. Participants in Part-2 Cohorts 1 to 3 will receive TAK-653 0.3 mg, 1.0 mg and 3.0 mg respectively. Dose for Part 2, from Cohort 4 onward will be based on review of safety, tolerability, and available PK and PD data from previous cohorts. All participants will be asked to take the drug at the same time each day on Day 1 for Part 1 and Day 1 and Days 6 to 18 in Part 2.

This single-center trial will be conducted in the United Kingdom. The overall time to participate in this study is approximately 14 days for Part 1 and 31 days for Part 2. Participants will be admitted to the clinic for 6 days in Part 1 and 22 days in Part 2. Participants will be followed up 14 days after last dose of study drug for a follow-up assessment.

Arms:
arm 1: TAK-653 0.3 milligram (mg), tablet, orally, once on Day 1 or TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. arm 2: TAK-653 1.0 mg, tablet, orally, once on Day 1 or TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. arm 3: TAK-653 3.0 mg, tablet, orally, once on Day 1 or TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. arm 4: TAK-653 5.0 mg, tablet, orally, once on Day 1 or TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. arm 5: TAK-653 9.0 mg, tablet, orally, once on Day 1 or TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. arm 6: TAK-653 18 mg, tablet, orally, once on Day 1 or TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. Dose escalation to be decided (TBD) based on safety, tolerability, and available PK and pharmacodynamics (PD) data from previous cohorts. arm 7: TAK-653 placebo-matching tablet, orally, once on Day 1. TAK-653 or placebo will be administered after an overnight fast of approximately at least 10 hours. Dose escalation TBD based on safety, tolerability, and available PK and PD data from previous cohorts. arm 8: TAK-653 0.3 mg, tablet, orally, once on Day 1, and once daily (QD) from Days 6 to 18 or placebo-matching tablet, orally, once on Day 1 and QD from Days 6 to 18. arm 9: TAK-653 1.0 mg, tablet, orally, once on Day 1, and QD from Days 6 to 18 or placebo-matching tablet, orally, once on Day 1 and QD from Days 6 to 18. arm 10: TAK-653 3.0 mg, tablet, orally, once on Day 1, and QD from Days 6 to 18 or placebo-matching tablet, orally, once on Day 1 and QD from Days 6 to 18. arm 11: TAK-653 6 mg, tablet, orally, once on Day 1, and QD from Days 6 to 18 or placebo-matching tablet, orally, once on Day 1 and QD from Days 6 to 18. Dose escalation TBD based on safety, tolerability, and available PK and PD data from previous cohorts. arm 12: TAK-653 9 mg, tablet, orally, once on Day 1, and QD from Days 6 to 18 or placebo-matching tablet, orally, once on Day 1 and QD from Days 6 to 18. Dose escalation TBD based on safety, tolerability, and available PK and PD data from previous cohorts. arm 13: TAK-653 placebo-matching tablet, orally, once on Day 1 and QD from Days 6 to 18. Dose escalation TBD based on safety, tolerability, and available PK and PD data from previous cohorts.

Interventions: intervention 1: TAK-653 Placebo intervention 2: TAK-653
Intervention descriptions: intervention 1: TAK-653 placebo-matching tablets. intervention 2: TAK-653 tablets.

Protocol document:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and
Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in Healthy
Subjects
NCT Number: NCT02561156
Protocol Approve Date: 24 March 2017
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 or company confidential information. 
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.


TITLE PAGE
CONFIDENTIAL
PROTOCOL AMENDMENT
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in Healthy 
Subjects
Phase 1 TAK-653 Escalating Single and Multiple Dose Study in Healthy Subjects
Sponsor:
Takeda Development Centre Europe Ltd.
61 Aldwych
London, WC2B 4AE
United Kingdom
Study Number:
TAK-653-1001
IND Number:
Not Applicable
EudraCT Number:
2015-002268-17
Compound:
TAK-653 
Date:
24 March 2017
Amendment Number:
06
Amendment History:
Date
Amendment Number
Amendment Type
Region
23 June 2015
Initial Protocol
Not applicable
United Kingdom
26 August 2015
1
Nonsubstantial
United Kingdom
29 March 2016
2
Substantial
United Kingdom
01 April 2016
3
Substantial
United Kingdom
28 June 2016
4
Substantial
United Kingdom
06 January 2017
5
Substantial
United Kingdom
24 March 2017
6
Substantial
United Kingdom
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 
Investigators will be provided with emergency medical contact information cards to be carried by 
each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines should 
be provided to the site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance 
Takeda Development Centre Europe Ltd. 
Email: eupv@tgrd.com (preferred method of reporting) 
Fax: + (44) 207 242 1820
Medical Monitor
(medical advice on protocol and compound)
Takeda Development Centre Europe Ltd.
Office: 
Mobile
Email: 
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
Takeda Development Centre Europe Ltd.
Office:
Mobile
Email: 
PPD
PPD
PPD
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.
SIGNATURES 
The responsible Takeda medical officer and other signatories are shown below. Electronic 
signatures are located on the last page of the document.
PPD


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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 Council for 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 Clinical Study Site Agreement.
!
Appendix D – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix F of this protocol.
PPD


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1.3
Protocol Amendment 06 Summary of Changes
Rationale for Amendment 06
This document describes the changes in reference to the protocol incorporating Amendment 
No. 06. The primary reasons for Protocol Amendment No.6 are to increase the approximate total 
number of subjects to be enrolled and to revise the parameters for dose escalation decisions, given 
the available nonclinical monkey toxicity data and favorable preliminary safety/tolerability and 
pharmacokinetic (PK) data for cohorts that have completed dosing to date. 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 H. 
Changes in Amendment 06
1. The approximate total number of subjects to be enrolled in the study has been increased.
2. The nonclinical basis used to support dose escalation decisions has been revised.
3. The summary of the 13-week repeat-dose monkey toxicity data has been revised.
4. A summary of the 13-week repeat-dose rat toxicity data has been added.
5. A summary of preliminary blinded safety/tolerability and PK data has been added for 
completed single-rising dose (SRD) Cohorts 1 to 5 and SRD/multiple-rising dose (MRD) 
Cohorts 1 and 2.
6. The need for an independent medical reviewer from the sponsor to endorse dose escalation 
decisions has been removed.
7. Text has been added to clarify that study drug–related central nervous system 
disorders/adverse events may result in the stopping of dose escalation or study drug dosing.
8. Change in peripheral levels of the biomarker 
 after 
dosing has been included as an endpoint for all cohorts (rather than just for SRD/MRD 
Cohort 3).
9. An additional blood sample collection at 168 hours postdose has been included for SRD 
Cohort 6 onward in Part 1.
10. Text was clarified to indicate that TAK-653 and the 
 only will be measured 
in 
 if feasible.
11. Text has been added to indicate that screening data for subjects who have undergone general 
screening procedures (ie, panel screening) before the effective date of this protocol amendment 
may be used to assess subject eligibility for enrollment in this study.
12. The responsibilities of the investigator have been revised to reflect the updated International 
Council for Harmonisation E6(R2) Good Clinical Practice Consolidated Guideline.
13. Procedures for bioanalytical and pharmacogenomic sample collecting, processing, and 
shipping have been removed and referenced to the laboratory manual instead.
14. The sponsor signatories for this protocol have been updated.
CCI
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 06 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Principal Investigator...............................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................20
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.2
Rationale for the Proposed Study.............................................................................24
4.3
Risk-Benefit Profile .................................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Primary Objective....................................................................................................26
5.2
Secondary Objective................................................................................................26
5.3
Exploratory/Additional Objectives...........................................................................26
5.4
Endpoints.................................................................................................................26
5.4.1
Primary Endpoints .............................................................................................26
5.4.2
Secondary Endpoints..........................................................................................27
5.4.3
Exploratory/Additional Endpoints......................................................................27
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................29
6.1
Study Design ...........................................................................................................29
6.1.1
Part 1: SRD........................................................................................................29
6.1.2
Part 2: SRD/MRD..............................................................................................31
6.1.3
Dose Escalation..................................................................................................33
6.2
Justification for Study Design, Dose, and Endpoints ................................................35
6.2.1
Study Design......................................................................................................35
6.2.2
Dose ..................................................................................................................36
6.2.3
Endpoints...........................................................................................................37
6.2.4
Risk Mitigation ..................................................................................................38
6.3
Premature Termination or Suspension of Study or Investigational Site.....................38
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................38


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6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........39
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site....................................................................39
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............40
7.1
Inclusion Criteria .....................................................................................................40
7.2
Exclusion Criteria ....................................................................................................40
7.3
Excluded Medications, Dietary Products..................................................................43
7.4
Diet, Fluid, and Activity Control..............................................................................43
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................45
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................46
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT......................................................47
8.1
Study Medication and Materials...............................................................................47
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................47
8.1.1.1 Sponsor-Supplied Drug ................................................................................47
8.1.2
Storage...............................................................................................................47
8.1.3
Dose and Regimen .............................................................................................47
8.1.4
Overdose............................................................................................................48
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................48
8.3
Randomization Code Creation and Storage..............................................................49
8.4
Investigational Drug Blind Maintenance ..................................................................49
8.5
Unblinding Procedure..............................................................................................49
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................49
9.0
STUDY PLAN ..............................................................................................................52
9.1
Study Procedures.....................................................................................................52
9.1.1
Informed Consent Procedure..............................................................................52
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................52
9.1.2
Demographics, Medical History, and Medication History Procedure..................52
9.1.3
Physical Examination Procedure ........................................................................52
9.1.4
Weight, Height, and BMI...................................................................................53
9.1.5
Vital Sign Procedure..........................................................................................53
9.1.6
Documentation of Concomitant Medications......................................................54
9.1.7
Documentation of Concurrent Medical Conditions.............................................54
9.1.8
Procedures for Clinical Laboratory Samples.......................................................55
9.1.9
Telemetry...........................................................................................................56
9.1.10 Contraception and Pregnancy Avoidance Procedure...........................................56
9.1.11 Pregnancy ..........................................................................................................57


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9.1.12 ECG Procedure..................................................................................................58
9.1.13 Safety EEG Procedure........................................................................................59
9.1.14 Pharmacogenomic Sample Collection ................................................................59
9.1.14.1
DNA Collection (all Cohorts).................................................................60
9.1.14.2
RNA Collection......................................................................................60
9.1.14.3
DNA and RNA Samples.........................................................................60
9.1.15 Pharmacokinetic Sample Collection...................................................................60
9.1.15.1
Collection of Plasma and Urine for Pharmacokinetic Sampling ..............60
9.1.15.2
Collection of 
...................................................................................62
9.1.15.3
Bioanalytical Methods............................................................................62
9.1.16 Pharmacokinetic Parameters ..............................................................................62
9.1.17 Pharmacodynamic Sample Collections...............................................................64
9.1.17.1
................................................................................................64
9.1.17.2
................................................................................................64
9.1.18 Pharmacodynamic Parameters............................................................................64
9.1.18.1
.................................................................................64
9.1.18.2
.................................................................................65
9.1.19 Documentation of Screen Failure .......................................................................65
9.1.20 Documentation of Randomization......................................................................65
9.1.21 Assessment of Suicidal Ideation and Behavior ...................................................65
9.2
Monitoring Subject Treatment Compliance..............................................................66
9.3
Schedule of Observations and Procedures................................................................66
9.3.1
Screening...........................................................................................................66
9.3.2
Check-In Procedures..........................................................................................67
9.3.3
Treatment Phase.................................................................................................68
9.3.4
Study Exit ..........................................................................................................69
9.3.5
Early Termination..............................................................................................70
9.3.6
Follow-up Call/Visit ..........................................................................................70
9.3.7
End-of-Trial Date...............................................................................................70
9.4
Blood Volume .........................................................................................................70
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................73
10.1
Definitions...............................................................................................................73
10.1.1 PTEs..................................................................................................................73
10.1.2 AEs....................................................................................................................73
10.1.3 Additional Points to Consider for PTEs and AEs................................................73
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10.1.4 SAEs..................................................................................................................75
10.1.5 Adverse Events of Special Interest .....................................................................76
10.1.6 Severity of PTEs and AEs..................................................................................76
10.1.7 Causality of AEs ................................................................................................77
10.1.8 Relationship to Study Procedures.......................................................................77
10.1.9 Start Date...........................................................................................................77
10.1.10
Stop Date .....................................................................................................77
10.1.11
Frequency ....................................................................................................77
10.1.12
Action Concerning Study Drug ....................................................................77
10.1.13
Outcome.......................................................................................................78
10.2
Procedures...............................................................................................................78
10.2.1 Collection and Reporting of AEs........................................................................78
10.2.1.1
PTE and AE Collection Period ...............................................................78
10.2.1.2
PTE and AE Reporting ...........................................................................78
10.2.1.3
AESI Reporting......................................................................................79
10.2.2 Collection and Reporting of SAEs......................................................................80
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................80
10.3
Follow-up of SAEs ..................................................................................................80
10.3.1 Safety Reporting to Investigators, IEC, and Regulatory Authorities....................81
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................82
12.0
DATA HANDLING AND RECORDKEEPING............................................................83
12.1
CRFs (Electronic)....................................................................................................83
12.2
Record Retention .....................................................................................................83
13.0
STATISTICAL METHODS..........................................................................................85
13.1
Statistical and Analytical Plans ................................................................................85
13.1.1 Analysis Sets......................................................................................................85
13.1.2 Analysis of Demographics and Other Baseline Characteristics...........................85
13.1.3 Pharmacokinetic Analysis ..................................................................................85
13.1.3.1
Concentrations in Plasma, Urine, and 
..............................................85
13.1.3.2
PK Parameters........................................................................................86
13.1.4 Pharmacodynamic Analysis ...............................................................................86
13.1.5 Safety Analysis ..................................................................................................87
13.1.6 AEs....................................................................................................................87
13.1.6.1
Clinical Laboratory Evaluation...............................................................87
13.1.6.2
Vital Signs..............................................................................................87
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13.1.6.3
ECGs......................................................................................................87
13.1.6.4
Safety EEGs...........................................................................................87
13.2
Interim Analysis and Criteria for Early Termination ................................................88
13.3
Determination of Sample Size..................................................................................88
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................89
14.1
Study-Site Monitoring Visits ...................................................................................89
14.2
Protocol Deviations..................................................................................................89
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................90
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................91
15.1
IEC Approval ..........................................................................................................91
15.2
Subject Information, Informed Consent, and Subject Authorization .........................91
15.3
Subject Confidentiality ............................................................................................92
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................93
15.4.1 Publication and Disclosure.................................................................................93
15.4.2 Clinical Trial Registration..................................................................................93
15.4.3 Clinical Trial Results Disclosure ........................................................................94
15.5
Insurance and Compensation for Injury....................................................................94
16.0
REFERENCES..............................................................................................................95
LIST OF IN-TEXT TABLES
Table 6.a
Summary of SRD Dose Cohorts.........................................................................31
Table 6.b
Summary of SRD/MRD Dose Cohorts...............................................................33
Table 7.a
Prohibited Medications and Dietary Products.....................................................43
Table 9.a
Schedule for Vital Signs Assessments................................................................54
Table 9.b
Clinical Laboratory Tests...................................................................................55
Table 9.c
Collection of Blood and Urine Samples for Pharmacokinetic Analysis...............61
Table 9.d
Collection of 
 Samples ................................................................................62
Table 9.e
Collection of Blood Samples for Analysis of
...........................................64
Table 9.f
Approximate Blood Volume: SRD Cohorts 1 to 5..............................................71
Table 9.g
Approximate Blood Volume: SRD Cohort 6 Onward.........................................71
Table 9.h
Approximate Blood Volume: SRD/MRD Cohorts..............................................72
Table 10.a
Takeda Medically Significant AE List................................................................76
Table 14.a
Windows for PK/PD Blood Sample Collection ..................................................90
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LIST OF IN-TEXT FIGURES
Figure 6.a
SRD Study Schematic........................................................................................30
Figure 6.b
SRD/MRD Study Schematic ..............................................................................32
LIST OF APPENDICES
Appendix A
SRD Part 1 Schedule of Study Procedures: Cohorts 1 to 5..................................97
Appendix B
SRD Part 1 Schedule of Study Procedures: Cohort 6 Onward.............................99
Appendix C
SRD/MRD Part 2 Schedule of Study Procedures..............................................101
Appendix D
Responsibilities of the Investigator...................................................................104
Appendix E
Elements of the Subject Informed Consent.......................................................106
Appendix F
Investigator Consent to Use of Personal Information........................................109
Appendix G
Neurological Examination................................................................................110
Appendix H
Detailed Description of Amendments to Text...................................................111


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2.0
STUDY SUMMARY 
Name of Sponsor:
Takeda Development Centre Europe Ltd.
Compound:
TAK-653
Title of Protocol: A Phase 1, Randomized, Double-Blind, 
Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Escalating Single and Multiple 
Doses of TAK-653 in Healthy Subjects
IND No.:
not applicable
EudraCT No.:
2015-002268-17
Study Number: TAK-653-1001
Phase: 1
Study Design:
This first-in-human, double-blind, placebo-controlled, combined single-rising dose (SRD)/multiple-rising dose 
(MRD) phase 1 study in healthy subjects is designed to assess the safety and tolerability of TAK-653. Approximately 
112 healthy male and female volunteers will be enrolled. 
This study consists of 2 parts: (1) single ascending doses in 5 cohorts (SRD) and (2) single and multiple ascending 
doses in 4 cohorts (SRD/MRD). Each cohort will consist of 8 subjects (6 active:2 placebo). Subjects will fast for at 
least 10 hours before dosing. Cohorts may be added or removed.
This study will also provide a preliminary assessment of the potential effect of food on TAK-653 PK. Subjects in a 
selected SRD cohort (fasted conditions) will return to receive the same dose of TAK-653 under fed conditions after 
safety and tolerability has been established for TAK-653 at a higher dose under fasted conditions. 
Follow-up assessments will occur approximately 14 days after the last dose of study drug to inquire for any ongoing 
adverse events (AEs) or serious adverse events (SAEs), new or worsening AEs or SAEs, and concomitant medications 
taken since final dose. The Follow-up will occur by telephone unless abnormal, clinically significant findings are 
observed upon discharge. Subjects may then return to the clinic for re-evaluation per investigator’s discretion. 
For all subjects in the SRD and SRD/MRD cohorts
 
 
SRD Part 1: Subjects will be enrolled in SRD cohorts. Sentinel dosing will be used for each SRD Cohort. The first 2 
subjects (1 active: 1 placebo) in each Cohort will receive either TAK-653 or placebo in parallel, followed by a 
minimum 24-hour gap to ensure adequate evaluation of safety and tolerability prior to administering the same dose of 
TAK-653 or placebo to the remaining subjects within the Cohort (5 active: 1 placebo). Dosing of the remaining 
subjects will proceed in a staggered fashion with no more than 3 subjects being dosed at a time and having an 
approximate 24-hour gap before the next group of subjects is dosed. Each dose cohort will be examined sequentially to 
ensure adequate evaluation of safety, tolerability, and available PK and PD data prior to administering the next dose 
level. Administration with food will not occur until safety is established at a higher dose.
A schematic of the study design for the SRD study arm is shown below:
Pretreatment Period
Treatment Period
Follow-up 
(d)
Screening
Check-in
Assessments 
(a)
TAK-653 Dosing
Study Assessments 
(a) (b) (c)
Safety/PK/PD 
Assessments 
(a) (c)
PK Assessments
PK Assessments 
Study Exit (a)
Days -28 
to -2
Day -1
Day 1
Days 2-5
Day 6 (Cohorts 1-5)
Days 6-7 (Cohort 6 
onward)
Day 7 (Cohorts 1-5)
Day 8 (Cohort 6 
onward)
Day 14 
(±2)
Confinement
(a) EEG assessments are scheduled on Days -1, 1, 2, and 5, at Study Exit, and at early termination (ET).
(b) Study assessments include PK sample collection throughout.
(c) For SRD Cohort 6 onward, blood samples for 
 will be collected on Days 1 to 5.
(d) The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon discharge. In 
these cases, subjects may then be brought back to the clinic for re-evaluation per investigator’s discretion.
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Subjects in SRD cohorts will be kept in the study unit for approximately 96 hours after dosing for safety, PK, and PD assessments 
before discharge. The total confinement period will be 5 days. Subjects in SRD Cohorts 1 to 5 will return to the clinic on Days 6 and 
7 for additional PK collections. Subjects in SRD Cohort 6 onward will return to the clinic on Days 6, 7, and 8 for additional PK 
collections. If the t1/2z of TAK-653 for any cohort differs significantly from what was predicted, the duration of confinement may 
also be adjusted. Subjects in the food effect cohort will be confined twice for 5 days each for a total of 10 days. For SRD Cohort 6 
onward,
 
. Follow-up assessments for all subjects in the SRD study arm will 
occur on Day 14 (±2).
SRD/MRD Part 2: Progression into the SRD/MRD study arm will occur only after review of all safety, tolerability, PK, and PD 
data collected in at least the first 3 SRD cohorts. All doses used in SRD/MRD Cohorts will be administered only if there is 
acceptable safety, tolerability, PK, and PD data at the same or higher dose level after a single dose in the SRD Cohorts. The
potential for accumulation and its impact on the likelihood of reaching the no-observed-adverse-effect level (NOAEL) exposure 
cap, will be taken into account when selecting doses for the MRD.
A single dose of TAK-653 or placebo will be administered on Day 1 followed by approximately 120 hours for safety, tolerability, 
PK, and PD assessments. Once daily (QD) multiple dosing will begin on Day 6 and continue through Day 18 (13 days). Initiation of 
the multiple-dose phase on Day 6 may be adjusted based on emerging PK data. Subjects in the SRD/MRD Cohorts will be kept in 
the study unit for at least 72 hours after the last dose for safety assessments before discharge. The total confinement period will be 
21 days. For SRD/MRD Cohort 3 only, a 
 sample will be collected from each subject to measure the 
concentration of TAK-653 at steady state. 
 in 
 (for SRD/MRD Cohort 3 only) or in
 only (for SRD/MRD Cohort 4 onward) to investigate the potential 
biological effects of TAK-653. Concentrations of 
 in 
 will also be measured for SRD/MRD Cohort 3, if possible. 
Follow-up assessments will occur on Day 31 (±2).
Each dose cohort will be examined sequentially to ensure adequate evaluation of all available safety, tolerability, PK, and PD data 
prior to administering the next dose level.
The study schematic for the SRD/MRD study arm is shown below.
Pretreatment Period
Treatment Period
Follow-u
p (e)
Screening
Check-in
Assessments
TAK-653 
Single Dose 
Study 
Assessments 
(a) (b) (d)
Safety and PK 
Assessments 
(d)
TAK-653 
QD dosing
Study 
Assessments 
(a) (b) (c) (d)
Safety and PK 
Assessments
Study 
Exit
Days -28 to 
-2
Day -1
Day 1
Days 2-5
Days 6-18
Days 19-20
Day 21
Day 31 
(±2)
Confinement
(a) Study assessments include PK sample collection throughout.
(b) EEG assessments are scheduled on Days 1, 11, 18, and ET.
(c) For SRD/MRD Cohort 3 only, a single 
 sample will be collected from each subject on Day 12.
(d) For SRD/MRD Cohort 3 onward, blood samples for 
 will be collected on Days 1 to 5, 18, and 19.
(e) The Follow-up Visit will occur by telephone unless abnormal, clinically significant findings are observed upon discharge. In 
these cases, subjects may then be brought back to the clinic for re-evaluation per investigator’s discretion. 
All decisions concerning dose escalation will be based on emerging safety, tolerability, and available PK and PD data. 
The planned dose levels may be modified in accordance with the following parameters:
!
Dosing in all Cohorts will be limited to an escalated dose which is predicted to give no greater than ~3-fold 
increase in either the maximum observed plasma concentration (Cmax) or area under the plasma 
concentration-time curve (AUC). A smaller increment may be used at higher doses and a larger increment may be 
used at lower doses if exposures obtained are not sufficiently high, and if it is deemed safe to do so. In the event 
that the majority of plasma concentrations of TAK-653 are below the limit of detection, the dose will be escalated 
to a higher dose level, if safety and tolerability are acceptable. 
!
In the SRD Part 1, following completion of Cohort 1, exposure to TAK-653 in humans compared with what was 
predicted utilizing nonclinical data will influence the dose to be studied in Cohort 2.
!
Administration with food for the food-effect cohort will not occur until safety is established at a higher dose. 
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!
Progression into the SRD/MRD Part 2 will occur only after review of all available safety, tolerability, PK, and PD 
data collected in SRD Cohorts 1-3. The actual dose used in the SRD/MRD Cohorts will not be administered 
unless there is adequate safety, tolerability, and PK data at the same or higher dose level from the SRD Cohorts. 
!
In a 13-week repeat-dose toxicity study conducted with TAK-653 in cynomolgus monkeys, test article–related 
toxicities occurred around time of first occurrence of Cmax (tmax), typically within the first few days of dosing, and 
were considered to be related to the Cmax rather than to the area under the plasma concentration-time curve from 
time 0 to 24 hours postdose (AUC24). Therefore, the predicted Cmax value for the TAK-653 dose selected for any 
cohort should not exceed 362 ng/mL, the mean Cmax value achieved in female monkeys on the first day of dosing 
at the NOAEL of 3 mg/kg/day. In addition, the predicted AUC value for any TAK-653 dose selected should not 
exceed 
, the mean AUC24 value achieved in female monkeys at the end of the 13-week dosing 
period at the NOAEL of 3 mg/kg/day. If PK data collected during a cohort indicate that exposure to TAK-653 has 
surpassed the mean 
 at the NOAEL, lower doses will 
be used in subsequent cohort(s).
!
Additionally, Takeda and the principal investigator may jointly decide to not escalate the dose for a particular 
cohort, but rather administer the same or a lower dose level to the next cohort.
End of trial (study completion date) is based on the final data collection date for the entire study which is the follow-up 
assessment.
Primary Objective:
To determine the safety and tolerability of TAK-653 when administered as single and multiple oral doses at escalating 
dose levels in healthy subjects.
Secondary Objectives:
To determine the PK of TAK-653 when administered as single and multiple oral doses at escalating dose levels in 
healthy subjects.
Exploratory/Additional Objectives:
Subject Population: Healthy male and female subjects aged 18 to 55 years, inclusive, at the time of consent.
Number of Subjects:
Per Cohort: 8 (6 active: 2 placebo)
Estimated total: Up to 112 randomized healthy subjects 
Number of Sites:
Estimated total: 1 in United Kingdom
Dose Levels:
SRD Cohorts: first dose 0.3 mg TAK-653, subsequent dose 
levels to be determined by emerging safety, tolerability, 
PK, and PD data in preceding Cohorts.
SRD/MRD Cohorts: to be determined by emerging safety, 
tolerability, PK, and PD data in the SRD cohorts and 
preceding SRD/MRD Cohorts.
Route of Administration: Oral
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Duration of Treatment:
SRD Cohorts: 1 day
SRD Food-Effect Cohort: 2 days
SRD/MRD Cohorts: 14 days
Period of Evaluation (First dose to Follow-up):
SRD Cohorts: 14 days
SRD Food-Effect Cohort: 28 days
SRD/MRD Cohorts: 31 days
Main Criteria for Inclusion:
!
The subject is a healthy male or female adult, aged 18 to 55 years, inclusive, at the time of consent.
!
The subject weighs at least 45 kg (99 lb) and has a body mass index (BMI) between 18.0 and 30.0 kg/m2, 
inclusive, at Screening.
Main Criteria for Exclusion:
!
Subject has any clinically significant illness, such as cardiovascular, neurologic, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, urologic, immunologic, endocrine, or psychiatric disease or disorder, or other 
abnormality which may affect safety, increase the risk for seizures, lower the seizure threshold, or potentially 
confound study results.
!
Subject has a risk of suicide per the Columbia-Suicide Severity Rating Scale (C-SSRS) (a score of 4 or 5 on 
ideation or any suicidal behavior) or according to the investigator’s clinical judgment, has made a suicide attempt 
in the previous 6 months, or has a history of deliberate self-harm in the past 6 months.
!
Subject has had previous episodes of seizures or convulsion (lifetime), including absence seizure and febrile 
convulsion.
!
Subject or any immediate family member has a history of epilepsy (including febrile convulsions).
!
Subject has a history of neurological abnormalities including abnormal electroencephalogram (EEG) at Screening 
or brain injury including traumatic injury, perinatal cerebropathy and postnatal brain damage, blood-brain barrier 
abnormality, or angioma cavernous.
!
Subject has a history of cerebral arteriosclerosis.
!
Subject has a condition that can potentially reduce drug clearance (eg, renal or hepatic insufficiency).
Additional exclusion criteria for 
 collection in SRD/MRD Cohort 3:
!
The subject has had 
 collected within 6 months prior to Check-in (Day -1).
!
The subject has a known hypersensitivity to the anesthetic or its derivatives used during 
 collection or any 
medication used to prepare the area of lumbar puncture.
!
The subject has any skin condition, abnormality of the lumbar spine, or medical or surgical condition that would 
preclude lumbar puncture (eg, coagulopathy, local or systemic infection, left ventricular outflow obstruction, 
aortic stenosis, raised intracranial pressure, previous back surgery).
Main Criteria for Evaluation and Analyses:
Safety: The primary endpoints include AEs, clinical laboratory test results, electrocardiogram (ECG), EEG, vital 
signs, and suicidality assessments.
Pharmacokinetics: The following PK parameters of TAK-653 will be determined from plasma: Cmax (Day 1 for all 
Cohorts and Day 6 for SRD/MRD Cohorts), maximum observed steady-state plasma concentration during a dosing 
interval (Cmax,ss) (Day 18 for SRD/MRD Cohorts), tmax (Day 1 for all Cohorts and Day 18 for SRD/MRD Cohorts), 
area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast) 
(Day 1 for all Cohorts), area under the plasma concentration-time curve from time 0 to infinity (AUC∞) (Day 1 for all 
Cohorts), area under the plasma concentration-time curve during a dosing interval (AUCτ) (Day 6 and Day 18 for 
SRD/MRD Cohorts). 
Pharmacodynamics: 
 
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Statistical Considerations:
Safety:
AEs will be presented in listings, and treatment-emergent adverse events will be summarized. Individual results of 
laboratory tests (hematology, chemistry, and urinalysis), vital signs, and ECGs will be listed and Baseline, postdose, 
and changes from Baseline to postdose laboratory, vital signs, and ECG data will be summarized. Physical 
examination findings and suicidality assessments (C-SSRS) will be presented in data listings. 
Pharmacokinetic Measures:
For each part of the study, the concentrations of TAK-653 and its metabolites in plasma and urine will be summarized 
by study Day, period (fasted vs fed), and dose level over each scheduled sampling time using descriptive statistics. 
Individual plasma concentration data vs time will be presented in a data listing. Descriptive statistics (N, arithmetic 
mean, SD, median, minimum, maximum and percent coefficient of variation [%CV]) will be used to summarize the 
plasma and urine PK parameters for TAK-653 and metabolites by study Day, period (fasted vs fed), and dose level. In 
addition, geometric mean and CV will be computed for Cmax and AUCs.
Dose proportionality will be tested for TAK-653 Cmax and AUCs using a power model. For the SRD part, data from the 
SRD fed Cohort will not be included in the power model. For the SRD/MRD cohorts, the power model will be run 
after multiple dosing only.
The concentrations of TAK-653 and 
 in 
 if available, will be presented in a listing for SRD/MRD Cohort 
3 only.
Food effect will be assessed for the food-effect SRD cohort subjects using the paired t-test for the natural logarithms of 
AUCs and Cmax.
Additional analyses will be included if appropriate.
Exploratory PD Endpoints: 
Sample Size Justification: The sample size chosen of 8 subjects in each Cohort (6 active: 2 placebo) is considered to 
be sufficient for evaluation of safety, tolerability, PK, and PD data of each cohort. The sample size was not based on 
statistical power considerations.
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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 vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
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3.3
List of Abbreviations
λz
terminal elimination rate constant
%CV
percent coefficient of variation
AE
adverse event
AESI
adverse event of special interest
Aet
total amount of drug excreted in urine from time 0 to time t
Aeτ
total amount of drug excreted in urine during a dosing interval
ALT
alanine aminotransferase
AMPA
alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid 
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours postdose
AUClast
area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable concentration 
AUCτ
area under the plasma concentration-time curve during a dosing interval
BCRP
breast cancer resistance protein
BMI
body mass index
BSA
body surface area
Cav,ss
average plasma concentration at steady-state
CL/F
apparent clearance after extravascular administration
CLR
renal clearance
Cmax 
maximum observed plasma concentration
Cmax,ss
maximum observed steady-state plasma concentration during a dosing interval
CNS
central nervous system
CRO
contract research organization
CS
clinically significant
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP 
cytochrome P-450
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
FDA
Food and Drug Administration
fe
fraction of drug excreted in urine
FFT
Fast Fourier transformation
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FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GluR1
L-Glutamate type 1 receptor
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HED
human equivalent dose
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IV 
intravenous(ly)
K2EDTA
potassium ethylenediamine tetraacetic acid
LFT
liver function test
MAV
markedly abnormal value
MDD
major depressive disorder
MED
minimally effective dose
MedDRA
Medical Dictionary for Regulatory Activities
MR(AUC∞)
metabolite ratio of AUC∞values of the metabolite to TAK-653
MR(Cmax)
metabolite ratio of Cmax values of the metabolite to TAK-653
MRD
multiple-rising dose
MRSD
maximum recommended starting dose
mTOR
mammalian target of rapamycin
NCS
not clinically significant
NIMH
National Institute of Mental Health
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamic(s)
Pgp 
P-glycoprotein
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
PTE
pretreatment event
QD
once daily
QTcB
QT interval with Bazett correction method
QTcF
QT interval with Fridericia correction method
Rac(AUC)
accumulation ratio based on AUC
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Rac(Cmax)
accumulation ratio based on Cmax
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SRD
single-rising dose
STAR*D
Sequenced Treatment Alternatives to Relieve Depression
SUSARs
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TK
toxicokinetic(s)
tmax
time of first occurrence of Cmax
TRD
treatment-resistant depression
UK-1
unidentified metabolite 1
ULN
upper limit of normal
UV
ultraviolet 
WHO
World Health Organization
Vz/F
apparent volume of distribution during the terminal disposition phase
3.4
Corporate Identification
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-653 is a potent and selective potentiator of the L-glutamate type 1 receptor (GluR1), a 
subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, 
which is currently in development for treatment-resistant depression (TRD).
Major depressive disorder (MDD) is characterized by a pervasive depressed mood or loss of 
interest or pleasure (anhedonia) in almost all activities in discrete episodes of at least 2 weeks 
duration involving clear-cut changes in affect, cognition, and neurovegetative functions and 
inter-episode remissions [1]. Other features include psychomotor retardation, tearfulness, 
irritability, anxiety, and slowed thinking. These are typically accompanied by biological 
symptoms such as sleep disturbances, loss of appetite, and changes in weight (gain/loss), fatigue, 
and loss of libido. This disorder has been identified as the second leading cause of years lived with 
disability, designating it as a major public health priority [2]. Up to 86% of subjects who commit 
suicide were shown to be suffering from depression at the time, based on psychological autopsy 
studies [3] and up to 15% of patients suffering from MDD commit suicide [4]. MDD is also 
associated with a significant economic burden. It is estimated that $210.5 billion in annual costs 
can be attributable to MDD and approximately 32 workdays per year are lost by the average 
worker with MDD [5]. 
While multiple treatments such as medication, psychotherapy, or electroconvulsive therapy exist, 
a significant proportion of patients do not respond adequately and some do not respond at all. In 
the National Institute of Mental Health (NIMH)-sponsored Sequenced Treatment Alternatives to 
Relieve Depression (STAR*D) study, only 27.5% of patients with depression responded with up 
to 14 weeks of treatment [6]. Furthermore, up to one-third of the patients did not achieve remission 
by the end of the study [7]. 
Despite years of research and efforts to develop effective treatments, currently available 
antidepressant medications have serious limitations, among which are low rates of treatment 
response (30% to 40% of patients with MDD have treatment-resistant depression) [8,9]. TRD by 
definition is the failure to respond to adequate doses and duration of therapy of 2 different 
antidepressants from 2 different classes [10]. Moreover, there is a time lag of several weeks to 
months before a therapeutic effect is observed, a serious problem given the high rate of suicide in 
depressed patients [2,4,9,11]. Thus, there is a large unmet medical need for novel antidepressant 
therapies with faster onset of action and efficacy in depression.
Recent findings support the AMPA receptor subunit GluR1 as a potential target for rapid onset of 
antidepressant action and activity in patients not responding to classical antidepressants [9,12-14]. 
This antidepressant action appears to be mediated via increased levels of 
 
 and increased mammalian target of rapamycin (mTOR) signaling 
[9,14], which is further supported by activity of AMPA receptor potentiators in experimental 
animal models of depression and cognition. 
In nonclinical studies, TAK-653 
 
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 In vivo, TAK-653 was efficacious in animal models of cognition and depression 
(reduction of submissive behavior), suggesting that it may be efficacious in a variety of psychiatric 
conditions. In vivo, TAK-653 was able to acutely enhance cognition in normal rats and reduce 
depression-like symptoms in a rat model of depression. In the novel object recognition model in 
the rat, TAK-653 at 0.03 and 0.1 mg/kg increased the time that animals spent interacting with a 
novel object, a result consistent with better remembering of a familiar object, which is indicative of 
cognitive improvement. At the lower dose of 0.03 mg/kg, TAK-653 was fully active suggesting 
high in vivo potency of the compound. In the second animal model of depression, the rat 
dominant-submissive model, TAK-653 at once daily (QD) oral doses of 0.1 and 1 mg/kg during 
3 weeks of treatment significantly reduced the dominance score in submissive animals, an 
antidepressant-like activity. While the overall antidepressant effect was significant at both doses, 
daily scoring revealed that the 1 mg/kg dose of TAK-653 showed a continuously significant 
antidepressant effect as of Day 6 of treatment until the end of the treatment period.
TAK-653 was absorbed rapidly after oral administration, with peak plasma concentrations 
generally occurring within 2 hours postdose in rats and 8 hours postdose in monkeys. The terminal 
elimination half-life (t1/2z) of TAK-653 after intravenous (IV) administration was 1.7 hours in rats
and 9.6 hours in monkeys. The predicted oral t1/2z of TAK-653 in humans is 10 hours based on rat 
pharmacokinetic (PK) data and 26 hours based on monkey PK data. The oral bioavailability of 
TAK-653 in animals was high (29.3% in rats and 65.4% in monkeys).
 
 
 
 
 
 
Toxicology studies conducted with TAK-653 include a single-dose study in Sprague-Dawley rats; 
an escalating-dose study in monkeys; repeat-dose toxicity studies up to 13 weeks in duration in rats 
and monkeys; and in vitro and/or in vivo genotoxicity and phototoxicity studies. 
In a Good Laboratory Practice (GLP)-compliant 4-week repeat-dose toxicity study in rats, tonic 
convulsions were reported in males dosed with 300 mg/kg/day at 4 hours postdose. The dose was 
subsequently lowered to 100 mg/kg/day for males and no convulsions were reported throughout 
the remainder of the dosing period. The no-observed-adverse-effect level (NOAEL) in the 4-week 
rat toxicity study was 100 mg/kg/day for males and ≥200 mg/kg/day for females.
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A 13-week GLP-compliant repeat-dose toxicity study was conducted in rats. Tonic convulsion 
was observed in 1 female at 200 mg/kg/day; therefore, the highest dose in females was reduced to 
100 mg/kg/day beginning on Day 2 of the study. After lowering the dose to 100 mg/kg/day, no 
convulsions were observed in any group through the end of the dosing period. In addition, there 
were no test article–related abnormalities observed in clinical signs, body weights, food 
consumption, ophthalmologic examination, urine output, urinalysis, hematology, coagulation tests, 
clinical chemistry, necropsy, organ weights, or histopathological examination. The NOAELs in 
this study were 50 mg/kg/day for males and 100 mg/kg/day for females. 
 
 
 
In a preliminary 2-week repeat-dose toxicity study in monkeys (2/sex/group), 1 female at 
30 mg/kg/day was euthanized moribund on Day 3. This animal demonstrated clonic convulsions, 
prone position, action tremors, and decreased locomotor activity on Days 1 and 2 and decreased 
feces on Days 1 to 3. Action/resting tremors, vomiting and marked decreases in feces, food 
consumption and body weights were seen in all animals postdose at 30 mg/kg/day. Therefore, after 
a 4-day treatment-free period, the high dose in the study was reduced to 10 mg/kg/day. No 
additional convulsions were seen; transient tremors, a slight decrease in body weight, and a slight 
increase in ALT were seen in one female at 10 mg/kg/day.
In the 4-week GLP-compliant repeat-dose toxicity study in monkeys dosed at 0, 0.3, 3, and 10 
mg/kg/day, resting and action tremors were noted at ≥3 mg/kg/day in females and at 10 mg/kg/day 
in males. Dose-dependent vomiting was reported at 3 and 10 mg/kg/day in both sexes, although 
this was transient and not considered adverse at 3 mg/kg/day. At 10 mg/kg/day, ptosis, prone 
position, decreased locomotor activity, and decreased feces were transiently reported in males 
and/or females. Except for effects on clinical signs, no other adverse effects were seen. As it was 
unknown if the tremors seen in this study were associated with adverse EEG changes, the 
assignment of the NOAEL took a conservative approach. Therefore, the NOAELs in the 4-week 
monkey toxicity study, based on observations of tremor at higher doses, were 3 mg/kg/day for 
males and 0.3 mg/kg/day for females.
 
A 13-week repeat-dose toxicity study was conducted in cynomolgus monkeys, dosed at 0, 0.3, 3, 
and 10 mg/kg/day; with some exceptions, the study was GLP-compliant. In this study, monkeys 
were monitored continuously for EEG and EMG activity and behavior the first 28 days of dosing 
and for 24-hour periods midstudy and at the end of the study; toxicokinetics were evaluated after 
the first, 29th, and 90th dose administrations and after a convulsion was observed. 
Tremors were seen in all dose groups, including controls, although they occurred with greater 
frequency in high-dose females. Tremors were not accompanied by underlying changes in EEG 
activity that were suggestive of seizure episodes (eg, no paroxysmal activity). Dosing of female 
monkeys with 10 mg/kg/day was associated with EEG paroxysmal activity, repeated sharp waves, 
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and seizure activity in 2 of 4 animals, first observed after the first or second dose administration. 
Although tremors were observed 2 to 4 hours before seizure episodes, there was no paroxysmal 
EEG activity associated with them. Overall, the occurrence of tremors did not reflect an ensuing 
seizure, and, in fact, the vast majority of tremors were recorded for animals that did not convulse. 
Given the apparent intolerability of 10 mg/kg/day in female monkeys, the high dose in this group 
was reduced to 6 mg/kg/day after a dosing holiday. After the second dosing of 6 mg/kg/day, 
1 female showed clinical signs of a convulsion but examination of the EEG, EMG, and 
video-recorded behavior of the animal indicated that it was likely to be an episode of ataxia rather 
than a generalized seizure as it was not accompanied by EEG signs of seizure activity (although a 
partial seizure could not be ruled out). On Day 79 of dosing the same monkey showed clinical 
signs of a convulsion; as videographic and EEG activity were not being recorded at that time, as 
per protocol, EEG confirmation of seizure activity was not possible. However, to err on the side of 
safety, the event was considered to be a seizure.
No adverse effects of treatment were seen in male monkeys at any dose level in the 13-week study.
Overall, the results of the 13-week toxicity study in monkeys indicate no adverse effects of 
treatment except on clinical signs. There was no adverse effect of treatment on mortality, body 
weights, or food consumption, electrocardiography, ophthalmology, urinalysis, hematology, 
clinical chemistry, organ weights, or macroscopic or microscopic observations. Evaluation of 
videographic recordings of clinical signs throughout the study indicate that tremors occurred in all 
dose groups, including vehicle controls, although the incidence was increased in females at 10 and 
6 mg/kg/day. Tremors were not associated with EEG changes indicative of seizure activity (ie, no 
synchrony, paroxysmal activity), were not predictive of a seizure, and likely represent an 
extension of the pharmacology of the compound. The NOAEL in this study was 10 mg/kg/day in 
males and 3 mg/kg/day in females based on a clinical observation of seizure (unconfirmed by 
EEG) in 1 female at 6 mg/kg/day.
 
 
 
In other studies, TAK-653 was not associated with genotoxic or phototoxic potential examined 
in vitro and/or in vivo. 
4.2
Rationale for the Proposed Study
The ubiquitous expression of AMPA receptors throughout the central nervous system (CNS) 
makes them central to a multitude of higher neurophysiological processes, including attention, 
learning, memory, and other cognitive functions. The central role of AMPA receptors in these 
functions makes them attractive as therapeutic targets for a multitude of diseases. In nonclinical 
studies, 
 
 In addition, TAK-653 has 
shown efficacy in a number of animal models underlining the potential to be efficacious in a 
variety of psychiatric conditions, including depression. This first-in-human (FIH) study has 
therefore been designed to evaluate safety, PK, and PD effects of TAK-653 in healthy volunteers 
before further clinical development.
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4.3
Risk-Benefit Profile
This FIH phase 1 study has been designed to mitigate the known risks associated with AMPA 
receptor potentiators as a class and the potential risks based on the nonclinical toxicity data and 
preliminary clinical data for TAK-653. Descriptions of the risk mitigation measures included in 
this study are detailed in Section 6.2 and summarized in Section 6.2.4. As this is a study in healthy 
subjects, there is no expected clinical benefit to the study participants.
To date in this study, a total of 56 subjects have been enrolled and administered study drug 
(42 active, 14 placebo) in 5 single-rising dose (SRD) cohorts (0.3, 1, 3, 5, and 9 mg) in Part 1 and 
2 SRD/multiple-rising dose (MRD) cohorts (0.3 and 1 mg) in Part 2. In addition, dosing in 
SRD/MRD Cohort 3 (3 mg) has started. A blinded review of the preliminary safety and tolerability 
data for these completed cohorts indicate that TAK-653 was generally well tolerated at single 
doses up to 9 mg in Part 1 and multiple doses up to 1 mg QD in Part 2. No serious 
treatment-emergent adverse events (TEAEs) or CNS-type adverse events (AEs) were reported. No 
clinically meaningful clinical laboratory, vital sign, electrocardiogram (ECG), or physical 
examination results were reported. Preliminary PK data from these cohorts indicate that TAK-653 
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Primary Objective
To determine the safety and tolerability of TAK-653 when administered as oral, single and 
multiple doses at escalating dose levels in healthy subjects.
5.2
Secondary Objective
To determine the PK of TAK-653 when administered as single and multiple oral doses at 
escalating dose levels in healthy subjects.
5.3
Exploratory/Additional Objectives
5.4
Endpoints
5.4.1
Primary Endpoints
!
Percentage of subjects who experience at least 1 TEAE.
!
Percentage of subjects who discontinue due to an AE.
!
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once postdose.
!
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at 
least once postdose.
!
Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram 
(ECG) parameters at least once postdose.
!
Percentage of subjects who experience clinically significant abnormal changes in EEG 
measurements at least once postdose.
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!
Columbia-Suicide Severity Rating Scale (C-SSRS):
–
Treatment-emergent suicidal ideation compared to Baseline, as measured by an increase in 
suicidal ideation category (1-5 on the C-SSRS) during treatment from the maximum 
suicidal ideation category at Baseline, or any suicidal ideation during treatment if there was 
none at Baseline.
–
Treatment-emergent suicidal behavior compared to Baseline, as measured by an increase 
in suicidal behavior category (6-10 on the C-SSRS) during treatment from the maximum 
suicidal behavior category at Baseline, or any suicidal behavior during treatment if there 
was none at Baseline.
5.4.2
Secondary Endpoints
Plasma PK parameters of TAK-653:
!
Cmax (Day 1 for all Cohorts and Day 6 for single-rising dose [SRD]/multiple-rising dose 
[MRD] Cohorts).
!
Maximum observed steady-state plasma concentration during a dosing interval (Cmax,ss) 
(Day 18 for SRD/MRD Cohorts).
!
Time to reach Cmax (tmax) (Day 1 for all Cohorts and Day 18 for SRD/MRD Cohorts).
!
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast) (Day 1 for all Cohorts).
!
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞) (Day 1 for all 
Cohorts).
!
Area under the plasma concentration-time curve during a dosing interval (AUCτ) (Day 6 and 
Day 18 for SRD/MRD Cohorts).
5.4.3
Exploratory/Additional Endpoints
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Additional PK endpoints for TAK-653 and metabolites:
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This FIH, double-blind, placebo-controlled, combined SRD/MRD phase 1 study in healthy 
subjects is designed to assess the safety and tolerability of TAK-653. Approximately 112 healthy 
male and female volunteers will be enrolled.
This study consists of 2 parts: (1) single ascending doses in 5 cohorts (SRD) and (2) single and 
multiple ascending doses in 4 cohorts (SRD/MRD). Each cohort will consist of 8 subjects 
(6 active:2 placebo). Subjects will fast for at least 10 hours before dosing. Cohorts may be added 
or removed.
This study will also provide a preliminary assessment of the potential effect of food on TAK-653 
PK. Subjects in a selected SRD cohort (fasted conditions) will return to receive the same dose of 
TAK-653 under fed conditions after safety and tolerability has been established for TAK-653 at a 
higher dose under fasted conditions. 
Follow-up assessments will occur approximately 14 days after the last dose of study drug to
inquire for any ongoing AEs or serious adverse events (SAEs), worsening of AEs or SAEs, or 
development of new AEs or SAEs, and concomitant medications taken since final dose. Follow-up 
will occur by telephone unless abnormal, clinically significant findings are observed upon 
discharge or at the investigator’s discretion. Subjects should then be brought back to the clinic for 
re-evaluation. 
For all subjects in the SRD and SRD/MRD cohorts, 
 
To assess change from baseline, the last assessment prior to the first dose of the 
study medication will be used. 
6.1.1
Part 1: SRD 
Subjects will be enrolled in SRD cohorts. Sentinel dosing will be used for each SRD Cohort. The 
first 2 subjects (1 active: 1 placebo) in each Cohort will receive either TAK-653 or placebo in 
parallel, followed by a minimum 24-hour gap to ensure adequate evaluation of safety and 
tolerability prior to administering the same dose of TAK-653 or placebo to the remaining subjects 
within the Cohort (5 active: 1 placebo). Dosing of the remaining subjects will proceed in a 
staggered fashion with no more than 3 subjects being dosed at a time and having an approximate 
24-hour gap before the next group of subjects is dosed. Each dose cohort will be examined 
sequentially to ensure adequate evaluation of all available safety, tolerability, PK, and PD data 
prior to administering the next dose level. 
A schematic of the study design for the SRD Part 1 is presented in Figure 6.a. The schedule of 
assessments in the SRD Part 1 is in Appendix A for Cohorts 1 to 5 and in Appendix B for Cohort 6 
onward.
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Figure 6.a
SRD Study Schematic
Pretreatment Period
Treatment Period
Follow up 
(d)
Screening
Check-in 
Assessments
(a)
TAK-653 Dosing
Study Assessments 
(a) (b) (c)
Safety and 
PK 
Assessments 
(a) (c)
PK 
Assessments
PK 
Assessments/
Study Exit (a)
Days -28 
to -2
Day -1
Day 1
Days 2-5
Day 6 
(Cohorts 1-5)
Days 6-7 
(Cohort 6 
onward)
Day 7 
(Cohorts 1-5)
Day 8 
(Cohort 6 
onward)
Day 14 (±2)
Confinement
(a) 
(b) Study assessments include PK sample collection throughout.
(c) 
(d) Follow-up will occur by telephone unless abnormal, clinically significant findings are observed upon discharge. In 
this case or at investigator’s discretion, subjects should return to the clinic for re-evaluation.
The planned first dose level to be studied is 0.3 mg for SRD Cohort 1. The actual choice of the dose 
levels in subsequent Cohorts will occur after the full review of all available safety, tolerability, PK, 
and PD data in the preceding cohorts. If necessary, the sponsor team (Takeda only) may unblind 
the data and perform additional analyses for an informed dose-escalation decision. The next dose 
level may be higher, lower, or remain the same as the preceding dose level. If the dose is not 
increased in the next Cohort, staggered dosing is not necessary.
The planned dose cohorts in the SRD study arm are listed in Table 6.a. 
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Table 6.a
Summary of SRD Dose Cohorts
Cohort (a)
TAK-653 Single Dose (b) (c)
No. of Subjects
Planned
Actual
1
0.3 mg 
0.3 mg 
6 TAK-653
2 placebo
2
X mg
1.0 mg
6 TAK-653
2 placebo
3 (food-effect 
cohort) (d)
X mg
3.0 mg
6 TAK-653
2 placebo
4
X mg
5.0 mg
6 TAK-653
2 placebo
5
X mg
9.0 mg
6 TAK-653
2 placebo
(a) Sentinel dosing will occur at the start of each Cohort in the SRD. After the investigator and sponsor review the 
24-hour safety and tolerability data, the remaining subjects can be dosed in a staggered fashion (no more than 
3 subjects at a time). A 24-hour gap will follow each subsequent administration to evaluate safety and tolerability data.
(b) Dose escalation to Cohort 2 onward will be based on review of safety, tolerability, and available PK and PD data 
from the previous cohort(s). 
(c) TAK-653 or placebo will be administered orally to subjects after an overnight fast of at least 10 hours.
(d) Subjects from SRD Cohort 3 (fasted conditions) will return to the clinic to receive the same dose of TAK-653 
following a standard meal.
Subjects in the SRD Cohorts will be kept in the study unit for approximately 96 hours after dosing 
for safety and PK assessments before discharge. The total confinement period is 5 days. Subjects 
in Cohorts 1 to 5 will return to the clinic on Days 6 and 7 for additional PK collections. Subjects in 
Cohort 6 onward will return to the clinic on Days 6, 7, and 8 for additional PK collections. If the 
t1/2z of TAK-653 for any cohort differs significantly from what was predicted, the duration of 
confinement may also be adjusted. Subjects in the food effect cohort will be confined twice for 
5 days each for a total of 10 days. For SRD Cohort 6 onward,
 
 
Follow-up assessments for all subjects in the SRD study arm will occur on 
Day 14 (±2).
6.1.2
Part 2: SRD/MRD 
Progression into the SRD/MRD Part 2 will occur only after review of all available safety, 
tolerability, PK, and PD data collected in at least the first 3 SRD cohorts. The actual dose in the 
SRD/MRD Cohorts will not be administered unless there is acceptable safety, tolerability, PK, and 
PD data at the same or higher dose level after a single dose in the SRD Cohorts. If necessary, the 
sponsor team (Takeda only) may unblind the data and perform additional analyses for an informed 
dose-escalation decision. The potential for accumulation and its impact on the likelihood of 
reaching the NOAEL exposure cap, will be taken into account when selecting doses for the MRD.
A single dose of TAK-653 or placebo will be administered on Day 1 followed by approximately 
120 hours for safety, tolerability, PK, and PD assessments. Once daily (QD) multiple dosing will 
begin on Day 6 and continue through Day 18 (13 days). Initiation of the multiple-dose phase on 
Day 6 may be adjusted based on emerging safety, PK, and/or PD data. Neither sentinels nor 
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staggered dosing are used in the SRD/MRD. Subjects in the SRD/MRD Cohorts will be kept in the 
study unit for at least 72 hours after the last dose for safety assessments before discharge. The total 
confinement period planned is 21 days. Cohort 4 is optional, to be used if emerging safety and/or 
PK or PD data warrant further study at a different dose. Follow-up assessments will occur on 
Day 31 (±2). 
Each dose cohort will be examined sequentially to ensure adequate evaluation of all available 
safety, tolerability, PK, and PD data prior to administering the next dose level. 
The study schematic for the SRD/MRD Part 2 is presented in Figure 6.b. The schedule of 
assessments in the SRD/MRD Part 2 is in Appendix C.
Figure 6.b
SRD/MRD Study Schematic 
Pretreatment Period
Treatment Period
Follow-
up (e)
Screening
Check-in
Baseline 
Assessments
TAK-653 
Single Dose 
Study 
Assessments 
(a) (b) (d)
Safety and 
PK 
Assessments 
(d)
TAK-653 
QD dosing
Study 
Assessments 
(a) (b) (c) (d)
Safety and 
PK 
Assessments
Study 
Exit
Days -28 
to -2
Day -1
Day 1
Days 2-5
Days 6-18
Days 19-20
Day 21
Day 31 
(±2)
Confinement
(a) Study assessments include PK sample collection throughout.
(b) 
(c) For SRD/MRD Cohort 3 only, a single CSF sample will be collected from each subject on Day 12.
(d) 
(e) The Follow-up assessments will occur by telephone unless abnormal, clinically significant findings are observed 
upon discharge. In this case or per investigator’s discretion, subjects should return to the clinic for re-evaluation.
A summary of the SRD/MRD dose cohorts is presented in Table 6.b.
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Table 6.b
Summary of SRD/MRD Dose Cohorts
Cohort 
Planned TAK-653 Dose (a) (b) (c)
Subjects
Planned 
Actual 
1
X mg 
0.3 mg
6 TAK-653
2 placebo
2
X mg
1.0 mg
6 TAK-653
2 placebo
3
X mg
3.0 mg
6 TAK-653
2 placebo
4
X mg
X mg
6 TAK-653
2 placebo
(a) Dosing for the first SRD/MRD Cohort will not begin until there is acceptable safety, tolerability, and available PK 
and PD data at the same or higher dose level after a single dose from at least the first 3 SRD Cohorts. Dose escalation 
to subsequent Cohorts will be based on review of safety, tolerability, and available PK and PD data from previous 
Cohorts. The subsequent dose level may be higher, lower, or the same as the preceding dose level.
(b) In each Cohort, a single dose will be administered on Day 1 followed by 120 hours of safety, tolerability, PK, and 
PD assessments. QD multiple doses will proceed from Day 6 through Day 18.
(c) TAK-653 or placebo tablets will be administered orally to subjects after an overnight fast of at least 10 hours.
6.1.3
Dose Escalation
All decisions concerning dose escalation will be made by Takeda (at a minimum, the clinical 
science representative and pharmacovigilance physician, or appropriate delegates) and the 
principal investigator. The investigator and subjects will remain blinded throughout the study, but 
at the completion of each cohort, Takeda personnel may be unblinded to analyze data considered 
necessary to determine subsequent doses. 
Therefore, based on emerging safety, tolerability, and available PK and PD data, the planned dose 
levels may be modified in accordance with the following parameters:

Dosing in all Cohorts will be limited to an escalated dose which is predicted to give no greater 
than ~3-fold increase in either Cmax or AUC. A smaller increment may be used at higher doses 
and a larger increment may be used at lower doses if exposures obtained are not sufficiently 
high, and if it is deemed safe to do so. In the event that the majority of plasma concentrations of 
TAK-653 are below the limit of detection, the dose will be escalated to a higher dose level, if 
safety and tolerability are acceptable. 

In SRD Part 1, following completion of Cohort 1, exposure to TAK-653 in humans as 
compared to what was predicted utilizing nonclinical data will influence the dose to be studied 
in Cohort 2.

Progression into SRD/MRD Part 2 will occur only after review of all available safety, 
tolerability, PK, and PD data collected in SRD Cohorts 1-3. All doses used in the SRD/MRD 
Cohorts will be administered only if there is adequate safety, tolerability, PK, and PD data at 
the same or higher dose level from the SRD Cohorts.


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!
In a 13-week repeat-dose toxicity study conducted with TAK-653 in cynomolgus monkeys, 
test article–related toxicities occurred around tmax, typically within the first few days of dosing, 
and were considered to be related to the Cmax rather than to the AUC24. Therefore, the predicted 
exposure for the TAK-653 dose selected for any cohort should not exceed the mean Cmax value 
) achieved in female monkeys on the first day of dosing or the mean AUC24 value 
(
) achieved in female monkeys at the end of the dosing period at the NOAEL 
of 3 mg/kg/mL in the 13-week repeat-dose toxicity study. If PK data collected during a cohort 
indicate that exposure to TAK-653 has surpassed the
) at the NOAEL, lower doses will be used in subsequent cohort(s). 
!
Administration with food will not occur until safety is established at a higher dose in the fasted 
state.
Additionally, Takeda and the principal investigator may jointly decide to not escalate the dose for 
a particular cohort, but rather administer the same or a lower dose level to the next cohort.
In all SRD Cohorts, there will be a minimum period of 24 hours following the dose in the 2 sentinel 
subjects to allow for collection and review of safety and tolerability data. The remaining 6 subjects 
in each Cohort will then be dosed in a staggered fashion of no more than 3 subjects at a time, 
followed by a minimum period of 24 hours for safety assessments. 
For each completed dose level Cohort, the principal investigator and Takeda will carefully review 
all safety, tolerability, PK, and PD data to determine whether dosing should stop or continue (and, 
if continue, at what dose, including whether to repeat the previous dose), whether additional 
staggered dosing should be implemented in future cohorts, or whether the blind should be broken 
to identify whether the subjects received TAK-653 or placebo.
All AEs reported during the Treatment Period, both within and across cohorts, up to the time of 
discharge (at least 96 hours after dosing for the SRD Cohorts, 72 hours after the last dose for the 
SRD/MRD Cohorts), will be evaluated to assess the need for subject, Cohort, and/or study 
termination in accordance with prespecified criteria (Section 6.3.1).
Following assessment of the AE data and predefined criteria for study termination, dose escalation 
may be interrupted/stopped and the blind broken for further analysis. Based on review of 
unblinded data, Takeda, in consultation with the principal investigator, will decide if and how it is 
appropriate for the study to proceed.
Dose escalation and study drug administration will be stopped if an SAE or 2 severe or clinically 
significant AEs, including CNS disorders/AEs (Section 6.3.1), are observed in a particular cohort 
and are considered by the investigator to be related to TAK-653. 
If agreement regarding a dose escalation decision cannot be reached between the principal 
investigator and Takeda, the study will be stopped.
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6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
This phase 1 study is randomized, double-blind, and placebo-controlled in order to avoid 
subjective bias in the assessment of the safety and tolerability of TAK-653. Each cohort dose level 
in both parts of this study will be examined sequentially prior to administering the next dose level 
in order to mitigate known risks associated with potentiators of AMPA receptors and potential 
risks based on nonclinical data for TAK-653. Study-specific eligibility criteria have been added to 
the standard criteria to ensure that subjects at increased risk of seizures/convulsions are excluded 
(eg, history of seizures, epilepsy, abnormal screening EEG; and renal and hepatic insufficiency). 
See Section 7.2.
Additional risk mitigation measures have been incorporated into the first part of this study. 
Sentinel dosing will be used within each SRD Cohort to evaluate safety and tolerability prior to 
administering TAK-653 to additional subjects in the same dose Cohort. As a further safety 
measure, staggered dosing will be employed with only 3 of the remaining 6 subjects in the same 
Cohort being dosed at one time. All subjects in the SRD cohorts will remain in the phase 1 unit for 
at least 96 hours after dosing for safety, PK, and PD assessments. The first dose in this study will 
be 0.3 mg, which represents a 20-fold safety factor. Choosing the dose level for the next Cohort 
will require review of all available safety, tolerability, PK, and PD data from all subjects in the 
preceding Cohorts.
This study will also provide a preliminary assessment of the potential effect of food on TAK-653 
PK, in which each subject serves as his or her own control when administered TAK-653 under fed 
and fasted conditions. Subjects in a selected SRD cohort (fasted conditions) will return to receive 
the same dose of TAK-653 under fed conditions (see Section 7.4) after safety has been established 
at a higher dose under fasted conditions.
The dose of TAK-653 chosen to be administered to the first SRD/MRD Cohort will be a dose that 
is equivalent to or lower than the highest dose administered to subjects in at least the first 3 SRD 
cohorts. The predicted exposure of the selected dose should not exceed the mean Cmax value 
(
) achieved in female monkeys on the first day of dosing or the mean AUC24 value 
(
) achieved in female monkeys at the end of the dosing period at the NOAEL of 
3 mg/kg/mL in the 13-week repeat-dose toxicity study.
By completing the first 3 SRD Cohorts before starting the first SRD/MRD Cohort, safety, 
tolerability, and available PK and PD data will have been reviewed from 24 subjects at 3 different 
dose levels. The SRD/MRD dosing begins with a single dose, followed by safety, PK and PD 
assessments over 120 hours before the QD multiple dosing commences for 13 days. The PK 
collected after both single and multiple doses of TAK-653 will allow assessment of 
time-independence in the PK of TAK-653. PK data collected on Day 1 and Day 6 will provide a 
preliminary estimate of intrasubject variability. 
Based on allometric scaling, the predicted t1/2z of TAK-653 in humans is 10 hours based on the rat 
PK data and 26 hours based on monkey PK data. Therefore, 13 days of dosing is sufficient for 
TAK-653 to reach steady-state based on the current estimates (it takes approximately 4 half-lives 
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for a drug to reach a concentration that is 90% of the steady-state concentration). Also based on 
nonclinical data, 13 days of QD multiple dosing is a substantial duration that allows for PD activity 
and safety events to appear before proceeding with clinical studies of longer duration in a patient 
population. Subjects in the SRD/MRD Cohorts will be kept in the study unit for 72 hours after the 
last dose for safety assessments before discharge. The total confinement period for the SRD/MRD 
Cohorts will be 21 days, with Follow-up safety assessments on Day 31 (± 2).
Based on the known risks of AMPA receptor potentiators and the potential risks based on 
TAK-653 nonclinical data, any Cohort may be stopped if a subject experiences tremors with 
corresponding changes in EEG, QT prolongation, or bradycardia. Dosing may be resumed at lower 
dose levels in subsequent cohorts.
6.2.2
Dose
The nonclinical toxicity studies conducted to date with TAK-653 provide adequate safety data to 
support a phase 1 clinical study. The human equivalent doses (HEDs) were derived using the 
methodology described in the Food and Drug Administration (FDA) Guidance for Industry: 
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers [15].
At the time that the starting dose for the current study was selected, the 13-week toxicity studies 
had not been conducted. The lowest NOAEL in repeat-dose toxicity studies was 0.3 mg/kg/day in 
the 4-week monkey study, and therefore the monkey is considered the more sensitive species. 
Allometric scaling (based on body surface area [BSA]) was calculated by multiplying the NOAEL 
from the 4-week monkey study by a conversion factor of 0.32 in order to obtain the HED of 
0.096 mg/kg/day (based on the female monkey), or approximately 5.76 mg/day for a 60 kg human. 
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Applying a 10-fold safety factor, the maximum recommended starting dose (MRSD) in humans is 
0.6 mg/day for a 60 kg human.
The minimally effective dose (MED) of TAK-653, defined on the basis of the novel object 
recognition test and reduction of submissive behavior model in rat is considered to be 0.1 mg/kg. 
AUC24 at this dose, based on available PK data, would be expected to be 24.5 h*ng/mL in rats. 
Utilizing the MED across the rat pharmacology models (TAK-653 0.1 mg/kg), the effective AUC 
value of TAK-653 in humans is estimated to be approximately 30 h*ng/mL. The predicted PK 
profile of TAK-653 in humans was generated utilizing PK parameters of TAK-653 in rat and 
monkey separately, with allometric scaling based on body weight and plasma protein binding 
differences between the species. With the assumptions of similar effective concentrations in the rat 
and humans, PK linearity, and that there is no difference between the animals within a species that 
were used in the toxicology, PK, and pharmacology studies, the expected effective exposure 
(AUC) in humans is approximately 3 mg TAK-653 and 0.5 mg TAK-653 based on rat and monkey 
PK data, respectively. The effective AUC24 in rat has an 85-fold margin to the NOAEL AUC24 in 
the monkey. Based on the current data package and all analyses, the recommended starting dose is 
0.3 mg (safety factor 20), which is lower than that which was efficacious in rat (HED utilizing 
BSA conversion is 1 mg).
In the current study, a blinded review of the preliminary safety and tolerability data for Part 1 SRD 
Cohorts 1 through 5 and Part 2 SRD/MRD Cohorts 1 and 2 indicate that TAK-653 was generally 
well tolerated at single doses up to 9 mg and multiple doses up to 1 mg QD. Preliminary PK data 
from these cohorts indicate that TAK-653 exhibits linear PK across the dose range tested. For SRD 
Cohort 5 (9 mg), the Cmax (mean [range]=69.5 [55.1-85.8] ng/mL) remained below the mean Cmax
value (
) in female monkeys at the NOAEL of 3 mg/kg/day in the 13-week 
repeat-dose toxicity study.
 
 For SRD/MRD Cohort 2 (1 mg), the Cmax
(mean [range]=24.9 [14.7-34.9] ng/mL) and AUC24 (mean [range]=503 [256-741] h*ng/mL) after 
multiple-dose administration (on Day 18) remained several fold below the mean Cmax and AUC24
values in female monkeys at the NOAEL. 
In the aforementioned monkey toxicity study, test article–related toxicities occurred around tmax, 
typically within the first few days of dosing, and were considered to be related to the Cmax rather 
than to the AUC24. Therefore, given the favorable preliminary safety/tolerability and PK data for 
the TAK-653 doses administered to date, further dose escalation is considered to be justified. The 
predicted Cmax value for the TAK-653 dose selected for any cohort should not exceed mean 
exposures at the monkey NOAEL (Day 1 Cmax=
 Day 91 AUC24=
6.2.3
Endpoints
The primary endpoints for this study are the composite of safety variables to determine tolerated 
doses and dose-limiting effects of TAK-653. The secondary endpoints are standard PK variables 
of TAK-653 to determine drug exposure at each dose and facilitate dose escalations. 
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6.2.4
Risk Mitigation 
TAK-653, like other AMPA receptor potentiators, may induce convulsions through the over 
activation of AMPA receptors [16]. Other potential risks associated with AMPA receptor 
potentiators include tremors, anxiety and insomnia. Based on TAK-653 nonclinical findings, the 
key risks associated with TAK-653 are convulsions, tremors, vomiting, reduced heart rate, and 
decreased locomotor activity.
Because Study TAK-653-1001 represents the first time that TAK-653 is being administered to 
humans, anticipated risks are based on the mode of action of TAK-653, nonclinical findings, 
dose-limiting toxicities, and human experience with other AMPA receptor potentiators. These 
potential risks have been considered when designing this study by excluding subjects at 
predictable risk of seizures, minimizing the number of subjects exposed at any one time at each 
dose level, following strict escalation criteria between Cohorts, and setting conservative stopping 
rules.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.
!
New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a significant change in the known risk/benefit profile for the drug, 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.
!
Study-specific criteria for terminating the study:
a) Subjects in more than 1 cohort have met Cohort Stopping Criteria. 
b) Any subject in any cohort experiences signs or symptoms of a tremor. (Subjects may not be 
dosed in this cohort at the same or higher dose level. However, dosing may be resumed at a 
lower dose level.)
The study may be terminated early prior to full attainment of these criteria (eg, if just 1 subject 
experiences 1 of these events), if warranted by safety data from the other subjects dosed in the 
study to that point.
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Cohort Stopping Criteria
If any of the following criteria occur, subsequent subjects in the same Cohort may not be given the 
same dose or a higher dose although dosing may be resumed at a lower dose.
1. Any subject experiences any of the Takeda Medically Significant events (Table 10.a).
2. An SAE or 2 severe or clinically significant AEs occur that can be considered related to 
TAK-653. This includes drug-related CNS disorders/AEs, including but not limited to motor, 
sensitive, cognitive, or sleep abnormalities detected during the course of the study.
3. Any subject develops a tremor (resting or otherwise) that is associated with EEG changes 
suggestive of seizures, or more than 1 subject in a Cohort develops a tremor without EEG 
changes suggestive of seizures.
4. Any subject develops QT prolongation on a postdose ECG, defined as a QT interval with 
Fridericia correction method (QTcF) > 500 msec or > 60 msec change from baseline.
5. Any subject develops bradycardia (heart rate of ≤ 40 bpm) on scheduled assessments only 
(ie, not on telemetry) or a reduction in heart rate of 30 bpm from baseline.
6. Any subject has abnormal liver function:
a) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations > 5 × 
upper limit of normal (ULN) in the absence of a concomitant bilirubin increase.
b) ALT and/or AST elevations > 3 × ULN in the presence of a total bilirubin increase > 2 × 
ULN or an international normalized ratio (INR) > 1.5 without findings of cholestasis or 
other alternate etiology to explain the elevations (ie, “Hy’s Law cases”).
c) ALT and/or AST elevations > 3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
6.3.2
Criteria for Premature Termination or Suspension of Investigational 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 Investigational Site
In the event that the sponsor, an independent ethics committee (IEC), or regulatory authority elects 
to terminate or suspend the study or the participation of an investigational site, a study-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or study 
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed at Screening and at Check-in 
(Day -1). 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures including requesting that a subject 
fast for any laboratory evaluations.
3. The subject is a healthy adult male or female.
4. The subject is aged 18 to 55 years, inclusive at the time of consent.
5. The subject weighs at least 45 kg (99 lb) and has a body mass index (BMI) between 18.0 and 
30.0 kg/m2, inclusive at Screening.
6. 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 90 days after 5 half-lives have elapsed since last dose of study 
drug. This should be interpreted as 90 days from the Follow-up Call/Visit unless data indicates 
otherwise.
7. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to routinely use highly effective contraception with low user dependency* from 
signing of informed consent, throughout the duration of the study, and for 30 days after 
5 half-lives have elapsed since the last dose of study drug. This should be interpreted as 
30 days from the Follow-up Call/Visit unless data indicates otherwise.
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.11 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. Subject has received any investigational compound within 90 days prior to the first dose of 
study drug.
2. 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. 


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3. Subject has any clinically significant illness, such as cardiovascular, neurologic, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine, or psychiatric 
disease or disorder, or other abnormality, which may affect safety, increase risk of seizure or 
lower the seizure threshold, or potentially confound the study results. It is the responsibility of 
the investigator to assess the clinical significance; however, consultation with the Takeda 
Medical Monitor may be warranted.
4. Subject has a known hypersensitivity to any component of the formulation of TAK-653.
5. Subject has a positive urine/blood result for drugs of abuse (defined as any illicit drug use) at 
Screening or Check-in (Day -1).
6. Subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse
within 1 year prior to Screening or is unwilling to agree to abstain from alcohol and drugs 
throughout the study. 
7. Subject has taken any excluded medication, supplements, or food products during the time 
periods listed in the Excluded Medications and Dietary Products table (listed in Table 7.a).
8. Subject is pregnant or lactating or intending to become pregnant before, during, or within 
30 days after 5 half-lives have elapsed since the last dose of study drug (ie, 30 days from the 
Follow-up Call/Visit unless available data indicates otherwise); or intending to donate ova 
during such time period. 
9. If male, subject intends to donate sperm during the course of this study or within 90 days after 
5 half-lives have elapsed since the last dose of study drug. This should be interpreted as 
90 days from the Follow-up Call/Visit unless data indicates otherwise.
10. Subject has had previous episodes of seizures or convulsion (lifetime), including absence 
seizure and febrile convulsion.
11. Subject or any immediate family member has a history of epilepsy (including febrile 
convulsions).
12. Subject has a history of neurological abnormalities including abnormal EEG at screening or 
brain injury including traumatic injury, perinatal cerebropathy and postnatal brain damage, 
blood-brain barrier abnormality, and angioma cavernous.
13. Subject has a history of cerebral arteriosclerosis.
14. Subject has a condition that can potentially reduce drug clearance (eg, renal or hepatic 
insufficiency).
15. Subject has current or recent (within 6 months) gastrointestinal disease that would be expected 
to influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention 
known to impact absorption [eg, bariatric surgery or bowel resection], esophageal reflux, 
peptic ulcer disease, erosive esophagitis, or frequent [more than once per week] occurrence of 
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16. Subject has a history of cancer, except basal cell carcinoma which has been in remission for at 
least 5 years prior to Check-in (Day 1). 
17. Subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or a known history of human immunodeficiency virus (HIV) infection at 
Screening.
18. Subject has used nicotine-containing products (including but not limited to cigarettes, pipes, 
cigars, chewing tobacco, nicotine patch, or nicotine gum) within 28 days prior to Check-in 
Day -1. Cotinine test is positive at Screening or Check-in (Day -1).
19. Subject has poor peripheral venous access.
20. Subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 90 days prior to first dose of 
study drug.
21. Subject has a Screening or Check-in (Day -1) abnormal (clinically significant [CS]) ECG. 
Entry of any subject with an abnormal (not clinically significant [NCS]) ECG must be 
approved, and documented by signature of the principal investigator or medically qualified 
subinvestigator. In the case of a QTcF interval >450 ms or >480 ms (subjects with Bundle 
Branch Block) or PR outside the range of 120 to 220 ms, assessment may be repeated once for 
eligibility determination at the Screening Visit and/or Check-in (Day -1) Visit.
22. Subject has a supine blood pressure outside the ranges of ≥90 to ≤140 mm Hg for systolic and 
≥50 to ≤90 mm Hg for diastolic. If out of range, assessment may be repeated once for 
eligibility determination at the Screening Visit and/or Check-in (Day -1).
23. Subject has a resting heart rate outside the range of 50 to 90 bpm (not on ECGs). If out of range, 
the assessment may be repeated once for eligibility determination at the Screening Visit and/or 
Check-in (Day -1).
24. Subject has abnormal Screening or Check-in (Day -1) laboratory values that suggest a 
clinically significant underlying disease or subject has the following lab abnormalities: ALT 
and/or AST >1.5 ULN. 
25. Subject has a risk of suicide per the C-SSRS (a score of 4 or 5 on ideation or any suicidal 
behavior) or according to the investigator’s clinical judgment, has made a suicide attempt in 
the previous 6 months, or has a history of deliberate self-harm in the past 6 months.
Additional exclusion criteria for 
 collection in SRD/MRD Cohort 3:
26. The subject has had 
 collected within 6 months prior to Check-in (Day -1).
27. The subject has a known hypersensitivity to the anesthetic or its derivatives used during 
 
collection or any medication used to prepare the area of lumbar puncture.
28. The subject has any skin condition, abnormality of the lumbar spine, medical or surgical 
condition that would preclude lumbar puncture (eg, coagulopathy, local or systemic infection, 
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left ventricular outflow obstruction, aortic stenosis, raised intracranial pressure, previous back 
surgery).
7.3
Excluded Medications, Dietary Products
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until subject is discharged from the unit.
Table 7.a
Prohibited Medications and Dietary Products
28 days prior to Check-in 
(Day -1)
7 days prior to Check-in 
(Day -1)
72 hours prior to Check-in 
(Day -1)
Prescription medications
OTC medications (a)
Products containing caffeine or 
xanthine
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Vitamin supplements
poppy seeds
Immunization/Vaccines (b)
Foods or beverages containing 
grapefruit or grapefruit juice, star 
fruit or star fruit juice, Seville-type 
(sour) oranges and marmalade, apple, 
orange, or pineapple juices, 
vegetables from the mustard green 
family (eg, kale, broccoli, watercress, 
collard greens, kohlrabi, Brussels 
sprouts, mustard), and charbroiled 
meats
Nicotine-containing products
Alcohol containing products
Intake of known OTC 
inhibitors/inducers of CYPs 3A4/5, 
2C9, 2C19, 2D6, 1A2, 2B6, 2E1, and 
2A6(c)
OTC=over-the-counter. 
(a) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication as approved by Takeda on a 
case-by-case basis is allowed. Prohibition and approval on case-by-case basis may both be acceptable terms.
(b) Inclusive of but not limited to H1N1 and other flu vaccinations.
(c) Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine. 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 
Subjects will be confined to the clinic for the duration of each treatment period (see SRD 
Figure 6.a and SRD/MRD Figure 6.b).
During the confinement period, subjects will be given a menu for the dosing period that includes 
3 meals and an evening snack, each containing approximately 30% fat (relative to the total 
calories). The meals served on the PK assessment days should be identical for each cohort in the 
study. The study menu should be recorded and submitted to the study file with a copy provided to 


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the sponsor prior to the start of the study. Record whether the meal was fully consumed, or, if not, 
record the percentage consumed (0, 25%, 50%, 75%).
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence 
followed by the study procedure and then the meal.
During the SRD Cohorts, except the fed portion of the food effect study, TAK-653 and placebo 
will be administered on Day 1 with 240 mL of water after a fast of at least 10 hours. Subjects will 
continue to fast for an additional 4 hours after dosing. Subjects may consume water ad libitum with 
the exception of 1 hour before and 1 hour after drug administration. Subjects do not have to fast on 
days when no dosing is scheduled.
During the food effect phase of the study, subjects should fast overnight for at least 10 hours and 
should start the recommended high-fat, high-calorie meal 30 minutes prior to administration of the 
drug. Subjects should complete the meal in 30 minutes or less; however, the drug product should 
be administered 30 minutes after start of the meal. Subjects may consume water ad libitum with 
the exception of 1 hour before and 1 hour after drug administration. The recommended high-fat, 
high-calorie meal will consist of the following: 2 eggs fried in butter, 2 strips of bacon, 2 slices of 
toast with butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk. The clinical site 
may make minor modifications to the high-fat, high-calorie meal as long as the same meal is 
served to all subjects and the meal meets the high-fat criteria together with comparable meal 
volume and viscosity. The clinical site will document the amount of protein, carbohydrate, and fat 
and total calorie content of the test meal for the study file and provide a copy to the sponsor. The 
date and time of the meal, whether fully consumed or, if not, what percentage was consumed will 
also be recorded on the electronic case report form (eCRF). 
For single and multiple dosing in the SRD/MRD Cohorts, TAK-653 and placebo will be 
administered in the morning on Day 1 and Days 6 through 18 with 240 mL of water after a fast of 
at least 10 hours. Food may be consumed approximately 2 hours after dosing. Subjects may 
consume water ad libitum with the exception of 1 hour before and 1 hour after drug administration. 
Subjects do not have to fast when no dosing is scheduled.
 collection - SRD/MRD Cohort 3 only
On SRD/MRD Day 12, the 1-hour predose vitals will be collected supine and standing. The vitals 
at 15 minutes, 30 minutes, and 1 hour post-lumbar puncture will be collected supine only. After the 
procedure, the subject will be observed by staff and will preferably lie in the supine position for 
1 hour—at the investigator’s discretion for up to 4 hours if necessary. Subjects may also rest 
comfortably in a seated or semirecumbent position at the investigator’s discretion.
All Cohorts
Subjects will remain upright (seated, standing, or ambulatory) for 4 hours following dose 
administration, except as necessitated by the occurrence of an AE/or study procedures (eg, 
obtaining 12-lead ECG). Subjects will refrain from strenuous and/or unaccustomed exercise 
throughout the entire course of the study. 
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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the eCRF using the following categories. For screen failure subjects, refer to 
Section 9.1.19.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or 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 PTE or AE.
2. 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 9.1.8), if any of the following circumstances occur at any time during study 
drug treatment:
–
ALT or AST >8 × ULN.
–
ALT or AST >5 × ULN and persists for more than 2 weeks.
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or INR >1.5.
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (>5%).
3. Significant protocol deviation. The discovery after randomization or 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.
4. 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.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
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.
6. Study termination. The sponsor, IEC, or regulatory agency terminates the study.
7. 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 9.1.11.
8. Other. The specific reason(s) should be recorded in the “specify” field of the eCRF.


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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 
Early Termination Visit. Discontinued or withdrawn subjects may be replaced (see Section 8.2).


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8.0
CLINICAL TRIAL 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 clinical trial material.
8.1
Study Medication 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.
TAK-653 tablets will be provided in the following strengths:

0.1 mg.

0.25 mg.

1 mg.

5 mg.

Matching placebo tablets.
8.1.1.1
Sponsor-Supplied Drug
TAK-653 study drug will be supplied as 0.1, 0.25, 1, and 5 mg, and matching placebo as round, 
yellow-red film-coated tablets. TAK-653 drug product is manufactured by Takeda Pharmaceutical 
Company Ltd., Osaka, Japan.
TAK-653 tablets will be supplied in amber glass bottles with metal screw caps. Each bottle will 
contain 50 tablets. 
Each bottle of TAK-653 active or placebo will bear a single-panel label that includes pertinent 
study information.
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational 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.
8.1.3
Dose and Regimen
The planned initial dose of TAK-653 for SRD Cohort 1 is 0.3 mg. Doses for subsequent cohorts 
will be determined based on the safety, tolerability, and available PK and PD data of previous 
cohorts. The doses will be administered to the subjects by the investigator or investigator’s 
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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned, in the order in which they are randomized into the study, to receive their 
treatment according to the randomization schedule allocated to the site. The tear-off portion of the 
medication label will be affixed to the Dispensing Log. The Randomization Sequence Number 
will be entered onto the eCRF. 
For each dosing cohort in both SRD and SRD/MRD parts, randomized subjects will be assigned a 
4-digit randomization number in the order which they are enrolled. Randomization sequence 
numbers will be XY01 to XY08, where X refers to SRD (part 1) or SRD/MRD (part 2) and Y 
refers to Cohort number.
For example:

Subjects in SRD Cohort 1 will have randomization sequence numbers 1101 to 1108 and 
subjects in SRD Cohort 2 will have numbers 1201 to 1208.

Subjects in SRD/MRD Cohort 1 will have randomization sequence numbers 2101 to 2108 and 
subjects in SRD/MRD Cohort 2 will have numbers 2201 to 2208.
In case a subject needs to be replaced, the replacement subject should receive the same treatment 
that the subject being replaced would have received. The replacement randomization numbers will 
be XX1X. For example, subject 1211 will replace subject 1201 with the same treatment. No 
replacement randomization schedule will be generated.
This 4-digit number will be used by the clinical site to facilitate the prelabeling of PK and PD 
samples, and will be the only subject identifier used on all sample collections. It should also be 
contained on the PK and PD transport vials shipped to the bioanalytical laboratory, and will be 
used by the laboratory to report the subject data results. This 4-digit number should only be used 
for the purposes described in this section. It does not replace the 3-digit subject number that is 
assigned at the time the informed consent is obtained and that is used for all other procedures to 
identify the subjects throughout the study.


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8.3
Randomization Code Creation and Storage 
The randomization schedule will be generated by Takeda’s Analytical Sciences Department and 
will be provided to the site pharmacist prior to the start of this study. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.
8.4
Investigational Drug Blind Maintenance
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist. 
At the completion of SRD/MRD Cohort 3 onward, Takeda nonstudy personnel may be unblinded 
(with the exception of the site monitor) for a preliminary review of the safety, PK, and PD data. 
The investigator and subjects will remain blinded until the completion of the study.
8.5
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All study 
assessments and causality should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by contacting the 
dispensing pharmacist. Code break envelopes will be supplied for emergency unblinding when the 
pharmacist is unavailable.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study.
No change should be made to any assessment of the subject after unblinding.
8.6
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, 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 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 


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should acknowledge the receipt of the shipment by signing bottom half of the packing list and 
faxing per instructions provided on the form. If there are any discrepancies between the packing 
list versus the actual product received, Takeda must be contacted to resolve the issue. The packing 
list should be filed in the investigator’s essential document file.
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:

Continuously monitoring expiration dates if expiry dates 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(s) 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.

A site representative or unblinded pharmacy monitor, otherwise uninvolved with study 
conduct, will review the randomization schedule and subject dosing log prior to Day 1 dosing 
for SRD portion and Days 1 and 4 to 16 dosing for MRD portion, and following dosing to 
ensure all subjects received the correct dose of study drug.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 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 and amount dispensed, including initials, seal, or signature 
of the person dispensing the drug, and the date and amount returned to the site by the subject, 
including the initials, seal, 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.
Prior to 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 expiry date or 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.


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In the event of expiry date extension of supplies 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 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 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 for SRD Part 1 Cohorts 1 to 5 is located in Appendix A, for SRD 
Part 1 Cohort 6 onward is located in Appendix B, and for SRD/MRD Part 2 is located in 
Appendix C.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
A unique subject identification number (subject ID=site + 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.
9.1.1.1
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include age, sex, race as described by the subject, 
height, weight, caffeine consumption, and smoking status of the subject at Screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and safety evaluation stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) lymph nodes; (10) genitourinary, and 
(11) a complete neurological examination (details are provided in Appendix G). 
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Any abnormal finding on a pretreatment physical examination assessment must be assessed as Not 
Clinically Significant (NCS) or Clinically Significant (CS) by the investigator and recorded in the 
source document and eCRF. All CS findings/changes will be recorded as a PTE or concurrent 
medical condition in the source document and on the appropriate eCRF described in Section 10.0
or Section 9.1.7. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the first dose of the investigational drug in each cohort 
must be assessed as NCS or CS by the investigator and recorded in the source document and eCRF. 
Any CS change or new diagnosis as a result of a CS change, as determined by the investigator, will 
be recorded as an AE in source documentation and on the PTE/AE eCRF described in 
Section 10.0.
9.1.4
Weight, Height, and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. 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:
Metric:
BMI = weight (kg)/height (m)2 
Note that although height is reported in centimeters, the formula uses meters for height; meters 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 
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. However, if the BMI is used as entry criteria, then this 
determination must be made after rounding.
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral), supine blood pressure (resting more than 
5 minutes), respiration rate, and heart rate. Heart rate and blood pressure will be measured after 
5 minutes supine and again at 1 and 3 minutes after standing. Vital signs will be collected 
according to the schedule shown in Table 9.a. When vital signs are scheduled at the same time as 
blood draws, the blood draw will take priority and vital signs will be obtained within 0.5 hour 
before or after the scheduled blood draw.
Vital signs may be repeated. All measurements will be recorded on the source documents and in 
the eCRF. Vital signs taken as safety measures (not protocol-specified) will be recorded as 
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Table 9.a
Schedule for Vital Signs Assessments
Vital Signs
Day
Schedule of Assessments
SRD
Oral temperature, 
respiration, heart rate 
(a, b), and blood 
pressure (a)
Screening, Check-in 
(Day -1)
1
Predose (within 50 minutes prior to dosing), and at 1, 2, 4, 6, 8, 10, 
12, and 16 hours postdose.
2-6, ET, Day 7 
(Study Exit)
On rising or early termination
14 (±2)
As appropriate, if the subject must return to the site for a follow-up 
visit.
SRD/MRD
Oral temperature, 
respiration, heart rate 
(a, c), and blood 
pressure (a)
Screening, Check-in 
(Day -1)
As appropriate
1, 6-18
Predose (within 30 minutes prior to dosing), and at 1, 6, and 12
hours postdose.
2-5, 19-20, ET, 21 
(Study Exit)
As appropriate
31 (±2)
As appropriate, if the subject must return to the site for a follow-up 
visit.
(a) Heart rate and blood pressure will be measured after 5 minutes supine and again 1 and 3 minutes after standing.
(b) SRD heart rate will also be obtained on dosing Day 1 at 0.5 and 1.5 hours postdose.
(c) SRD/MRD heart rate will also be obtained on the days of dosing (Day 1 and Days 6-18) at 0.5, 1.5, and 2 hours 
postdose.
If a vital sign is found to be abnormal, it will be collected every 30 minutes until it returns to the 
Baseline /normal range.
9.1.6
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 eCRF. Drugs given during the 
 collection will be 
recorded as concomitant medication. Documentation will include generic medication name, dose, 
unit, frequency, route of administration, start and end dates, and reason for use. 
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at Screening/Baseline examination. The condition (ie, diagnosis) 
should be described.
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9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 10-hour overnight fast on the days stipulated in the 
Schedule of Study Procedures for SRD Part 1 (Appendix A and Appendix B) and SRD/MRD 
Part 2 (Appendix C).
Table 9.b lists the tests that will be obtained for each laboratory specimen.
Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells (RBC)
White blood cells (WBC)
with differential (absolute 
counts)
Hemoglobin
Hematocrit
Platelets
PT/INR
aPTT
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase (GGT)
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Leukocyte esterase
Ketones
Bilirubin
Urobilinogen
Diagnostic Screening:
Serum
Urine/Blood
HIV test
Hepatitis panel, including HBsAg and anti-HCV
Drug screen including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and 
cotinine. (c)
Female subjects: urine hCG (a).
Female subjects: serum hCG (a)
Female subjects, if menopause is suspected and not 
surgically sterile: FSH (b)
aPTT=activated partial thromboplastin time, FSH=follicle-stimulating hormone, hCG=human chorionic gonadotropin.
(a) Serum hCG pregnancy test will be done at Screening and Study Exit/Early termination, and at the Follow-up Visit 
if the subject is brought back to the clinic for re-evaluation. Urine hCG pregnancy test will be done at Check-in 
(Day -1).
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal (ie, no menses for 12 
months without an alternative medical cause) and not surgically sterile. The result must be >40 IU/L for the subject to 
be enrolled.
(c) To be performed at Screening and Check-in Day -1.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results. All laboratory safety data will be transferred electronically to 
Takeda or designee in the format requested by Takeda.


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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 within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation 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, 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
Reporting of Abnormal Liver Function Tests for reporting requirements).
The investigator or designee is responsible for transcribing or attaching laboratory results to the 
eCRF. The investigator will maintain a copy of the laboratory accreditation and the reference 
ranges for the laboratory used.
Laboratory reports must be signed and dated by the principal investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with enrollment/randomization.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable 
level or a satisfactory explanation has been obtained.
9.1.9
Telemetry
In the SRD Part 1, continuous cardiac monitoring (telemetry) will be performed from dosing on 
Day 1 through to approximately 36 hours postdose.
9.1.10 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 90 days after 
5 half-lives have elapsed since the last dose of study drug (ie, 90 days from the Follow-up 
Call/Visit unless data indicates otherwise), 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. 
From signing of informed consent, throughout the duration of the study, and for 30 days after 
5 half-lives have elapsed since the last dose of study drug (ie, 30 days from the Follow-up 
Call/Visit unless data indicates otherwise), female subjects of childbearing potential* who are 
sexually active with a nonsterilized male partner** must use highly effective contraception (<1% 


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failure rate/year), which has low user dependency. 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 at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study drug is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
A highly effective method of contraception for women of child bearing potential is defined as one 
that has no higher than a 1% failure rate per year. The acceptable methods of contraception are:

Intrauterine device (IUD).

Bilateral tubal occlusion.

Vasectomized partner (provided that the partner is the sole sexual partner of the trial 
participant and that the absence of sperm in the ejaculate has been confirmed).

Sexual abstinence if it is the preferred and usual lifestyle of the subject. Subjects practicing 
abstinence as a method of contraception must refrain from heterosexual intercourse throughout 
the duration of the study and for 30 days (females) or 90 days (males) after 5 half-lives have 
elapsed since the last dose of the study drug. This should be interpreted as 30 days (females) or 
90 days (males) from the Follow-up Call/Visit unless available data indicates otherwise.
The use of hormonal contraceptives is not recommended for TAK-653 studies as there is currently 
no data on possible drug-drug interactions between TAK-653 and hormonal contraceptives.
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.
Serum hCG pregnancy tests must be conducted for all female subjects at Screening and Study 
Exit/Early Termination. In addition to a negative serum hCG pregnancy test at Screening, subjects 
also must have a negative urine hCG pregnancy test prior to receiving any dose of study drug (eg, 
at Check-in Day -1). 
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.
See Appendix A and Appendix B (SRD cohorts) and Appendix C (SRD/MRD cohorts) for the 
schedules for these procedures. 
9.1.11 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 


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partner of a male subject during the study or for 12 weeks 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, eg, within 12 weeks 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 1.0.
Should the pregnancy occur during or after administration of blinded 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 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/male partner of 
the subject was participating in a clinical study at the time the woman became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable).
All reported pregnancies 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.
9.1.12 ECG Procedure 
Twelve-lead ECGs will be recorded using an ECG machine that automatically calculates the heart 
rate and measures PR interval, RR interval, QRS interval, QT interval, and QTcF. QTcF may also 
be calculated manually by the site.
All stationary 12-lead ECG machines will be supplied by the site. Subjects should be in a supine 
position and should have an approximate 10-minute rest period prior to ECG recordings. Should 
technical difficulties occur during recording of the ECG, a reasonable attempt should be made to 
repeat the ECG shortly after the failed attempt.
ECGs will be read automatically and the investigator or subinvestigator will also manually 
interpret the ECG using 1 of the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant. All 12-lead ECGs will be stored for 
manual measurement of intervals, if necessary.
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. If the original ECG is printed on 
thermal paper, the ECG report must be photocopied and certified. The photocopy will be filed with 
the original ECG in the source.
The schedule for ECG assessments in the SRD part of the study is shown in Appendix A and 
Appendix B and in the SRD/MRD part of the study is shown in Appendix C. When an ECG is 
scheduled at the same time as blood draws or vital signs, the blood draws and vital signs will take 
priority and the ECG will be obtained within 0.5 hours before or after the scheduled blood 
draw/vital sign assessment. If an ECG coincides with a meal, ECG will take precedence followed 
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Additional unscheduled ECGs may be recorded where clinically necessary for subject safety. For 
eligibility determination, ECGs may be repeated once at Screening and/or Day -1.
9.1.13 Safety EEG Procedure
EEG data will be collected in a resting state with eyes open and closed, with photic stimulation, 
and with 3 minutes hyperventilation. EEG time may be adjusted in consultation with the PI and 
sponsor, and based on emerging PK or other data. When an EEG is scheduled at the same time as 
blood draws, the blood draws will take priority and the EEG will be obtained within 2 hours before 
or after the scheduled blood draw and/or vital sign assessment. 
EEGs will be evaluated by a qualified individual for clinically significant abnormalities. Findings 
will be categorized as (1) within normal limits, (2) abnormal but not clinically significant, or 
(3) clinically significant abnormal. Abnormal EEG findings should be described. If a subject has a 
tremor during the study, an EEG must be conducted as soon as possible.
Prior to randomization, EEG reports must be reviewed by the investigator. Descriptive text reports 
will be provided for all screening and postdose EEGs. A subject with an EEG categorized as 
significantly abnormal during screening will not be eligible for randomization. To aid with EEG 
interpretation, video recordings and live streams of the volunteers’ faces may be done during the 
EEG, at the investigator’s and/or qualified individual’s discretion.
A study manual of EEG assessments will be prepared and provided to the site before the start of the 
study. The EEG study manual will be stored with the study file.
9.1.14 CCI
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9.1.14.1
9.1.14.2
9.1.14.3
Instructions for collecting, processing, and shipping of samples are provided in the laboratory 
manual.
9.1.15 Pharmacokinetic Sample Collection
9.1.15.1 Collection of Plasma and Urine for Pharmacokinetic Sampling
Blood and urine samples will be collected for the determination of concentrations of TAK-653, 
 Urine samples will only be collected for the SRD/MRD Cohorts. The 
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sampling schedule may change based on emerging data but will not exceed the number of planned 
samples.
Serial blood and urine samples for determination of plasma and urinary concentrations of 
TAK-653 and its metabolites will be collected according to Table 9.c. The actual time of sample 
collection will be recorded on the source document and eCRF.
Table 9.c
Collection of Blood and Urine Samples for Pharmacokinetic Analysis
Sample Type
Dosing Day
Time Postdose (hours)
SRD (Cohorts 1-5)
Plasma
1
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, 48, 72, 96, 120, and 144 hours postdose.
SRD (Cohort 6 onward)
Plasma
1
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose.
SRD/MRD (All cohorts)
Plasma
1
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, 48, 72, 96, and 120 (a) hours postdose.
Plasma
6
0.5, 1, 2, 4, 6, 8, 12, 16, and 24 (b) hours postdose.
Plasma
12,14, 16
Predose (within 15 minutes of dosing) (and following 
 collection procedure on 
Day 12, SRD/MRD Cohort 3 only).
Plasma
18
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 
12, 16, and 24 hours postdose.
Urine
1
Predose (-12 to 0 hours) and at (0 to 6), (6 to 12), (12 to 24), (24 to 48), and (48 to 
72) hour intervals postdose.
Urine
18
(0 to 6), (6 to 12), and (12 to 24) hour intervals postdose.
(a) The 120-hour sample must be collected before dosing on Day 6.
(b) The 24-hour sample must be collected before dosing on Day 7.
Blood samples (one 4-mL sample per scheduled time) for PK analysis will be collected into chilled 
Vacutainers containing anticoagulant (K2EDTA) according to the schedules in Appendix A, 
Appendix B, and Appendix C. 
Blood samples for placebo will not be analyzed by the bioanalytical laboratory except for 
2 samples per subject receiving placebo, 1 predose and the other around the expected time at which 
Cmax occurred (as emerging from the actual measurement of the samples of the first dose group) to 
ensure from a safety perspective that no additional subjects could have been on active treatment. 
Urine samples will not be collected for the SRD cohorts. Urine samples in the SRD/MRD for 
subjects randomized to placebo will not be analyzed.
Instructions for collecting, processing, and shipping of samples are provided in the laboratory 
manual.
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9.1.15.2
9.1.15.3 Bioanalytical Methods
Plasma and urine concentrations of TAK-653 and
 and 
 
concentrations of TAK-653 and 
, if feasible, will be measured by 
high-performance liquid chromatography with tandem mass spectrometry.
Part of the archival plasma and urine samples will be sent to Takeda Pharmaceutical Company 
Limited (Japan) for potential analysis of unknown metabolite characterization, if appropriate.
9.1.16 Pharmacokinetic Parameters
The PK parameters of TAK-653, 
 will be determined from the 
concentration-time profiles for all evaluable subjects. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times. The 
following PK parameters will be calculated for plasma concentration values of TAK-653, 
 
):
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Symbol/Term
Definition
Plasma
AUC24
Area under the plasma concentration-time curve from time 0 to 24 hours postdose.
AUCτ
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval.
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated as 
AUC∞=AUClast+Clast/λz
Cav,ss
Average plasma concentration at steady state, calculated as AUCτ/τ.
Cmax
Maximum observed plasma concentration.
Cmax,ss
Maximum observed steady-state plasma concentration during a dosing interval.
 
λz
Terminal disposition phase rate constant, calculated as the negative of the slope of the 
log-linear regression of the natural logarithm concentration-time curve during the terminal 
phase.
τ
Dosing interval.
tmax
Time of first occurrence of Cmax.
 
Urine
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9.1.17 Pharmacodynamic Sample Collections 
9.1.17.1
9.1.17.2
Table 9.e
Collection of Blood Samples for Analysis 
Study Day
Time Points 
SRD (Cohort 6 onward) and SRD/MRD (Cohort 3 onward)
1
Predose and 4, 8, 12 hours postdose
2-5
24, 48, 72, 96 hours postdose
SRD/MRD (Cohort 3 onward)
18
Predose and 4, 8, and 12 hours postdose
19
24 hours postdose
 
Note: A single dose is administered on Day 1. No additional doses are administered until Day 6 when QD dosing 
begins from Day 6 through 18.
 
he subjects will be required to consent to this additional analysis.
9.1.18 Pharmacodynamic Parameters
9.1.18.1
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9.1.18.2
. 
 
9.1.19 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the eCRF screen failure form.
The primary reason for screen failure is recorded in the eCRF using the following categories:
!
PTE/AE.
!
Did not meet inclusion criteria or did meet exclusion criteria (specify reason).
!
Significant protocol deviation.
!
Lost to follow-up.
!
Voluntary withdrawal (specify reason).
!
Study termination.
!
Other (specify reason).
Subject 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 number and treated as a stand-alone 
subject.
9.1.20 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.1.21 Assessment of Suicidal Ideation and Behavior
The C-SSRS was developed by researchers at Columbia University as a tool to help systematically 
assess suicidal ideation and behavior in subjects during participation in a clinical trial of 
centrally-acting drugs. The C-SSRS is composed of 3 questions addressing suicidal behavior and 
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5 questions addressing suicidal ideation, with subquestions assessing the severity. The tool is 
administered via interview with the subject.
SRD
The Screening/Baseline C-SSRS will be administered at Screening and Check-in (Day -1) and the 
Since Last Visit C-SSRS will be administered on discharge Day 5 and Study Exit Day 7 or Early 
Termination.
SRD/MRD
The Screening/Baseline C-SSRS will be administered at Screening and Check-in (Day -1) and the 
Since Last Visit C-SSRS will be administered on Day 11, and Study Exit (Day 21) or Early 
Termination.
9.2
Monitoring Subject Treatment Compliance
Study drug will be administered while subjects are under observation in the clinical research unit. 
Following administration of the study drug, appropriate mouth and/or hand checks will be 
performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the eCRFs. An inventory of the 
study drug supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate logistics 
at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). Additional assessments 
may be conducted or timing of existing assessments may be amended based on emerging safety, 
PK or PD data.
9.3.1
Screening 
Subjects will be screened within 28 days prior to randomization, in accordance with predefined 
inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.19 for procedures for 
documenting screening failures.
Procedures to be completed at Screening (all cohorts) include the following:

Informed consent.

Inclusion/exclusion criteria.

Demographics, medical history, and medication history.

Physical examination (including a comprehensive neurological examination-details in 
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
Vital signs.

Weight, height, and BMI.

Concurrent medical conditions.

Screening clinical laboratory tests.

Hepatitis panel.

FSH (postmenopausal women).

Serum pregnancy test (hCG) (all female subjects).

Pregnancy avoidance counseling.

Urine drug screen and alcohol breathalyzer.

ECG procedure.

EEG assessments.

C-SSRS (Baseline/Screening version).

PTE assessment.
In the event that subjects have undergone general screening assessments (ie, panel screening) 
before the effective date of this protocol amendment, the data from this general screening may be 
used to assess subject eligibility for enrollment in this study, provided that the procedures were 
performed within the protocol-defined Screening Period window.
9.3.2
Check-In Procedures
Procedures to be completed at Check-in (Day -1) include the following:
SRD Cohorts

Inclusion/exclusion criteria assessments.

Physical examination, including complete neurological examination (see Appendix G). 

Vital signs.

Weight.

Concomitant medications.

Concurrent medical conditions.

Clinical Laboratory tests.

Urine pregnancy test (hCG) (all female subjects).

Urine drug screen.

Alcohol breathalyzer.


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!
ECG.
!
EEG.
!
C-SSRS (Baseline/Screening version).
!
PTE assessments.
SRD/MRD Cohorts
!
Inclusion/exclusion criteria assessments.
!
Physical examination, including complete neurological examination (see Appendix G). 
!
Vital signs.
!
Weight.
!
Concomitant medications.
!
Concurrent medical conditions.
!
Clinical laboratory tests.
!
Urine pregnancy test (hCG) (all female subjects).
!
Urine drug screen.
!
Alcohol breathalyzer.
!
ECG.
!
C-SSRS (Baseline/Screening version).
!
PK urine collection.
!
PTE assessments.
9.3.3
Treatment Phase
Procedures to be completed during the treatment phase include the following:
SRD Cohorts
!
Vital signs.
!
Telemetry (36 hours postdose).
!
Concomitant medications.
!
Clinical laboratory tests (Days 1, 2, 5). 
!
ECG procedures (Days 1, 2, 5).
!
!
C-SSRS (Day 5) (Since Last Visit version).
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!
DNA (Day 1) and RNA (Days 1, 2) sample collections.
!
PK blood collections.
!
blood collections (Days 1-5; SRD Cohort 6 onward only).
!
Dispense study medication (Day 1).
!
PTE assessments (Day 1 predose).
!
AE assessments.
SRD/MRD Cohorts
!
Vital signs.
!
Concomitant medications.
!
Clinical laboratory tests (Days 1, 6, 9, 12, 15, 18).
!
ECG procedures (Days 1, 6, 9, 12, 15, 18).
!
!
C-SSRS (Day 11) (Since Last Visit version).
!
DNA (Day 1) and RNA (Days 1 and 18) sample collections.
!
PK blood collections (Days 1-7, 12, 14, 16, 18-19).
!
 collections (Day 12, SRD/MRD Cohort 3 only).
!
 blood collections (Days 1-5, 18, 19; SRD/MRD Cohort 3 onward only).
!
PK urine collections (Days 1-4, 18-19).
!
Dispense study medication (Day 1, Days 6-18).
!
PTE assessments (Day 1 predose).
!
AE assessments.
9.3.4
Study Exit 
Procedures to be completed by all Cohorts at Study Exit (SRD Cohorts 1-5 on Day 7, SRD 
Cohort 6 onward on Day 8, SRD/MRD on Day 21) include the following:
!
Physical examination, including complete neurological examination (described in 
Appendix G).
!
Vital signs.
!
Weight.
!
Concomitant medications.
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
Clinical laboratory tests.

Serum pregnancy test (hCG). 

Pregnancy avoidance counseling.

ECG.

EEG assessments.

C-SSRS (Since Last Visit version).

PK blood collections (SRD only).

AE assessments.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.5
Early Termination
The reason for discontinuation must be documented in the source document and eCRF. All of the 
procedures listed in Section 9.3.4, Study Exit, should be performed with the following differences:

EEG assessments should be performed at early termination.

PK blood collection is not required at early termination in either SRD or SRD/MRD.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.6
Follow-up Call/Visit
Follow-up assessments are scheduled to occur on Day 14 (±2 days) for SRD subjects and Day 31 
(±2 days) for SRD/MRD subjects to inquire for any ongoing AEs or SAEs, worsening of AEs or 
SAEs, or development of new AEs or SAEs, and for concomitant medications taken since final 
dose.
Subjects with unresolved SAEs, CS laboratory abnormalities, ECG or physical examination 
findings or at the investigator’s discretion should return to the clinic for appropriate repeat 
procedure(s). A follow-up phone call will be made to all other subjects on Day 14 (±2) for an 
assessment of AEs and concomitant medications.
9.3.7
End-of-Trial Date
The End-of-Trial date will be based on the final data collection date for the entire study, which is 
the date of the last Follow-up call/visit.
9.4
Blood Volume
Total blood sampling volume for an individual subject in the SRD Cohorts is shown in Table 9.f.


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Table 9.f
Approximate Blood Volume: SRD Cohorts 1 to 5
Sample Type
Sample 
Volume
(mL)
Number of Samples per Subject
Total Volume
(mL)
Study Day
Screening
-1
1
2
3
4
5
6
7
Safety 
Laboratory (a)
10
1(b)
1
1
1
--
--
1
--
1
60 (110 for food-effect cohort)
PK 
4
--
--
13
2
1
1
1
1
1
80 (160 for food-effect cohort)
6
--
--
1
--
--
--
--
--
--
6 
2.5
--
--
6
2
--
--
--
--
--
20 
Total Blood Sampling Volume (mL)
166 (296 for food-effect 
cohort) 
-- = no samples collected.
(a) No blood is collected on Days 3, 4, and 6 for safety laboratory assessments.
(b) For the food effect cohort, blood will be collected for safety laboratory collections only once at Screening. 
Table 9.g
Approximate Blood Volume: SRD Cohort 6 Onward
Sample Type
Sample 
Volume
(mL)
Number of Samples per Subject
Total Volume
(mL)
Study Day
Screening
-1
1
2
3
4
5
6
7
8
Safety Laboratory (a)
10
1
1
1
1
--
--
1
--
--
1
60
PK 
4
--
--
13
2
1
1
1
1
1
1
84 
4
--
--
4
1
1
1
1
--
--
--
32
6
--
--
1
--
--
--
--
--
--
--
6 
2.5
--
--
6
2
--
--
--
--
--
--
20 
Total Blood Sampling Volume (mL)
202
-- = no samples collected.
(a) No blood is collected on Days 3, 4, 6, and 7 for safety laboratory assessments.
The maximum volume of blood collected per subject on any single day is approximately 99 mL, 
and the approximate total volume of blood per subject in SRD Cohorts 1 to 5 is 166 mL and in 
SRD Cohort 6 onward is 202 mL. Subjects in the food effect cohort will have participated twice, 
once under fasted conditions and again under fed conditions. Therefore, the total volume of blood 
per subject in the food effect cohort will be approximately 296 mL. These totals do not include 
overage (eg, repeat samples, discard blood volume).
Total blood sampling volume for an individual subject in the SRD/MRD Cohorts is shown in 
Table 9.h.
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Table 9.h
Approximate Blood Volume: SRD/MRD Cohorts
Sample 
Type
Sample 
Volume
(mL)
Number of Samples per Subject
Study Day
Total 
Volume
(mL)
Screen-
ing
-1
1
2
3-5
6
7
9
12
14
15
16
18
19
21
Safety 
Laboratory
10
1
1
1
-
-
1
-
1
1
--
1
--
1
--
1
90
PK
4
--
--
13
2
3
9
1
--
2 (a)
1
-
1
13
1
--
184
(b)
4
--
--
4
1
3
--
--
--
--
--
--
--
4
1
--
52
6
--
--
1
-
-
-
-
--
--
--
--
--
--
--
--
6
2.5
--
--
2
-
-
-
-
--
--
--
--
--
2
--
--
10
Total Blood Sampling Volume (mL)
342
-- = no samples collected.
(a) An additional PK sample will be taken following the 
 collection procedure in SRD/MRD Cohort 3 only.
(b) Collected only for SRD/MRD Cohort 3 onward.
The maximum volume of blood collected per subject on any single day in the SRD/MRD is 
approximately 89 mL and the approximate total volume of blood collected per subject is 342 mL. 
These totals do not include overage (eg, repeat samples, discard blood volume).
Direct venipuncture is the preferred method of blood collection. Any other method will need to be 
approved by Takeda. If an intravenous cannula with a normal saline flush is used, the total blood 
volume does not include discarded blood from predraws (assuming approximately 3 mL of blood 
is discarded each time a sample is collected from an intravenous cannula).
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A 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 drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
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.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or 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. 

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/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 PTE(s) or as AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, evaluation
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays, etc) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or 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 condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study drug, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”).

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 severity of AEs/Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 


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worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.
3. 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.
4. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
5. Results in persistent or significant DISABILITY/INCAPACITY.
6. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
7. 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 
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Table 10.a
Takeda Medically Significant AE List
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes /ventricular fibrillation /ventricular 
tachycardia
Acute liver failure
Anaphylaxis
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
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Adverse Events of Special Interest
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and 
medical concern specific to the compound or program, for which ongoing monitoring and rapid 
communication by the investigator to Takeda may be appropriate. Such events may require further 
investigation in order to characterize and understand them and would be described in protocols and 
instructions provided for investigators as to how and when they should be reported to Takeda.
Based on nonclinical data to date and AMPA receptor potentiator class effects, the AESIs for this 
study are:

Tremors.

Convulsions.
10.1.6 Severity of PTEs and 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.


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10.1.7 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.10 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.11 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12 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, 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 Increased – the dose was increased due to the particular AE.

Dose Interrupted – the dose was interrupted due to the particular AE.


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10.1.13 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one 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/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved.”

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs are considered the cause of death.

Unknown – the course of the AE/PTE 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 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and will continue until the subject is first administered study drug or until 
screen failure. For subjects who discontinue prior to study drug administration, PTEs are collected 
until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug. 
Routine collection of AEs will continue for 30 days after the last dose of study drug.
10.2.1.2 PTE and 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. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.


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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 PTEs and AEs will be documented in the PTE/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:

Event term.

Start and stop date and time.

Frequency.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).

Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.

Action concerning study drug (not applicable for PTEs).

Outcome of event.

Seriousness.
10.2.1.3 AESI Reporting 
If an AESI that occurs during the treatment period or the follow-up period is considered clinically 
significant based on the criteria below, it should be recorded in an AESI Form or an SAE Form. 
The Form should be completed and reported to the clinical contract research organization 
(CRO)/Pharmacovigilance (PV) department within 24 hours.
AESI / abnormality criteria include:

Laboratory value threshold, if applicable.

Premature termination for the AESI, if applicable.

Tremors. 

Convulsion.
The standard query form in the eCRF is to be completed for tremors and convulsions. All other 
AESIs must be recorded as AEs in the eCRF. An evaluation form along with all other required
documentation must be submitted to the sponsor.


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10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A 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 identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.
If a 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 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.


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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, IEC, 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 (EMA), investigators and the IEC, in accordance with national regulations in 
the country where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and within 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
will also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of an investigational medicinal product or that would be sufficient 
to consider changes in the investigational medicinal products administration or in the overall 
conduct of the trial. The investigational site also will forward a copy of all expedited reports to the 
IEC in accordance with national 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.
Takeda (at a minimum, the clinical science representative, clinical pharmacologist, and 
pharmacovigilance physician) and the Principal Investigator will review the safety and tolerability 
data and available PK data for each Cohort prior to dosing an additional Cohort. The decision for 
the subsequent dose must be agreed upon by all representatives of Takeda and the Principal 
Investigator. If any one person has concerns regarding subsequent dosing then this acts as veto and 
the decision not to proceed with an additional Cohort will be escalated to management.


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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, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative 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 the 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. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should be included.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date 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 the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. 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 study monitors. 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 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Phase 1 Site Specifications document 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.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1 Analysis Sets
Safety Set
The safety analysis set will consist of all subjects who are enrolled and received 1 dose of study 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
PK Set
The PK set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration or amount of drug in the urine. 
PD Set
The PD set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement.
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the analysis but will be 
presented in the subject listings.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
For each part of the study, descriptive statistics (N, mean, SD, median, minimum, and maximum) 
will be generated for continuous demographic variables and baseline characteristics variables (age, 
height, weight, and BMI) for pooled placebo, each TAK-653 dose level, TAK-653 overall and 
overall total. For each part, the number and percentage of subjects in each class of the categorical 
demographic variables and baseline characteristics variables (sex, ethnicity, and race) will be 
tabulated for pooled placebo group, each TAK-653 dose level, TAK-653 overall and overall total. 
Placebo data will be pooled across the cohorts within each part.
For each part, demographic variables of screen failure subjects and reasons for screen failures will 
be summarized overall for subjects who are screened, but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, and reason for screen failure will be listed.
13.1.3 Pharmacokinetic Analysis
13.1.3.1 Concentrations in Plasma, Urine, and 
The concentration of TAK-653, 
) in plasma and urine (urine collected in 
SRD/MRD Cohorts only) will be summarized by Day, period (fasted vs fed) and dose level over 
CCI
CCI


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each scheduled sampling time using descriptive statistics. Individual plasma concentration data vs 
time will be presented in a data listing. 
The concentrations of TAK-653 and 
 in 
 if available, will be presented in a listing for 
SRD/MRD Cohort 3 only. The ratio of TAK-653 concentration in plasma to the concentration in 
 on Day 12 will be presented.
13.1.3.2 PK Parameters
Descriptive statistics (N, arithmetic mean, SD, median, minimum, maximum and percent 
coefficient of variation [%CV]) will be used to summarize the plasma and urine PK parameters for 
TAK-653, 
) by Day, period (fasted vs fed) and dose level. In addition, 
geometric mean and CV will be computed for Cmax and AUCs.
Dose proportionality will be tested for TAK-653 Cmax and AUCs using a power model. For the 
SRD part, data from the SRD fed Cohort will not be included in the power model. For the 
SRD/MRD cohorts, the power model will be run after multiple dosing only. The power fit will be 
assumed as described by the following equation:
where ∃0 is the intercept and ∃1 is the slope. The dose proportionality would be declared when the 
90% CI for β1 lies entirely within the critical region
, where r is the 
ratio of the highest and the lowest dose in this study. This criterion implies that the 90% CI for the 
ratio of the central values of PK parameter of interest from the highest dose to the lowest dose is 
contained completely within the bioequivalence range of (0.80, 1.25). Plots of ln(AUC) or ln(Cmax) 
vs ln(Dose) may also be used to illustrate dose proportionality or lack of it.
A more detailed analysis will be presented in the SAP.
13.1.4 Pharmacodynamic Analysis
%
&
∋
∃
∃
(
(
)
Dose
Parameter
PK
ln
)
ln(
1
0
∗∗
+
,
−−
.
/
(
(
)
ln(
)
25
.1
ln(
1
,
)
ln(
)
80
.0
ln(
1
r
r
CCI
CCI
CCI
CCI
CCI


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13.1.5 Safety Analysis
All safety data will be presented in listings. Where applicable, within each part, safety data will be 
summarized by placebo, each TAK-653 dose level, TAK-653 overall, and overall total. Placebo 
data will be pooled across cohorts within each part. These summaries will not contain data from 
the fed portion. Data from the food effect cohort will be summarized separately by placebo fed, 
placebo fasted, TAK-653 fed, and TAK-653 fasted.
13.1.6 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA. 
TEAEs with onset occurring within 30 days (onset date – last date of dose +1≤30) after study drug 
administration will be listed, and included in the summary tables. TEAEs will be summarized by 
SOC and PT. The following summary tables will be included in the report: summary of TEAEs 
and drug-related AEs, relationship of AEs to study drug (related vs not-related), severity of AEs 
and related AEs. AEs leading to study drug discontinuation and SAEs will be listed. Data listings 
will be provided for all AEs including PTE, TEAEs, AEs leading to study drug discontinuation, 
and SAEs.
13.1.6.1 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s markedly abnormal value (MAV) criteria to be defined in the SAP will be listed and 
summarized. Baseline, postdose, and change from Baseline to postdose laboratory data will be 
summarized. All clinical laboratory data will be listed.
13.1.6.2 Vital Signs
Individual results of vital signs that meet Takeda’s MAV criteria to be defined in the SAP will be 
listed and summarized. Observed values and changes from Baseline in vital sign measurements 
(systolic and diastolic blood pressure, heart and respiratory rate, and oral temperature) will be 
summarized. All vital signs data will be provided in the data listings.
13.1.6.3 ECGs
Individual results of ECG parameters that meet Takeda’s MAV criteria to be defined in the SAP 
will be listed and summarized. Observed values and changes from Baseline in ECG parameters 
will be summarized. All vital signs data will be provided in the data listings.
Shift tables will be generated for the investigator’s ECG interpretations by above group. All ECG 
data will be provided in the data listings.
13.1.6.4 Safety EEGs
All screening and postdose safety EEG assessments will be listed. A shift table will summarize the 
number of subjects who changed status from Baseline.


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13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size chosen of 8 subjects in each Cohort (6 active: 2 placebo) is considered to be 
sufficient for evaluation of safety, tolerability, and PK of each cohort. The sample size was not 
based on statistical power considerations.


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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 institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 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 IEC, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
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 IEC, 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/or 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 windows allowed for sample collections. 
However, blood samples not collected within the interval specified for the scheduled sample time 
should be reported to Takeda using the Protocol Deviation Form.
Protocol Deviation Forms are to be completed for PK/PD samples collected outside of the 
following intervals:


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Table 14.a
Windows for PK/PD Blood Sample Collection 
Minutes
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5
immediately postdose to ≤6 hours
±10
>6 hours to 12 hours postdose
±15
>12 hours to 24 hours
±30
>24 hours
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 FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency [MHRA], 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 institution 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 D. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IEC Approval
The IEC must be constituted according to the applicable requirements of the participating region. 
The sponsor or designee will require documentation noting all names and titles of members who 
make up the IEC. If any member of the IEC has direct participation in this study, written 
notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the IEC for review and 
approval of the protocol. This protocol, the Investigator’s Brochure, a copy of the informed 
consent form (ICF), and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to the IEC for 
approval. The IEC’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 IEC approval 
must refer to the study by exact protocol title, number, and version date; identify versions of other 
documents (eg, ICF) reviewed; and state the approval date. The sponsor will notify the site and 
ship drug 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 trial. 
Until the site receives drug, no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by the IEC. This may include notification to the 
IEC regarding protocol amendments, updates to the ICF, 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 IEC, and submission of the investigator’s 
final status report to the IEC. All IEC 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 IEC and sponsor.
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 describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The ICF further explains the nature of the study, its objectives, 


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and potential risks and benefits, as well as the date informed consent is given. The ICF will detail 
the requirements of the participant and the fact that he or she is free to withdraw at any time 
without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IEC approval of the ICF. The 
informed consent form, must be approved by the IEC and the sponsor prior to use.
The ICF 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 ICF to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IEC. 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 ICF 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 name, 
not nicknames, using blue or black ballpoint ink. The investigator must also sign and date the 
informed consent form 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 ICF 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 ICF shall be given to the subject.
All revised ICFs 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 PGx samples 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 study database or documentation via a unique identification 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 
identification number.


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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the IEC 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 clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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.
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 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov 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 trial 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 


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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 Takeda providing this 
information to callers must provide Takeda 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 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 clinical study subjects. 
Refer to the Clinical 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
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(DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013.
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depressive disorders by country, sex, age, and year: findings from the global burden of disease 
study 2010. PLoS Med 2013;10(11):e1001547.
3. Barraclough B, Bunch J, Nelson B, Sainsbury P. A hundred cases of suicide: clinical aspects. 
Br J Psychiatry 1974;125(0):355-73.
4. Santini ZI, Koyanagi A, Tyrovolas S, Mason C, Haro JM. The association between social 
relationships and depression: A systematic review. J Affect Disord 2015;175C:53-65.
5. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry 
2015;76(2):155-62.
6. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of 
outcomes with citalopram for depression using measurement-based care in STAR*D: 
implications for clinical practice. Am J Psychiatry 2006;163(1):28-40.
7. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a 
comprehensive review of findings. Curr Psychiatry Rep 2007;9(6):449-59.
8. Bentley SM, Pagalilauan GL, Simpson SA. Major depression. Med Clin North Am 
2014;98(5):981-1005.
9. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid 
antidepressant actions of ketamine. Neuropharmacology 2012;62(1):35-41.
10. Guideline on Clinical Investigation of Medicinal Products in the Treatment of Depression. 
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 30 
May 2013. Publication No. EMA/CHMP/185423/2010 Rev. 2.
11. Epstein I, Szpindel I, Katzman MA. Pharmacological approaches to manage persistent 
symptoms of major depressive disorder: rationale and therapeutic strategies. Psychiatry Res 
2014;220S1:S15-S33.
12. Farley S, Apazoglou K, Witkin JM, Giros B, Tzavara ET. Antidepressant-like effects of an 
AMPA receptor potentiator under a chronic mild stress paradigm. Int J 
Neuropsychopharmacol 2010;13(9):1207-18.
13. Messer M, Haller IV, Larson P, Pattison-Crisostomo J, Gessert CE. The use of a series of 
ketamine infusions in two patients with treatment-resistant depression. J Neuropsychiatry Clin 
Neurosci 2010;22(4):442-4.
14.
 
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15. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers. US Dept of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research. 06 July 2005. Publication 
No. 5541.
16. Yamada KA. Therapeutic potential of positive AMPA receptor modulators in the treatment of 
neurological disease. Expert Opin Investig Drugs 2000;9(4):765-78.


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Appendix A
SRD Part 1 Schedule of Study Procedures: Cohorts 1 to 5
Screening
Check-in
Treatment Period
Study Exit
Early 
Termination
(ET) (a)
Follow-up
(b) 
Confinement
Study Day:
-28 to -2 
-1
1
2
3
4
5
6
7
14 (±2) 
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical examination, including neurological examination 
(c)
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
Telemetry (e)
X
X
Weight, height, and BMI (f)
X
X
X
X
Concomitant medications (g)
X
X
X
X
X
X
X
X
X
X
Concurrent medical conditions
X
X
Clinical laboratory tests (h)
X
X
X
X
X
X
X
Hepatitis panel
X
FSH (i)
X
Serum pregnancy test (hCG) (j)
X
X
X
Urine pregnancy test (hCG) (j)
X
Pregnancy avoidance counseling
X
X
X
Urine drug screen
X
X
Alcohol breathalyzer
X
X
ECG (k)
X
X
X
X
X
X
X
EEG Assessment (l)
C-SSRS (m)
X
X
X
X
X
PK blood collection (p)
X
X
X
X
X
X
X
Dispense study medication
X
PTE assessment (q)
X
X
X
AE assessment (r)
X
X
X
X
X
X
X
X
X
Footnotes are on the last table page.
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Note: Subjects from a selected cohort will come back to the clinical site and receive the study drug in fed state (Period 2). During Period 2, the procedures to be performed for Day -1 
to Follow-up as in the table above will be: physical examination, including neurological examination, vital signs, telemetry, weight, clinical laboratory tests, serum pregnancy test 
(hCG), urine pregnancy test (hCG), pregnancy avoidance counseling, urine drug screen, alcohol breathalyzer, ECG, EEG, C-SSRS and PK blood collection. There is no screening 
period for this part of the study.
(a) Procedures for subjects discontinued early per Section 7.6. 
(b) Subjects with unresolved SAEs, CS laboratory abnormalities, ECG or physical examination findings or at the investigator’s discretion should be seen for a Follow-up visit on Day 
14 (±2) for appropriate repeat procedure(s). A follow-up phone call will be made to all other subjects on Day 14 (±2) for an assessment of AEs and concomitant medications.
(c) The physical examination will include a complete neurological examination. Details are provided in Appendix G.
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, Check-in (Day -1), Day 1 (predose [within 50 minutes prior to dosing], and at 
1, 2, 4, 6, 8, 10, 12, and 16 hours postdose), Days 2 through 5 (upon rising), Days 6 and 7 or ET, and as appropriate at the Follow-up Visit Day 14 (±2). Heart rate and blood pressure 
will be measured after 5 minutes supine and again at 1 and 3 minutes after standing. In addition, pulse will be obtained on Day 1 at 0.5 and 1.5 hours postdose. If a vital sign is found 
to be abnormal, it will be collected every 30 minutes till it returns to the baseline/normal range.
(e) Continuous 12-lead cardiac telemetry will be performed from dosing until approximately 36 hours postdose.
(f) Height and BMI will only be collected at Screening.
(g) Record all ongoing medications from Screening and throughout the study.
(h) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening, Day -1, Days 1, 2, and 5 (upon rising), Day 7 or ET, and as appropriate at the 
Follow-up Visit Day 14 (±2). Fasting is required on dosing day (Day 1).
(i) An FSH level will be obtained on postmenopausal women (defined as no menses for 12 months without an alternative medical cause).
(j) For all female subjects. 
(k) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Day 1 (predose [within 50 minutes prior to dosing], and at 1, 4, 8, and 12 hours postdose), Days 2 and 
5 (upon rising/waking up), Day 7, or ET, and as appropriate at Follow-up Day 14 (±2).
(l) For subjects who meet all other eligibility criteria (eg, clinical laboratory assessments), EEGs will be performed during Screening, Check-in (Day -1), on Day 1 approximately 1.5 
hours postdose, Day 2 at least 23 hours but not more than 25 hours postdose, Days 5 and 7, at ET, or if a subject develops a tremor (resting or otherwise). The investigator must review 
the Screening EEG results and verify that there are no CS abnormalities for the subject to be eligible for randomization.
(m) C-SSRS: Columbia-Suicide Severity Rating Scale. The C-SSRS (Baseline/Screening version) will be administered at Screening and Day -1 (Check-in). The ‘Since Last Visit’ 
version of the C-SSRS will be administered on Discharge Day 5 and Study Exit Day7, ET.
(n)
.
(p) For SRD Cohorts 1 to 5, blood samples (4 mL) for PK analyses will be collected at predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 
36, 48, 72, 96, 120, and 144 hours postdose. 
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1.
(r) Any event after dosing on Day 1 will be captured as an AE.
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Appendix B
SRD Part 1 Schedule of Study Procedures: Cohort 6 Onward
Screening
Check-in
Treatment Period
Study Exit
Early 
Termination
(ET) (a)
Follow-up
(b) 
Confinement
Study Day:
-28 to -2 
-1
1
2
3
4
5
6
7
8
14 (±2) 
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical examination, including neurological 
examination (c)
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
Telemetry (e)
X
X
Weight, height, and BMI (f)
X
X
X
X
Concomitant medications (g)
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical conditions
X
X
Clinical laboratory tests (h)
X
X
X
X
X
X
X
Hepatitis panel
X
FSH (i)
X
Serum pregnancy test (hCG) (j)
X
X
X
Urine pregnancy test (hCG) (j)
X
Pregnancy avoidance counseling
X
X
X
Urine drug screen
X
X
Alcohol breathalyzer
X
X
ECG (k)
X
X
X
X
X
X
X
EEG Assessment (l)
X
X
X
X
X
X
X
C-SSRS (n)
X
X
X
X
X
PK blood collection (q)
X
X
X
X
X
X
X
X
Dispense study medication
X
PTE assessment (r)
X
X
X
AE assessment (s)
X
X
X
X
X
X
X
X
X
X
Footnotes are on the last table page.
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(a) Procedures for subjects discontinued early per Section 7.6. 
(b) Subjects with unresolved SAEs, CS laboratory abnormalities, ECG or physical examination findings or at the investigator’s discretion should be seen for a Follow-up visit on Day 
14 (±2) for appropriate repeat procedure(s). A follow-up phone call will be made to all other subjects on Day 14 (±2) for an assessment of AEs and concomitant medications.
(c) The physical examination will include a complete neurological examination. Details are provided in Appendix G.
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, Check-in (Day -1), Day 1 (predose [within 50 minutes prior to dosing], and at 
1, 2, 4, 6, 8, 10, 12, and 16 hours postdose), Days 2 through 5 (upon rising), Days 6, 7, and 8 or ET, and as appropriate at the Follow-up Visit Day 14 (±2). Heart rate and blood 
pressure will be measured after 5 minutes supine and again at 1 and 3 minutes after standing. In addition, pulse will be obtained on Day 1 at 0.5 and 1.5 hours postdose. If a vital sign 
is found to be abnormal, it will be collected every 30 minutes till it returns to the baseline/normal range.
(e) Continuous 12-lead cardiac telemetry will be performed from dosing until approximately 36 hours postdose.
(f) Height and BMI will only be collected at Screening.
(g) Record all ongoing medications from Screening and throughout the study.
(h) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening, Day -1, Days 1, 2, and 5 (upon rising), Day 8 or ET, and as appropriate at the 
Follow-up Visit Day 14 (±2). Fasting is required on dosing day (Day 1).
(i) An FSH level will be obtained on postmenopausal women (defined as no menses for 12 months without an alternative medical cause).
(j) For all female subjects. 
(k) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Day 1 (predose [within 50 minutes prior to dosing], and at 1, 4, 8, and 12 hours postdose), Days 2 and 
5 (upon rising/waking up), Day 8, or ET, and as appropriate at Follow-up Day 14 (±2).
(l) For subjects who meet all other eligibility criteria (eg, clinical laboratory assessments), EEGs will be performed during Screening, Check-in (Day -1), on Day 1 approximately 1.5 
hours postdose, 
 at ET, or if a subject develops a tremor (resting or otherwise). The investigator must review 
the Screening EEG results and verify that there are no CS abnormalities for the subject to be eligible for randomization.
(m) 
 
).
(n) C-SSRS: Columbia-Suicide Severity Rating Scale. The C-SSRS (Baseline/Screening version) will be administered at Screening and Day -1 (Check-in). The ‘Since Last Visit’ 
version of the C-SSRS will be administered on Discharge Day 5 and Study Exit Day 8 or ET.
(o) 
(p) 
.
(q) For SRD Cohort 6 onward, blood samples (4 mL) for PK analyses will be collected at predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 
24, 36, 48, 72, 96, 120, 144, and 168 hours postdose.
(r) PTEs will be collected from signing of informed consent up until dosing on Day 1.
(s) Any event after dosing on Day 1 will be captured as an AE.
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Appendix C
SRD/MRD Part 2 Schedule of Study Procedures
Screening
Check-in
Treatment Period
Study 
Exit
ET (a)
Follow-up 
(b)
SRD
MRD
Study Day:
-28 to -2 
-1
1
2-5
6
7-8
9
10
11
12
13-14
15
16-17
18
19-20
21
31 (±2) 
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical examination, including 
neurological examination (c)
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, height, and BMI (e)
X
X
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical conditions
X
X
Clinical laboratory tests (g)
X
X
X
X
X
X
X
X
X
X
Hepatitis panel
X
FSH (h)
X
Serum pregnancy test (hCG) (i)
X
X
X
Urine pregnancy test (hCG) (i)
X
Pregnancy avoidance counseling
X
X
X
Urine drug screen
X
X
Alcohol breathalyzer
X
X
ECG (j)
X
X
X
X
X
X
X
X
X
X
C-SSRS (n)
X
X
X
X
X
PK blood collection (q)
X
X
X
X
X
X
X
X
X
Footnotes are on the last table page.
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Appendix C
SRD/MRD Part 2 Schedule of Study Procedures (continued)
Screening
Check-in
Treatment Period
Study 
Exit
ET (a)
Follow-up 
(b)
SRD
MRD
Study Day:
-28 to -2 
-1
1
2-5
6
7-8
9
10
11
12
13-14
15
16-17
18
19-20
21
31 (±2) 
PK urine collection (r)
X
X
X
X
X
Dispense study medication (s)
X
X
X
X
X
X
X
X
X
X
X
PTE assessment (t)
X
X
X
AE assessment (u)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(a) Procedures for subjects discontinued early per Section 7.6. 
(b) Subjects with unresolved SAEs, CS laboratory abnormalities, ECG, or physical examination findings or at the investigator’s discretion should be seen for a Follow-up visit on 
Day 31 (±2) for appropriate repeat procedure(s). A follow-up phone call will be made to all other subjects on Day 31 (±2) for an assessment of AEs and concomitant medications.
(c) The physical examination will occur at Screening, Day -1, Day 21 (study exit) or ET and will include a complete neurological examination. Details are provided in Appendix G.
(d)Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, Check-in (Day -1); on days of dosing (Day 1 and Days 6 through 18) (predose 
[within 30 minutes prior to dosing], and at 1, 6, and 12 hours postdose); on days with no dosing (Days 2-5 and 19-20), and Study Exit (Day 21) or ET, and as appropriate at the 
Follow-up assessment on Day 31 (±2). In addition, heart rate will be obtained on the days of dosing (Day 1 and Days 6-18) at 0.5, 1.5, and 2 hours postdose. If a vital sign is found to 
be abnormal, it will be collected every 30 minutes till it returns to the baseline/normal range. Heart rate and blood pressure will be measured after 5 minutes supine and again at 1 and 
3 minutes after standing for all scheduled time points except for the 
 collection in SRD/MRD Cohort 3 (Day 12). On Day 12, the vitals at 15 minutes, 30 minutes, and 1 hour 
post-lumbar puncture will be collected supine only. After the procedure, the subject will be observed by staff and will preferably lie in the supine position for 1 hour—at the 
investigator’s discretion for up to 4 hours if necessary. Subjects may also rest comfortably in a seated or semirecumbent position at the investigator’s discretion.
(e) Height and BMI will only be collected at Screening.
(f) Record all ongoing medications from Screening and throughout the study.
(g) Clinical laboratory tests (hematology, serum chemistry, and urinalysis) will be collected at Screening, Day -1, predose on Days 1, 6, 9, 12, 15, and 18 (upon rising), and prior to 
check-out on Study Exit (Day 21) or ET, and as appropriate at the Follow-up assessment Day 31 (±2). Fasting is required on dosing days (Day 1 and Days 6 to 18).
(h) An FSH level will be obtained on postmenopausal women (defined as no menses for 12 months without an alternative medical cause).
(i) For all female subjects. 
(j) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Days 1, 6, 9, 12, 15, and 18 at predose (within 50 minutes prior to dosing), and Study Exit (Day 21) or 
ET, and as appropriate at Follow-up Day 31 (±2).
(k) For subjects who meet all other eligibility criteria (eg, clinical laboratory assessments), EEGs will be performed during Screening and on Days 1, 
 
hours postdose, or ET. The investigator must review the Screening EEG results and verify that there are no CS abnormalities for the subject to be eligible for randomization.
(l) Part 2 SRD/MRD Cohort 3 onward only: Blood samples (serum and plasma, 2 mL each for Cohort 3; serum only, 4 mL each for Cohort 4 onward
 
.
(m) Part 2 SRD/MRD Cohort 3 only:
 samples (1 mL per subject) for PK (
) will be collected on Day 12. All attempts will be made to have a distribution of 
 collection times within the prescribed window of 2 to 6 hours postdose on Day 12; for example, the 
 sample may be collected at 2 hours postdose from the first subject, 
3 hours postdose from the second subject, 4 hours postdose from the third subject, and 6 hours postdose from the fourth subject with a collection window of +1 hour for each subject.
n) C-SSRS: Columbia-Suicide Severity Rating Scale. The C-SSRS Baseline/Screening version will be administered at Screening and Check-in (Day -1); the C-SSRS Since last visit 
version will be administered on Day 11 and Day 21 or ET.
(o)
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(p) 
(q) Blood samples (4 mL) for PK analyses will be collected on Day 1 at predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 
and 120 hours postdose (the 120-hour collection should occur predose on Day 6). Blood samples for PK analyses will be collected on Day 6 at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours 
postdose (the 24-hour collection should occur predose on Day 7). Blood samples will be collected predose (within 15 minutes prior to dosing) on Days 12, 14, and 16. Blood samples 
will be collected on Day 18 predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose. For Part 2 SRD/MRD Cohort 3 only, 
an additional PK blood sample will be collected following the 
 collection procedure.
(r) Urine samples for PK analyses will be collected on Day 1 predose at (-12 to 0 hours) and at (0 to 6), (6 to 12), (12 to 24), (24 to 48), and (48 to 72) hour intervals postdose. Urine 
samples for PK analyses will be collected on Day 18 at (0 to 6), (6 to 12), and (12 to 24) hour intervals postdose. 
(s) Study medication is dispensed QD on Day 1 and Days 6-18.
(t) PTEs will be collected from signing of informed consent up until dosing on Day 1.
(u) Any event after dosing on Day 1 will be captured as an AE.
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Appendix D
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 investigator agrees to assume the following responsibilities:
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 the IEC that conform to ICH and local 
regulatory requirements.
7. Ensure that the IEC will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the 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 IEC, and issue 
a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 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 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 
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 
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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 
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Appendix E
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:

A statement that the study involves research.

An explanation of the purposes of the research.

The expected duration of the subject’s participation.

A description of the procedures to be followed, including invasive procedures.

The identification of any procedures that are experimental.

The estimated number of subjects involved in the study.

A description of the subject’s responsibilities.

A description of the conduct of the study.

A statement describing the treatment(s) and the probability for random assignment to each 
treatment.

A description of the possible side effects of the treatment that the subject may receive.

A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.

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.

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.

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), 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.

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.

The anticipated prorated payment(s), if any, to the subject for participating in the study.

The anticipated expenses, if any, to the subject for participating in the study.

An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IEC and whom to contact in the event of a research-related 
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!
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 may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
!
The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
!
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.
!
 
!
The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
!
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) IEC.
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.
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e) that the subject’s identity will remain confidential in the event that study results are 
published.

Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening and throughout the duration of the study, and for 30 days after 5 half-lives have 
elapsed since the last dose of study drug (ie, 30 days from the Follow-up Call/Visit unless data 
indicates otherwise). 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. 

Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening and throughout the duration of the study and for 90 days after 5 half-lives have 
elapsed since the last dose of study drug (ie, 90 days from the Follow-up Call/Visit unless data 
indicates otherwise). 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. 

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 F
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 
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Appendix G
Neurological Examination
I. 
Basic mental status

Level of consciousness

Orientation

Memory

Language / speech
II. 
Cranial nerves II –XII

CN II: visual acuity, visual fields, papillary reaction and fundi

CN III, IV and VI: papillary reaction and extra-ocular movements

CN V: facial sensation, corneal response and muscles of mastication

CN VII: muscles of facial expression

CN VIII: hearing, nystagmus and balance

CN IX and X: palatal rise to phonation and coordinated swallowing

CN XI: sternocleidomastoid and upper trapezius strength

CN XII: tongue size and movement
III. 
Motor function

Muscle bulk

Muscle tone

Strength of upper major and lower extremity muscle groups
IV. 
Reflexes

Upper extremity DTRs (deep tendon reflexes = biceps, brachioradialis and triceps)

Lower extremity DTRs (patellar and Achilles)

Plantar (Babinski) response
V. 
Sensation

Pinprick (anterolateral spinothalamic tract) and/ or light touch (combined spinothalamic 
and posterior [dorsal] column tracts)

Joint position and / or vibration sense (posterior column tracts)

Romberg’s test
VI. 
Cerebellar function

Finger-to-nose and heel-to-shin tests

Rapid alternating movements

Gait (including heel-to-toe walking)


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Appendix H
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 06 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: The approximate total number of subjects to be enrolled in the study has been 
increased.
The primary change occurs in Section 6.1 Study Design:
Initial 
wording:
This FIH, double-blind, placebo-controlled, combined SRD/MRD phase 1 study in 
healthy subjects is designed to assess the safety and tolerability of TAK-653. 
Approximately 72 healthy male and female volunteers will be enrolled.
This study consists of 2 parts: (1) single ascending doses in 5 cohorts (SRD) and 
(2) single and multiple ascending doses in 4 cohorts (SRD/MRD). SRD/MRD 
Cohort 4 is optional; the decision to dose will be based on emerging safety, PK, and 
PD data. Each cohort will consist of 8 subjects (6 active:2 placebo). Subjects will 
be fasted for 10 hours before dosing. Cohorts may be added or removed.
Amended or 
new wording:
This FIH, double-blind, placebo-controlled, combined SRD/MRD phase 1 study in 
healthy subjects is designed to assess the safety and tolerability of TAK-653. 
Approximately 72112 healthy male and female volunteers will be enrolled.
This study consists of 2 parts: (1) single ascending doses in 5 cohorts (SRD) and 
(2) single and multiple ascending doses in 4 cohorts (SRD/MRD). SRD/MRD 
Cohort 4 is optional; the decision to dose will be based on emerging safety, PK, and 
PD data. Subjects will fast be fasted for at least 10 hours before dosing. Cohorts 
may be added or removed.
Rationale for Change: 
Given the favorable preliminary safety/tolerability data, including lack of CNS AEs, the linear PK 
profile for cohorts that have completed dosing to date, the determination from the 13-week 
monkey toxicity study that seizures are related to Cmax (thus allowing revision of the AUC NOAEL 
margin from AUC24 on the first day of dosing to AUC24 at the end of the dosing period), and a 
consequent improvement in the safety margin, further dose escalation in additional SRD and 
SRD/MRD cohorts is planned.
Section 2.0 STUDY SUMMARY also contains this change.


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Change 2: The nonclinical basis used to support dose escalation decisions has been revised.
The primary change occurs in Section 6.1.3 Dose Escalation:
Initial 
wording:
!
In any case, the predicted exposure of the highest dose administered should not 
exceed the NOAEL mean exposure achieved in females on Day 1/2 in the 
13-week GLP safety monkey study 
). If 
PK collected during a cohort shows that exposure to TAK-653 has surpassed 
the exposures at the NOAEL, lower doses will be used in subsequent cohort(s).
Amended or 
new wording:
!
In any case, the predicted exposure of the highest dose administered should not 
exceed the NOAEL mean exposure achieved in females on Day 1/2 in the 
13-week GLP safety monkey study (
). In 
a 13-week repeat-dose toxicity study conducted with TAK-653 in 
cynomolgus monkeys, test article–related toxicities occurred around tmax, 
typically within the first few days of dosing, and were considered to be 
related to the Cmax rather than to the AUC24. Therefore, the predicted 
exposure for the TAK-653 dose selected for any cohort should not exceed 
the mean Cmax value (
) achieved in female monkeys on the first 
day of dosing or the mean AUC24 value (
 achieved in 
female monkeys at the end of the dosing period at the NOAEL of 
3 mg/kg/mL in the 13-week repeat-dose toxicity study. If PK data collected 
during a cohort shows indicate that exposure to TAK-653 has surpassed the 
exposures mean 
at the NOAEL, lower doses will be used in subsequent cohort(s).
Rationale for Change: 
In the 13-week repeat-dose monkey toxicity study conducted with TAK-653, test article–related 
toxicities occurred around tmax, typically within the first few days of dosing, and were considered 
to be related to the Cmax rather than to the AUC24. Therefore, the mean Cmax value (362 ng/mL) 
achieved on the first day of dosing and mean AUC24 value (14,000 h*ng/mL) achieved at the end 
of the dosing period in female monkeys at the NOAEL of 3 mg/kg/mL in the toxicity study are 
more appropriate exposure caps to support dose escalation decisions.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Section 6.2.1 Study Design.
!
Section 6.2.2 Dose.
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Change 3: The summary of the 13-week repeat-dose monkey toxicity data has been revised.
The primary change occurs in Section 4.1 Background:
Initial 
wording:
A draft report is available of the results of a 13-week repeat-dose toxicity study in 
cynomolgus monkeys, dosed at 0, 0.3, 3, and 10 mg/kg/day; except for some 
exceptions, the study was Good Laboratory Practice (GLP)-compliant. In this 
study, monkeys were monitored continuously for EEG and EMG activity and 
behavior the first 28 days of dosing and toxicokinetics were evaluated after the 
first, 29th, and 90th dose administrations and after a convulsion was observed. 
…
Given the apparent intolerability of 10 mg/kg/day in female monkeys, the high 
dose in this group was reduced to 6 mg/kg/day. At 6 mg/kg/day on Day 7, 1 female 
showed clinical signs of a convulsion but examination of the EEG, EMG, and 
video-recorded behavior of the animal indicated that it was likely to be an episode 
of ataxia rather than a generalized seizure as it was not accompanied by EEG signs 
of seizure activity (although a partial seizure could not be ruled out). On Day 79 of 
dosing the same monkey showed clinical signs of a convulsion; as videographic 
and EEG activity were not being recorded at that time, confirmation of seizure 
activity was not possible. Therefore, the event was considered to be a seizure.
…
Overall, the draft results of the 13-week toxicity study in monkeys indicate no 
adverse effects of treatment except on clinical signs. There was no adverse effect of 
treatment on mortality, body weights, or food consumption, electrocardiography, 
ophthalmology, urinalysis, hematology, clinical chemistry, organ weights, or 
macroscopic or microscopic observations. Evaluation of videographic recordings 
of clinical signs throughout the study indicate that tremors occurred in all dose 
groups, including vehicle controls, although the incidence was increased in females 
at 10/6 mg/kg/day. Tremors were not associated with EEG changes indicative of 
seizure activity (ie, no synchrony, paroxysmal activity), were not predictive of a 
seizure, and likely represent an extension of the pharmacology of the compound. 
The NOAEL in this study was 10 mg/kg/day in males and 3 mg/kg/day in females 
based on the observation of seizure (unconfirmed by EEG) in 1 female at 
6 mg/kg/day (draft report). At the NOAEL, mean exposures in females on the first 
and last days of dosing were 362 and 825 ng/mL (Cmax) and 5940 and 
 (AUC24), respectively. 
Amended or 
new wording:
A draft report is available of the results of a 13-week repeat-dose toxicity study was 
conducted in cynomolgus monkeys, dosed at 0, 0.3, 3, and 10 mg/kg/day; except 
for with some exceptions, the study was Good Laboratory Practice 
(GLP)-compliant. In this study, monkeys were monitored continuously for EEG 
and EMG activity and behavior the first 28 days of dosing and for 24-hour periods 
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midstudy and at the end of the study; toxicokinetics were evaluated after the 
first, 29th, and 90th dose administrations and after a convulsion was observed. 
…
Given the apparent intolerability of 10 mg/kg/day in female monkeys, the high 
dose in this group was reduced to 6 mg/kg/day after a dosing holiday. At After 
the second dosing of 6 mg/kg/day on Day 7, 1 female showed clinical signs of a 
convulsion but examination of the EEG, EMG, and video-recorded behavior of the 
animal indicated that it was likely to be an episode of ataxia rather than a 
generalized seizure as it was not accompanied by EEG signs of seizure activity 
(although a partial seizure could not be ruled out). On Day 79 of dosing the same 
monkey showed clinical signs of a convulsion; as videographic and EEG activity 
were not being recorded at that time, as per protocol, EEG confirmation of seizure 
activity was not possible. However, to err on the side of safetyTherefore, the 
event was considered to be a seizure.
…
Overall, the draft results of the 13-week toxicity study in monkeys indicate no 
adverse effects of treatment except on clinical signs. There was no adverse effect of 
treatment on mortality, body weights, or food consumption, electrocardiography, 
ophthalmology, urinalysis, hematology, clinical chemistry, organ weights, or 
macroscopic or microscopic observations. Evaluation of videographic recordings 
of clinical signs throughout the study indicate that tremors occurred in all dose 
groups, including vehicle controls, although the incidence was increased in females 
at 10 and /6 mg/kg/day. Tremors were not associated with EEG changes indicative 
of seizure activity (ie, no synchrony, paroxysmal activity), were not predictive of a 
seizure, and likely represent an extension of the pharmacology of the compound. 
The NOAEL in this study was 10 mg/kg/day in males and 3 mg/kg/day in females 
based on the a clinical observation of seizure (unconfirmed by EEG) in 1 female at 
6 mg/kg/day(draft report). At the NOAEL, mean exposures in females on the first 
and last days of dosing were 362 and 825 ng/mL (Cmax) and 5940 and 
 
(AUC24), respectively.
Rationale for Change:
The report for the 13-week repeat-dose monkey toxicity study has been finalized.
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Change 4: A summary of the 13-week repeat-dose rat toxicity data has been added.
The primary change occurs in Section 4.1 Background:
Added text:
A 13-week GLP-compliant repeat-dose toxicity study was conducted in rats. 
Tonic convulsion was observed in 1 female at 200 mg/kg/day; therefore, the 
highest dose in females was reduced to 100 mg/kg/day beginning on Day 2 of 
the study. After lowering the dose to 100 mg/kg/day, no convulsions were 
observed in any group through the end of the dosing period. In addition, there 
were no test article–related abnormalities observed in clinical signs, body 
weights, food consumption, ophthalmologic examination, urine output, 
urinalysis, hematology, coagulation tests, clinical chemistry, necropsy, organ 
weights, or histopathological examination. The NOAELs in this study were 
50 mg/kg/day for males and 100 mg/kg/day for females. 
 
 
 
 
 
Rationale for Change:
To report the data from the completed 13-week repeat-dose toxicity study in rats.
Change 5: A summary of preliminary blinded safety/tolerability and PK data has been added for 
completed single-rising dose (SRD) Cohorts 1 to 5 and SRD/multiple-rising dose (MRD) Cohorts 
1 and 2.
The primary change occurs in Section 4.1 Background:
Initial 
wording:
This first-in-human (FIH) phase 1 study has been designed to mitigate the known 
risks associated with AMPA receptor potentiators as a class and the results of the 
nonclinical toxicity studies in TAK-653. Descriptions of the risk mitigation 
measures included in this study are detailed in Section 6.2 and summarized in 
Section 6.2.4.
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Amended or 
new wording:
This first-in-human (FIH) phase 1 study has been designed to mitigate the known 
risks associated with AMPA receptor potentiators as a class and the results of the 
nonclinical toxicity studies in TAK-653. Descriptions of the risk mitigation 
measures included in this study are detailed in Section 6.2 and summarized in 
Section 6.2.4.
…
4.3 Risk-Benefit Profile
This FIH phase 1 study has been designed to mitigate the known risks 
associated with AMPA receptor potentiators as a class and the potential risks 
based on the nonclinical toxicity data and preliminary clinical data for 
TAK-653. Descriptions of the risk mitigation measures included in this study 
are detailed in Section 6.2 and summarized in Section 6.2.4. As this is a study 
in healthy subjects, there is no expected clinical benefit to the study 
participants.
To date in this study, a total of 56 subjects have been enrolled and 
administered study drug (42 active, 14 placebo) in 5 single-rising dose (SRD) 
cohorts (0.3, 1, 3, 5, and 9 mg) in Part 1 and 2 SRD/multiple-rising dose 
(MRD) cohorts (0.3 and 1 mg) in Part 2. In addition, dosing in SRD/MRD 
Cohort 3 (3 mg) has started. A blinded review of the preliminary safety and 
tolerability data for these completed cohorts indicate that TAK-653 was 
generally well tolerated at single doses up to 9 mg in Part 1 and multiple doses 
up to 1 mg QD in Part 2. No serious treatment-emergent adverse events 
(TEAEs) or CNS-type adverse events (AEs) were reported. No clinically 
meaningful clinical laboratory, vital sign, electrocardiogram (ECG), or 
physical examination results were reported. Preliminary PK data from these 
cohorts indicate that TAK-653 exhibits linear PK across the dose range tested.
Rationale for Change:
To provide support for further dose escalation based on blinded review of the available 
preliminary data collected in the study to date.
The following sections also contain this change:

Section 6.2.2 Dose.

Table 6.a Summary of SRD Dose Cohorts.

Table 6.b Summary of SRD/MRD Dose Cohorts.


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Change 6: The need for an independent medical reviewer from the sponsor to endorse dose 
escalation decisions has been removed.
The primary change occurs in Section 6.1.3 Dose Escalation:
Initial 
wording:
All decisions concerning dose escalation will be made by Takeda (at a minimum, 
the clinical science representative and pharmacovigilance physician, or appropriate 
delegates) and the principal investigator. The investigator and subjects will remain 
blinded throughout the study, but at the completion of each cohort, Takeda 
personnel may be unblinded to analyze data considered necessary to determine 
subsequent doses. Such decisions will need to be endorsed by an independent 
medical reviewer (a Takeda physician who is not involved with the conduct of the 
study) after reviewing all available safety, tolerability, PK, and PD data from the 
previous cohort.
Amended or 
new wording:
All decisions concerning dose escalation will be made by Takeda (at a minimum, 
the clinical science representative and pharmacovigilance physician, or appropriate 
delegates) and the principal investigator. The investigator and subjects will remain 
blinded throughout the study, but at the completion of each cohort, Takeda 
personnel may be unblinded to analyze data considered necessary to determine 
subsequent doses. Such decisions will need to be endorsed by an independent 
medical reviewer (a Takeda physician who is not involved with the conduct of the 
study) after reviewing all available safety, tolerability, PK, and PD data from the 
previous cohort.
Rationale for Change:
Text has been amended to reflect the requirements in the most current sponsor Standard Operating 
Procedure on dose escalation.
Change 7: Text has been added to clarify that study drug–related central nervous system 
disorders/adverse events may result in the stopping of dose escalation or study drug dosing.
The primary change occurs in Section 6.1.3 Dose Escalation:
Initial 
wording:
Dose escalation will be stopped if an SAE or 2 severe or clinically significant AEs 
occur that can be considered related to study drug.
Amended or 
new wording:
Dose escalation will be stopped if an SAE or 2 severe or clinically significant AEs 
occur that can be considered related to study drug.
Dose escalation and study drug administration will be stopped if an SAE or 
2 severe or clinically significant AEs, including CNS disorders/AEs 
(Section 6.3.1), are observed in a particular cohort and are considered by the 
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Rationale for Change:
To be more descriptive in the type of TEAEs that would result in stopping dose escalation or study 
drug administration.
Section 6.3.1 Criteria for Premature Termination or Suspension of the Study also contains this 
change.
Change 8: Change in peripheral levels of the
 
 
SRD/MRD Cohort 3).
The primary change occurs in Section 5.4.3 Exploratory/Additional Endpoints:
Initial 
wording:
Additional endpoint for all cohorts:
Amended or 
new wording:
Additional endpoint for all cohorts:
Rationale for Change:
 levels in plasma and/or serum will be measured for subjects in all cohorts to explore the 
potential effect of TAK-653 on this biomarker.
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The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Section 6.1.1 Part 1: SRD.
!
Figure 6.a SRD Study Schematic.
!
Section 6.1.2 Part 2: SRD/MRD.
!
Figure 6.b SRD/MRD Study Schematic, Footnote (d).
!
Section 6.2.1 Study Design.
!
Section 9.1.17.2
!
Table 9.e Collection of Blood Samples for Analysis of 
!
Section 9.3.3 Treatment Phase.
!
Section 9.4 Blood Volume.
!
Table 9.g Approximate Blood Volume: SRD Cohort 6 Onward.
!
Table 9.h, Approximate Blood Volume: SRD/MRD Cohorts, Footnote (b).
!
Section 13.1.4 Pharmacodynamic Analysis.
!
Appendix B SRD Part 1 Schedule of Study Procedures: Cohort 6 Onward.
!
Appendix C SRD/MRD Part 2 Schedule of Study Procedures, Footnote (l).
Change 9: An additional blood sample collection at 168 hours postdose has been included for 
SRD Cohort 6 onward in Part 1.
The primary change occurs in Table 9.c Collection of Blood and Urine Samples for 
Pharmacokinetic Analysis:
Description
of change:
!
Row added with PK blood sampling times specifically for SRD Cohort 6 
onward.
Rationale for Change:
To more precisely characterize the t1/2,z for the higher-dose SRD cohorts.
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The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Section 6.1.1 Part 1: SRD.
!
Figure 6.a SRD Study Schematic.
!
Section 9.3.4 Study Exit.
!
Section 9.4 Blood Volume.
!
Table 9.f Approximate Blood Volume: SRD Cohorts 1 to 5.
!
Table 9.g Approximate Blood Volume: SRD Cohort 6 Onward.
!
Appendix B SRD Part 1 Schedule of Study Procedures: Cohort 6 Onward.
Change 10: Text was clarified to indicate that TAK-653 and the 
 only will be 
measured in 
 if feasible.
The primary change occurs in Section 9.1.15.3 Bioanalytical Methods:
Initial 
wording:
Plasma, urine, and 
 concentrations of TAK-653 and 
, 
if feasible, will be measured by high-performance liquid chromatography with 
tandem mass spectrometry.
Amended or 
new wording:
Plasma and urine , and 
concentrations of TAK-653 and cis/trans
 
 if feasible, and 
 concentrations of TAK-653 and 
 
, if feasible, will be measured by high-performance liquid 
chromatography with tandem mass spectrometry.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Section 9.1.15.2 Collection of 
!
Section 13.1.3.1 Concentrations in Plasma, Urine, and 
Rationale for Change:
Only TAK-653 and the 
 will be measured in 
 if feasible.
Change 11: Text has been added to indicate that screening data for subjects who have undergone 
general screening procedures (ie, panel screening) before the effective date of this protocol 
amendment may be used to assess subject eligibility for enrollment in this study.
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The primary change occurs in Section 9.3.1 Screening:
Added text:
In the event that subjects have undergone general screening assessments (ie, 
panel screening) before the effective date of this protocol amendment, the 
data from this general screening may be used to assess subject eligibility for 
enrollment in this study, provided that the procedures were performed within 
the protocol-defined Screening Period window.
Rationale for Change:
To allow enrollment into this study of subjects who have been screened by the clinical site in 
accordance with their internal approved panel screening protocol and ICF.
Change 12: The responsibilities of the investigator have been revised to reflect the updated 
International Council for Harmonisation E6(R2) Good Clinical Practice Consolidated Guideline.
The primary change occurs in Appendix D Responsibilities of the Investigator:
Added text:
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.
Rationale for Change:
The responsibilities of the investigator have been revised in the ICH E6(R2) GCP Consolidated 
Guideline.
Change 13: Procedures for bioanalytical and pharmacogenomic sample collecting, processing, 
and shipping have been removed and referenced to the laboratory manual instead.
The primary change occurs in Appendix F (Collection, Storage, and Shipment of Bioanalytical 
Samples) and Appendix G (Collection, Shipment, and Storage of Pharmacogenomic Samples):
Deleted text:
Appendix F Collection, Storage, and Shipment of Bioanalytical Samples 
Instructions for Processing of Plasma Samples for Pharmacokinetic Analysis 
of TAK-653 and Metabolites
Collect 4 mL of venous blood for the plasma into a chilled Becton-Dickinson 
Vacutainer. All TAK-653 and 
 blood samples should be 
collected into Vacutainers containing K2EDTA.
Gently invert the Vacutainer several times to mix the additive with the collected 
blood prior to centrifugation and place immediately on ice.
Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 (RCF) at 
4°C. Note: if using a collection device other than Becton-Dickinson, refer to 
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CONFIDENTIAL
manufacturer’s instruction for proper centrifugation force and time.
Immediately following centrifugation, gently remove plasma from the packed 
cells. To ensure a more homogeneous sample, all plasma should first be transferred 
into 1 aliquot. From there, split the plasma evenly between the 2 aliquots. A 
minimum of 1.2 mL needs to be obtained for each sample. Labeling may include 
protocol number (TAK-653-1001), sample matrix (ie, plasma), 4-digit 
randomization number, Part 1 or 2, profile day and time, and either “SET 1” (for 
original sample) or “SET 2” (for duplicate sample).
Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately 20°C or lower until shipment to PPD, Richmond, Virginia, USA.
No more than 45-60 minutes should elapse between blood collection and freezing 
the plasma sample.
Instructions for Processing of Urine Samples for Pharmacokinetic Analysis of 
TAK-653 and Metabolites
Collect urine into polypropylene containers. During the collection interval, the 
urine will be stored at approximately 4°C. The urine collection will require the use 
10% (w/v) Tween80 to prevent compound absorption to collection/storage 
containers.
At the end of each void, mix the urine, transfer to a graduated cylinder, measure 
and record the volume. For the urine sample in the graduated cylinder intended for 
bioanalysis, measure “X” amount of 10% Tween80 solution (10% Tween80 by 
weight in water) into a separate graduated cylinder (where “X” equals 1 part in 10 
of the urine volume in the cylinder).
Pour ¾ of the “X” amount of the 10% Tween80 solution into the graduated cylinder 
containing the subject’s urine. Mix and transfer to the bioanalysis sample jug for 
the time period.
With the remaining 10% Tween80 solution, rinse the original collection jug and 
combine with the sample in the bioanalysis sample jug for the time period.
Store the collection jug at approximately 4°C during the collection period. Record 
the final volume of the urine fortified with the 10% Tween80 solution.
Mix well and measure the urine volume within 2 hours of the end of the collection 
period. 
Transfer approximately 10 mL aliquots of urine in duplicate into appropriate 
polypropylene containers. Container should be filled to within 60%-90% of the 
nominal volume. Labeling should include protocol number (TAK-653-1001), 
4-digit randomization number, Part 1 or 2, profile day and time, and either “SET 1” 
(for original sample), or “SET 2” (for duplicate sample).
Freeze the urine samples immediately and store frozen at approximately -80°C or 


TAK-653
Study No. TAK-653-1001
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Protocol Incorporating Amendment No. 06
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CONFIDENTIAL
lower. Keep samples frozen at approximately -80°C or lower until shipment to 
(PPD, Richmond, Virginia, USA).
Instructions for processing 
 samples will be provided in a laboratory 
manual.
Shipping of Plasma, Urine, and 
 Samples
The following instructions are recommended unless they differ from the site’s 
SOPs for labeling, packaging, or shipping of PK samples.
1. Biological samples should be shipped on dry ice to prevent thawing during 
transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, 
and at least 2 days prior to a national holiday, in order to minimize the 
possibility of samples in transit over a weekend or holiday. If duplicate samples 
are to be shipped, send SET 1 samples and await confirmation of arrival before 
shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each 
subject’s samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) 
containing additional absorbent material.
5. Using a permanent marker, write the 4-digit randomization number, sample 
matrix (ie, plasma, urine, or 
 number of samples, and “SET 1” on each 
self-sealing bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that 
samples are double bagged. Duplicate SET 2 samples should be returned to the 
freezer for storage. Repeat steps 1 through 4 above when preparing duplicate 
samples for shipment, except self-sealing bags should be marked “SET 2.”
7. An inventory of individual samples should accompany each shipment and 
should include the Sponsor’s name (Takeda), study drug (TAK-653), protocol 
number (TAK-653-1001), investigator’s name, sample type (ie, plasma, urine, 
or 
 subject’s 4-digit randomization number, Part 1 or 2, profile collection 
day and time, and intended sample storage conditions. When duplicate SET 2 
samples are being shipped, make a copy of the original SET 1 sample inventory 
and mark as “SET 2.” Place the inventory paperwork into a large self-sealing 
bag. SET 1 samples will be shipped first on dry ice, followed by shipment of 
duplicate SET 2 samples after SET 1 samples have been received by the 
analytical laboratory.
8. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of 
transit) to safeguard against longer than expected shipping times and delays. 
Use newspaper or other material to insulate the double-bagged samples from 
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CONFIDENTIAL
direct contact with the dry ice. Place the sample bundles into a Styrofoam 
container (or other suitable container) and fill the excess space with dry ice 
slabs or ice pellets (preferably the latter). Make a note of the estimated weight 
of the dry ice used per shipping container.
9. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice 
in the Styrofoam container. Place the lid on the Styrofoam container and seal 
completely with strapping tape. Place the Styrofoam container in a cardboard 
shipping carton and seal securely with strapping tape.
10. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
11. Affix an address label to each shipping carton. Complete the address label with 
the following information:
Plasma, Urine, and 
 Samples for TAK-653
PPD
Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP 
FROZEN on each carton. Specify a return address and contact person on the 
carton.
Obtain the airway bill number and a receipt of shipment from the carrier.
After shipping of the TAK-653 samples, please contact
to notify her of next day delivery. When contacting, 
provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
 Processing and Shipping Samples
Instructions for processing and shipping biomarker 
serum and plasma 
samples will be provided in a laboratory manual.
 
PPD
PPD
PPD
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Samples
Rationale for Change:
Detailed procedures for PK, PD, and PGx sample collecting, processing, and shipping are 
provided in the laboratory manual.
The following sections also contain this change:
!
Section 9.1.15.1 Collection of Plasma and Urine for Pharmacokinetic Sampling.
!
Section 9.1.15.2 Collection of 
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CONFIDENTIAL
Change 14: The sponsor signatories for this protocol have been updated.
The primary change occurs in Section 1.2 Approval:
Initial 
wording:
The responsible Takeda medical officer and other signatories are shown below. 
Electronic signatures are located on the last page of the document.
Amended or 
new wording:
The responsible Takeda medical officer and other signatories are shown below. 
Electronic signatures are located on the last page of the document.
Rationale for Change:
Signatories were updated to reflect current signature requirements at the sponsor.
PPD
PPD


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PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 


• 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 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in Healthy Subjects
NCT Number: NCT02561156
 SAP Approve Date:  22 August 2017
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 information or company confidential information. 
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
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-653-1001
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and 
Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in Healthy 
Subjects
PHASE 1 TAK-653 ESCALATING SINGLE AND MULTIPLE DOSE STUDY IN 
HEALTHY SUBJECTS
Version: Final
Date: 22 August 2017
Prepared by:
Prepared by:
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.
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1.1
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.


TAK-653-1001
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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..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective......................................................................................................7
4.2
Secondary Objective..................................................................................................7
4.3
Exploratory/ Additional Objectives............................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................12
5.1
Primary Endpoints ...................................................................................................12
5.2
Secondary Endpoints ...............................................................................................12
5.3
Exploratory/ Additional Endpoints...........................................................................13
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................15
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................16
7.1
General Principles....................................................................................................16
7.1.1
Missing Data......................................................................................................16
7.1.2
Derived Datasets and Variables..........................................................................16
7.1.3
Definition of Study Days and Baseline...............................................................16
7.2
Analysis Sets ...........................................................................................................17
7.3
Disposition of Subjects ............................................................................................17
7.4
Demographic and Other Baseline Characteristics.....................................................17
7.5
Study Drug Exposure and Compliance.....................................................................18
7.6
Efficacy Analysis.....................................................................................................18
7.7
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................18
7.7.1
Plasma Pharmacokinetic Concentrations ............................................................18
7.7.2
Plasma Pharmacokinetic Parameters ..................................................................19
7.7.3
................................................................21
7.7.4
Urine Pharmacokinetic Concentrations...............................................................22
7.7.5
Urine Pharmacokinetic Parameters.....................................................................22
7.7.6
 Pharmacodynamic Analysis ....................................................................23
7.7.7
 Pharmacodynamic Parameters ...................................................................24
7.8
Other Outcomes.......................................................................................................24
7.9
Safety Analysis........................................................................................................24
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7.9.1
Adverse Events ..................................................................................................24
7.9.2
Clinical Laboratory Evaluations .........................................................................25
7.9.3
Vital Signs .........................................................................................................25
7.9.4
12-Lead ECGs ...................................................................................................26
7.9.5
Safety EEG........................................................................................................26
7.9.6
Other Observations Related to Safety.................................................................26
7.10
Interim Analysis ......................................................................................................27
7.11
Changes in the Statistical Analysis Plan...................................................................27
8.0
REFERENCES..............................................................................................................28
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................29
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................31
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms.........................32


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3.0
LIST OF ABBREVIATIONS
λz
terminal disposition phase rate constant
τ
dosing interval
%CV
percent coefficient of variation
Aet
amount of drug excreted in urine from time 0 to time t
Aeτ
amount of drug excreted in urine during a dosing interval
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC24
AUC from the time 0 to time 24 hours postdose
AUClast
AUC from time 0 to time of the last quantifiable concentration
AUC∞
AUC from time 0 to infinity
AUCτ
AUC during a dosing interval
AUEC
area under the effect-time curve
BMI
body mass index
Cav,ss
average plasma concentration during a dosing interval, at steady state
CL/F
apparent clearance after extravascular administration
CLR
renal clearance
CPAP
Clinical Pharmacology Analysis Plan
Cmax
maximum observed plasma concentration
Cmax,ss
maximum observed plasma concentration during a dosing interval, at steady state
CSF
cerebrospinal fluid
ECG
electrocardiogram
EEG
Electroencephalogram
Emax
maximum observed effect
fe
fraction of administered dose of drug excreted in urine from time 0 to time t
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MR(AUC)
ratio of AUC values of the metabolite compared to parent
MR(Cmax)
ratio of Cmax values of the metabolite compared to parent
MRD
multiple-rising dose
PD
pharmacodynamics
PK
pharmacokinetics
PT
preferred term
PTE
pretreatment event
qEEG
quantitative electroencephalogram
Rac(AUC)
accumulation ratio based on AUCτ
Rac(Cmax)
accumulation ratio based on Cmax
SAE
serious adverse event
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SOC
system organ class
SRD
single-rising dose
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
WHO
World Health Organization


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4.0
OBJECTIVES
4.1
Primary Objective
To determine the safety and tolerability of TAK-653 when administered as oral, single and 
multiple doses at escalating dose levels in healthy subjects.
4.2
Secondary Objective
To determine the pharmacokinetics (PK) of TAK-653 when administered as single and multiple 
oral doses at escalating dose levels in healthy subjects.
4.3
Exploratory/ Additional Objectives
4.4
Study Design
This first-in-human, double-blind, placebo-controlled, combined single-rising dose 
(SRD)/multiple-rising dose (MRD) phase 1 study in healthy subjects is designed to assess the 
safety, tolerability, and PK of TAK-653. Approximately 112 healthy male and female volunteers 
will be enrolled.
This study consists of 2 parts: (1) single ascending doses in 5 cohorts (SRD) and (2) single and 
multiple ascending doses in 4 cohorts (SRD/MRD). Each cohort will consist of 8 subjects
(6 active:2 placebo). Subjects will fast for at least 10 hours before dosing. Cohorts may be added
or removed. The decision to dose will be based on emerging safety, PK, and PD data.
Follow-up assessments will occur approximately 14 days after the last dose of study drug to
inquire about any ongoing adverse events (AEs) or serious adverse events (SAEs), worsening of 
AEs or SAEs, or development of new AEs or SAEs, and concomitant medications taken since 
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final dose. Follow-up will occur by telephone unless abnormal, clinically significant findings are 
observed upon discharge or at the investigator’s discretion. Subjects should then be brought back 
to the clinic for re-evaluation.
End of trial (study completion date) will be based on the final data collection date for the entire
study which is the Follow-up call/visit.
Part 1: SRD
Subjects will be enrolled in SRD Cohorts. Sentinel dosing will be used for each SRD Cohort. 
The first 2 subjects (1 active: 1 placebo) in each Cohort will receive either TAK-653 or placebo 
in parallel, followed by a minimum 24-hour gap to ensure adequate evaluation of safety and 
tolerability prior to administering the same dose of TAK-653 or placebo to the remaining 
subjects within the Cohort (5 active: 1 placebo). Dosing of the remaining subjects will proceed in 
a staggered fashion with no more than 3 subjects being dosed at a time and having an 
approximate 24-hour gap before the next group of subjects is dosed. Each dose cohort will be 
examined sequentially to ensure adequate evaluation of all available safety, tolerability, PK, and 
PD data prior to administering the next dose level.
Part 1: SRD Study Schematic
Pretreatment Period
Treatment Period
Follow up
(d)
Screening
Check-in
Assessments
(a)
TAK-653 Dosing
Study Assessments 
(a) (b) (c)
Safety and 
PK 
Assessments
(a) (c)
PK 
Assessments
PK 
Assessments/ 
Study Exit (a)
Day -28 
to -2
Day -1
Day 1
Days 2-5
Day 6 
(Cohorts 1-5) 
Days 6-7 
(Cohort 6 
onward)
Day 7 
(Cohorts 1-5) 
Day 8 (Cohort 
6 onward)
Day 14 (±2)
Confinement
(a) EEG assessments are scheduled on Days -1, 1, 2, and 5, at Study Exit, and at ET.
(b) Study assessments include PK sample collection throughout.
(c) 
(d) Follow-up will occur by telephone unless abnormal, clinically significant findings are observed upon discharge. 
In this case or at investigator’s discretion, subjects should return to the clinic for re-evaluation.
The planned first dose level to be studied is 0.3 mg for SRD Cohort 1. The actual choice of the 
dose levels in subsequent Cohorts will occur after the full review of all available blinded safety, 
tolerability, PK, and PD data in the preceding cohorts. If necessary, the sponsor team (Takeda 
only) may unblind the data and perform additional analyses for an informed dose-escalation 
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decision. The next dose level may be higher, lower, or remain the same as the preceding dose 
level. If the dose is not increased in the next Cohort, staggered dosing is not necessary.
Part 1: Summary of SRD Dose Cohorts
TAK-653 Single Dose (b) (c)
Cohort (a)
Planned
Actual
No. of Subjects
1
0.3 mg
0.3 mg
6 TAK-653
2 placebo
2
X mg
1.0 mg
6 TAK-653
2 placebo
3 (food-effect cohort) 
(d)
X mg
3.0 mg
6 TAK-653
2 placebo
4
X mg
5.0 mg
6 TAK-653
2 placebo
5
X mg
9.0 mg
6 TAK-653
2 placebo
6
X mg
18.0 mg
6 TAK-6536
2 placebo
(a) Sentinel dosing will occur at the start of each Cohort in the SRD. After the investigator and sponsor review the 
24-hour safety and tolerability data, the remaining subjects can be dosed in a staggered fashion (no more than 
3 subjects at a time). A 24-hour gap will follow each subsequent administration to evaluate safety and tolerability 
data.
(b) Dose escalation to Cohort 2 onward will be based on review of safety, tolerability, and available PK and PD data 
from the previous cohort(s).
(c) TAK-653 or placebo will be administered orally to subjects after an overnight fast of approximately 10 hours.
(d) Subjects from SRD Cohort 3 (fasted conditions) will return to receive the same dose of TAK-653 following a 
standard meal.
Subjects in the SRD Cohorts will be kept in the study unit for approximately 96 hours after 
dosing for safety and PK assessments before discharge. The total confinement period is 5 days. 
Subjects in Cohorts 1 to 5 will return to the clinic on Days 6 and 7 for additional PK 
collections. Subjects in Cohort 6 onward will return to the clinic on Days 6, 7, and 8 for 
additional PK collections. If the t1/2z of TAK-653 for any cohort differs significantly from what 
was predicted, the duration of confinement may also be adjusted. Subjects in the food effect 
cohort will be confined twice for 5 days each for a total of 10 days. For SRD Cohort 6 onward, 
 
ollow-up assessments for all subjects 
in the SRD study arm will occur on Day 14 (±2).
Part 2: SRD/MRD
Progression into the SRD/MRD Part 2 will occur only after review of all available safety, 
tolerability, PK, and PD data collected in at least the first 3 SRD cohorts. The actual dose in 
the SRD/MRD Cohorts will not be administered unless there is acceptable safety, tolerability, 
PK, and PD data at the same or higher dose level after a single dose in the SRD Cohorts. If 
necessary, the sponsor team (Takeda only) may unblind the data and perform additional 
analyses for an informed dose-escalation decision. The potential for accumulation, and its 
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impact on the likelihood of reaching the no-observed-adverse-effect level exposure cap, will 
be taken into account when selecting doses for the MRD.
A single dose of TAK-653 or placebo will be administered on Day 1 followed by 
approximately 120 hours for safety, tolerability, PK, and PD assessments. Once daily (QD) 
multiple dosing will begin on Day 6 and continue through Day 18 (13 days). Initiation of the 
multiple-dose phase on Day 6 may be adjusted based on emerging safety, PK, and/or PD data. 
Neither sentinels nor staggered dosing are used in the SRD/MRD. Subjects in the SRD/MRD 
Cohorts will be kept in the study unit for at least 72 hours after the last dose for safety 
assessments before discharge. The total confinement period planned is 21 days. Cohort 4 as 
well as any additional cohorts are optional (Note: at the time of this SAP, Cohort 4 has been 
initiated), to be used if emerging safety and/or PK or PD data warrant further study at a 
different dose. Follow-up assessments will occur on Day 31 (±2).
Each dose cohort will be examined sequentially to ensure adequate evaluation of all available
safety, tolerability, PK, and PD data prior to administering the next dose level.
 
Part 2: SRD/MRD Study Schematic
Pretreatment Period
Treatment Period
Follow-
up (e)
Screening
Check-in
Baseline 
Assessments
TAK-653
Single Dose
Study 
Assessments 
(a) (b) (d)
Safety and 
PK 
Assessments 
(d)
TAK-653
QD dosing
Study 
Assessments (a) 
(b) (c) (d)
Safety and 
PK
Assessments
Study Exit
Day -28 to
-2
Day -1
Day 1
Days 2-5
Days 6-18
Days 19-20
Day 21
Day 31
(±2)
Confinement
(a) Study assessments include PK sample collection throughout.
(b) EEG assessments are scheduled on Days 1, 11, 18, and ET.
(c)
(d) 
(e) The Follow-up assessments will occur by telephone unless abnormal, clinically significant findings are observed 
upon discharge. In this case or per investigator’s discretion, subjects should return to the clinic for re-evaluation.
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Part 2: Summary of SRD/MRD Dose Cohorts
Planned TAK-653 Dose (a) (b) (c)
Cohort
Planned
Actual
Subjects
1
X mg
0.3 mg
6 TAK-653
2 placebo
2
X mg
1.0 mg
6 TAK-653
2 placebo
3
X mg
3.0 mg
6 TAK-653 
2 placebo
4
X mg
6.0 mg
6 TAK-653
2 placebo
5
X mg
9.0 mg
6 TAK-653
2 placebo
(a) Dosing for the first SRD/MRD Cohort will not begin until there is acceptable safety, tolerability, and available 
PK and PD data at the same or higher dose level after a single dose from at least the first 3 SRD Cohorts. Dose 
escalation to subsequent Cohorts will be based on review of safety, tolerability, and available PK and PD data from 
previous Cohorts. The subsequent dose level may be higher, lower, or the same as the preceding dose level.
(b) In each Cohort, a single dose will be administered on Day 1 followed by 120 hours of safety, tolerability, PK,
and PD assessments. QD multiple doses will proceed from Day 6 through Day 18.
(c) TAK-653 or placebo tablets will be administered orally to subjects after an overnight fast of at least 10 hours.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints will be the following safety variables:

Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).

Percentage of subjects who discontinue due to an AE.

Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once post-dose.

Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements 
at least once post-dose.

Percentage of subjects who meet the markedly abnormal criteria for safety electrocardiogram 
(ECG) parameters at least once post-dose.

Percentage of subjects who experience clinically significant abnormal changes in EEG 
measurements at least once post-dose.

Columbia-Suicide Severity Rating Scale (C-SSRS):
–
Treatment-emergent suicidal ideation compared to Baseline, as measured by an increase 
in suicidal ideation category (1-5 on the C-SSRS) during treatment from the maximum 
suicidal ideation category at Baseline, or any suicidal ideation during treatment if there 
was none at Baseline.
–
Treatment-emergent suicidal behavior compared to Baseline, as measured by an increase 
in suicidal behavior category (6-10 on the C-SSRS) during treatment from the maximum 
suicidal behavior category at Baseline, or any suicidal behavior during treatment if there 
was none at Baseline.
5.2
Secondary Endpoints
The secondary endpoints include the following PK parameters of TAK-653:

Cmax (Day 1 for all Cohorts and Day 6 for SRD/MRD Cohorts).

Maximum observed steady-state plasma concentration during a dosing interval (Cmax,ss)
(Day 18 for SRD/MRD Cohorts).

Time to reach Cmax (tmax) (Day 1 for all Cohorts and Day 18 for SRD/MRD Cohorts).

Area under the plasma concentration-time curve (AUC) from time 0 to time of the last 
quantifiable concentration (AUClast) (Day 1 for all Cohorts).

AUC from time 0 to infinity (AUC∞) (Day 1 for all Cohorts).

AUC during a dosing interval (AUCτ) (Day 6 and Day 18 for SRD/MRD Cohorts).


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5.3
Exploratory/ Additional Endpoints
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size chosen of 8 subjects in each Cohort (6 active: 2 placebo) is considered to be
sufficient for evaluation of safety, tolerability, and PK of each cohort. The sample size was not
based on statistical power considerations.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles
All study-related raw and derived data will be presented in data listings as appropriate. 
Continuous data will be summarized using number of subjects (N), mean, standard deviation 
(SD), median, minimum, and maximum, where appropriate. Where indicated, coefficient of 
variation (%CV) and geometric mean will also be included in the summary of continuous data. 
Categorical data will be summarized using the number and percentage of subjects for each 
category where appropriate.
All statistical tests will be 2-tailed at =0.05 level for significance unless otherwise stated. The 
p-values less than or equal to (when rounded to 3 digits) are reported as “significant”. The 
phrase “no significant difference” indicates that all p-values for the tests are greater than . All 
computations will be performed prior to rounding.
Subjects who take placebo in each cohort group will be pooled together in all safety summaries 
for each part (Part 1 and Part 2) and will be analyzed as one placebo group.
7.1.1
Missing Data
There will be no imputation of incomplete or missing data. Decisions regarding inclusion or 
exclusion of data from an analysis for subjects who are noncompliant with the dose schedule, or 
who have incomplete data, will be made on a case-by-case basis, but the data will be presented in 
data listings regardless.
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero for 
summarizing concentration values and deriving PK parameters. 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.
7.1.2
Derived Datasets and Variables
Derived datasets will be generated according to CDISC guidance documents: Analysis Data 
Model (ADaM) Implementation Guide, Version 1.0 (17 Dec 2009); ADaM Data Structure for 
Adverse Event Analysis, Version 1.0 (10 May 2012).
7.1.3
Definition of Study Days and Baseline
For all safety endpoints, Baseline is defined as the last non-missing measurement prior to first 
dose of study drug for Part 1 SRD Cohorts and Part 2 SRD/MRD Cohorts. Baseline is defined as 
the last non-missing measurement prior to the first dose of study drug in each period (fed and 
fasted) for Part 1 Food Effect Cohort. Study day will be calculated relative to the date of the first 
dose in the study. 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.


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7.2
Analysis Sets
Safety Set
The safety set will consist of all subjects who are enrolled and 
received 1 dose of study drug. Subjects in this analysis set will be
used for demographic, other baseline characteristic, and safety
summaries.
Randomized Set
The randomized set will consist of all subjects who are enrolled 
and randomized.
PK Set
The PK set will consist of all subjects who receive study drug and
have at least 1 measurable plasma concentration or amount of 
drug in the urine.
PD Set
The PD set will consist of all subjects who receive study drug and 
have at least 1 postdose PD measurement.
If any subjects are found to be noncompliant in dosing schedule or to have incomplete data, a
decision will be made on a case-by-case basis as to their inclusion in the analysis but data for 
these subjects will be presented in the data listings.
7.3
Disposition of Subjects
Number of subjects randomized by site will be summarized separately by pooled placebo, each 
TAK-653 dose level, pooled TAK-653, and overall total for each part.
The number and percentage of subjects, who are randomized but not treated, complete study 
drug, prematurely discontinue study drug and study visits will be summarized by pooled placebo, 
each TAK-653 dose level, pooled TAK-653, and overall total for each part for subjects in the 
Randomized Set. In addition, the number and percentage of subjects will be summarized for each 
reason of discontinuation of study drug and study visits by pooled placebo, each TAK-653 dose 
level, pooled TAK-653, and overall total for each part. Subjects’ study completion data, 
including reasons for premature termination, will be listed by dose level for all subjects.
The number and percentage of subjects who comprised each analysis set will be summarized by 
pooled placebo, each TAK-653 dose level, pooled TAK-653, and overall total for each part.
7.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics (caffeine consumption, smoking status, and 
female reproductive status) will be summarized by pooled placebo, each TAK-653 dose level, 
pooled TAK-653, and overall total for each part, and by overall total for combined Part 1 and 
Part 2. Summary statistics (N, mean, SD, median, minimum, and maximum) will be generated 
for continuous variables (eg, age, height, weight and BMI), and the number and percentage of 
subjects within each category will be presented for categorical variables (eg, gender, race, and 
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For each part, demographic variables of screen failure subjects and reasons for screen failure will 
be summarized for all 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
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all subjects. 
Summaries of PK plasma concentration and exposure data will be provided by TAK-653 dose 
level as well as listed in data listings. No other summary statistics for the extent of exposure to 
study drug or compliance calculations will be performed for this study.
7.6
Efficacy Analysis
Not applicable.
7.7
Pharmacokinetic/Pharmacodynamic Analysis
7.7.1
Plasma Pharmacokinetic Concentrations
Collection of Blood Samples for PK Analysis (All SRD Cohorts)
Sample Type
Dosing Day
Scheduled Time (hours)
Plasma
1
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 
3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120 and 144 hours postdose.
Additional collection at 168 hours postdose for Cohort 6 onward.
Collection of Blood Samples for PK Analysis (All SRD/MRD Cohorts)
Sample 
Type
Dosing Day
Scheduled Time (hours)
Plasma
1
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 
3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 and 120 (a) hours postdose.
Plasma
6
0.5, 1, 2, 4, 6, 8, 12, 16, and 24 (b) hours postdose.
Plasma
12, 14, 16
Predose (within 15 minutes prior to dosing) (and following 
collection procedure on Day 12 (SRD/MRD Cohort 3 only).
Plasma
18
Predose (within 15 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 
3, 4, 6, 8, 10, 12, 16, and 24 hours postdose.
(a) The 120-hour sample must be collected before dosing on Day 6.
(b) The 24-hour sample must be collected before dosing on Day 7.
For each part, the concentration of TAK-653, 
in plasma will be 
summarized by TAK-653 dose level, Day, and period (fasted vs fed) over each scheduled 
sampling time using descriptive statistics (N, arithmetic mean, SD, median, minimum, and 
maximum). Individual plasma concentration data versus time will be presented in a data listing.
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Blood samples for placebo will not be analyzed by the bioanalytical laboratory except for 2 
samples per subject receiving placebo, 1 predose and the other around the expected time at which 
Cmax occurred (as emerging from the actual measurement of the samples of the first dose group) 
to ensure from a safety perspective that no additional subjects were on active treatment. These 
data will be listed but not summarized.
For each part, individual concentrations of TAK-653, 
 in plasma will 
be plotted by actual time on linear and semilogarithmic scales. Plots of mean TAK-653, 
 
plasma concentrations versus nominal time will also be provided on linear and 
semilogarithmic scales.
7.7.2
Plasma Pharmacokinetic Parameters
The PK parameters of plasma TAK-653 and its metabolites 
 will be 
determined from the concentration-time profiles for all evaluable subjects. Actual sampling times, 
rather than scheduled sampling times, will be used in all computations involving sampling times. 
The following PK parameters will be calculated using non-compartmental analysis using 
Phoenix WinNonLin version 6.4 or higher.
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PK Parameters for TAK-653, 
 
Symbol/Term
Definition
AUC24
Area under the plasma concentration-time curve from the time 0 to time 24 hours postdose. 
AUCτ
Area under the plasma concentration-time curve during a dosing interval 
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration.
Cav,ss
Average plasma concentration during a dosing interval, at steady state.
Cmax
Maximum observed plasma concentration.
Cmax,ss
Maximum observed plasma concentration during a dosing interval, at steady state.
CL/F
Apparent clearance after extravascular administration, calculated using the observed value 
of the last quantifiable concentration (TAK-653 only).
λz
Terminal disposition phase rate constant.
tmax
Time of first occurrence of Cmax.
(a) 
.
Dose-normalized AUC, Cmax, and Cmax,ss will also be calculated. Additional information 
regarding the plasma PK analysis and plasma PK parameter calculation and presentation will be 
provided in the Clinical Pharmacology Analysis Plan (CPAP). Additional plasma PK parameters 
may be calculated if necessary, in accordance with the CPAP.
Descriptive statistics (N, arithmetic mean, SD, median, minimum, maximum and %CV) will be 
used to summarize the plasma PK parameters for TAK653, 
 by 
TAK-653 dose level, Day, and period (fasted vs fed) for each part. In addition, geometric mean 
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and %CV will be computed for Cmax and AUCs. Individual plasma PK parameters will be 
presented in a data listing for each part. 
For each part, scatter plots of individual plasma TAK-653 ln-transformed Cmax and AUCs 
versus ln-transformed dose will be provided (fasted cohorts only). 
Additionally, box plots of TAK-653 dose-normalized Cmax and AUCs versus dose will be 
provided for each part (fasted cohorts only). Box plots of TAK-653 Cmax and AUCs comparing 
fasted versus fed cohorts will also be provided.
Dose proportionality will be tested for SRD cohorts (fasted cohorts only) on Day 1 and for 
SRD/MRD cohorts after multiple dosing on Day 18 for TAK-653 Cmax and AUCs using a power 
model. The power fit will be assumed as described by the following equation:
ln( 	
	
) =  +  ln() +   
where #∃is the intercept and #% is the slope. The dose proportionality will be declared when the 
90% confidence interval for #% lies entirely within the critical region.
1 + ln(0.80)
ln(
)
, 1 + ln(1.25)
ln(
)    
where r is the ratio of the highest and the lowest dose in this study. This criterion implies that the 
90% CI for the ratio of the central values of PK parameter of interest from the highest dose to the 
lowest dose is contained completely within the bioequivalence range of (0.80, 1.25) [2]. Plots of
ln(AUC) or ln(Cmax) vs ln(Dose) may also be used to illustrate dose proportionality or lack of it.
A power model will be performed to test whether the slope=1 in the power model and whether 
the point estimate of the slope is significantly different from 0 or not.
The effect of food on the PK of TAK-653 will be evaluated via a paired t-test. The point 
estimates and 90% CIs for the ratio of Cmax and AUC central values for TAK-653 tablets 
administered after fed conditions vs those obtained in the fasted state will be determined. The 
food effect on tmax will also be evaluated using a non-parametric Wilcoxon rank sum test.
7.7.3
All attempts will be made to have a distribution of 
 times within the prescribed 
window of 2 to 6 hours postdose on Day 12 for SRD/MRD Cohort 3; for example, the 
 
may be collected at 2 hours postdose from the first subject, 3 hours postdose from the 
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second subject, 4 hours postdose from the third subject, and 6 hours postdose from the fourth 
subject with a collection window of +1 hour for each subject.
The 
, if available, will be presented 
in a data listing. The ratio of TAK-653 
 on Day 12 to the TAK-653 plasma 
concentration on Day 12 will also be listed. TAK-653, 
 
 and TAK-653
plasma ratios will be summarized using descriptive statistics 
(N, arithmetic mean, SD, median, minimum, and maximum).
7.7.4
Urine Pharmacokinetic Concentrations
Collection of Urine Samples for PK Analysis (All SRD/MRD Cohorts)
Sample Type
Dosing Day
Time post-dose (hours)
Urine 
1
Predose (-12 to 0 hours) and at (0 to 6), (6 to 12), (12 to 24), (24 to 
48), and (48 to 72) hour intervals postdose
Urine
18
(0 to 6), (6 to 12), and (12 to 24) hour intervals postdose.
The amount of TAK-653, 
in urine will be summarized by TAK-653 
dose level and Day over each scheduled sampling interval using descriptive statistics (N, 
arithmetic mean, SD, median, minimum, and maximum). Individual urine concentration data 
versus time interval along with urine volume will be presented in a data listing.
7.7.5
Urine Pharmacokinetic Parameters
The PK parameters of urine TAK-653, 
will be determined from urine 
concentrations for all evaluable subjects. The following PK parameters will be calculated using
SAS version 9.3:
Symbol/Term
Definition
Aet
Amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval.
fe,t
Fraction of administered dose of drug excreted in urine from time 0 to time t. Molecular weight 
adjustment needed for metabolites (a).
(a) 
.
Additional information regarding the urine PK analysis and urine PK parameter calculation and 
presentation will be provided in the CPAP. Additional urine PK parameters may be calculated if 
necessary, in accordance with the CPAP.
Descriptive statistics (N, arithmetic mean, SD, median, minimum, maximum and %CV) will be 
used to summarize the urine PK parameters for TAK-653, 
 by 
TAK-653 dose level and Day. Individual urine PK parameters will be presented in a data listing.
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7.7.6
 Pharmacodynamic Analysis
Collection of Blood Samples for PD Analysis of 
Sample Type
Study Day
Time Points
SRD (Cohort 6 onward) and SRD/MRD (Cohort 3 onward)
Serum
1
Predose and at 4, 8, and 12 hours postdose
Serum
2-5
24, 48, 72, and 96 hours postdose
SRD/MRD (Cohort 3 onward)
Serum
18
Predose and at 4, 8, and 12 hours postdose
Serum
19
24 hours postdose
Note: Hemolyzed PD samples will not be redrawn.
Note: A single dose is administered on Day 1. No additional doses are administered until Day 6 when QD dosing
begins from Day 6 through 18.
PD Parameters for 
 
Symbol/Term
Definition
AUEC
Area under the effect-time curve over 96 hours after a single dose and over 24 hours after 
multiple dosing.
Emax
Maximum observed effect.
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7.7.7
 Pharmacodynamic Parameters
All the analyses, including data listings, for this section will be performed independently outside 
this document.
7.8
Other Outcomes
Not applicable. 
7.9
Safety Analysis
For each part, data for all subjects in the safety analyses set will be summarized by pooled 
placebo and each TAK-653 dose level for clinical laboratory, vital signs, ECG, and C-SSRS 
results, and by pooled placebo, each TAK-653 dose level, pooled TAK-653, and overall total for 
other safety variables. These summaries will not contain data from the food effect cohort (SRD 
Cohort 3); data from this cohort will be summarized separately by placebo fed, placebo fasted, 
TAK-653 fed, and TAK-653 fasted.
7.9.1
Adverse Events
A TEAE will be defined as an AE or a SAE that occurs or gets worse after receiving the first 
dose of study drug and within 30 days (onset date – last date of dose + 1 ≤ 30) after the last dose 
of study drug. A TEAE may also be a pretreatment event (PTE) or a concurrent medical 
condition diagnosed prior to the date of first dose of study drug that increases in severity after the 
start of dosing. Adverse events data with onset occurring more than 30 days after last dose of 
study drug (AE start date – last dose date >30) will be listed, but not included in the summary 
tables.
AE verbatim reported terms will be coded by system organ class (SOC), high-level term (HLT) 
and preferred term (PT) using MedDRA.
The following is a list of AE summary tables that will be generated:
–
Overview of TEAE.
–
TEAEs by SOC and PT at subject and event level.
–
Subject Mappings for TEAEs.
–
TEAEs by PT.
–
Non-Serious TEAEs by PT.
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–
Relationship of TEAEs to Study Drug by SOC and PT.
–
Drug-Related TEAEs by SOC and PT.
–
Intensity of TEAEs by SOC and PT.
–
Intensity of Drug-Related TEAEs by SOC and PT.
–
PTEs by SOC and PT
–
Serious PTEs by SOC and PT.
A subject with 2 or more different AEs within the same level of the MedDRA term will be 
counted only once in that level using the most extreme incident for the intensity tables, and 
relationship to study drug for the causality tables.
Data listings will be provided for all AEs (including PTEs for enrolled subjects), AEs leading to 
study drug discontinuation, AEs leading to study visit discontinuation, SAEs, and AEs resulting 
in death.
7.9.2
Clinical Laboratory Evaluations
Clinical laboratory tests include hematology, serum chemistry and urinalysis.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of clinical laboratory 
variables in SI units will be summarized for Baseline, postdose, and change from Baseline at 
each visit. Only the scheduled measurements will be included in the summary. No statistical tests 
will be performed.
Individual results for hematology and chemistry laboratory tests will be evaluated against the 
Takeda predefined laboratory markedly abnormal value (MAV) criteria (Appendix A) using the 
result and criteria in SI units. All subjects with results that meet the MAV criteria will be 
presented in a data listing. The number and percentage of subjects with at least one postdose 
markedly abnormal laboratory test result will also be summarized. The mapping of the subjects 
who meet the MAV criteria after dosing will be listed as a table. All postdose clinical laboratory
results within 7 days of the last dose, including scheduled and unscheduled measurements, will 
be included in the MAV summaries. 
All clinical laboratory data will be presented in both SI and conventional units in data listings.
7.9.3
Vital Signs
Vital signs will include body temperature (oral), supine blood pressure (resting more than 
5 minutes), respiration rate, and heart rate. Heart rate and blood pressure will be measured after 5 
minutes supine and again at 1 and 3 minutes after standing.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of these vital signs will be 
summarized for Baseline, postdose, and change from Baseline at each visit. Only the vital signs 
collected at the scheduled visits or time points will be included in the summary. No statistical 
tests will be performed for the observed vital signs.


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All individual vital signs that meet Takeda’s predefined MAV criteria (Appendix B) will be 
listed. The number and percentage of subjects with at least one postdose markedly abnormal vital 
sign measurement will be summarized. The mapping of the subjects who meet the MAV criteria 
after dosing will be listed as a table. All postdose vital signs within 7 days of the last dose, 
including both scheduled and unscheduled measurements, will be included in the MAV 
summaries.
7.9.4
12-Lead ECGs
ECG measurements include clinical interpretation, heart rate, and PR, QRS, RR, QT, and QTcF 
intervals.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of the quantitative ECG 
will be summarized for Baseline, postdose, and change from Baseline at each visit. Only the 
ECGs collected at the scheduled visits or time points will be included in the summary. No 
statistical tests will be performed for the observed ECGs.
All individual ECGs that meet Takeda’s predefined MAV criteria (Appendix C) will be listed. 
The number and percentage of subjects with at least one postdose markedly abnormal ECG 
measurement will be summarized. Subjects who meet the MAV criteria after dosing will be 
mapped to their respective qualifying ECG result. All postdose MAV ECGs within 7 days of the 
last dose, including both scheduled and unscheduled measurements, will be included in the MAV 
summaries.
For ECG interpretation data, shift tables will be provided for the number and percentage of 
subjects who change status on the interpretation from Baseline to each scheduled postbaseline 
measurement.
All ECG data will be presented in data listings.
7.9.5
Safety EEG
For EEG interpretation data, shift tables will be provided for the number and percentage of 
subjects who change status on the interpretation from Baseline to each scheduled postbaseline 
measurement.
All safety EEG data will be presented in data listings.
7.9.6
Other Observations Related to Safety
All results for the physical examination, neurological examination, meal time, telemetry, 
C-SSRS, and pregnancy avoidance counseling will be presented in data listings.
The C-SSRS has 2 domains, Suicidal Ideation, and Suicidal Behavior.
Treatment-emergent suicidal ideation compared with Baseline and treatment-emergent suicidal 
behavior compared with Baseline will be summarized by category, visit, and TAK-653 dose 
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7.10
Interim Analysis
Not applicable.
7.11
Changes in the Statistical Analysis Plan 
The analysis for EEG pharmacodynamic parameters outlined in the Section of 13.1.4 in Protocol 
TAK-653-1001 [1] will be performed outside this SAP.


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8.0
REFERENCES
1. Protocol: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability 
and Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-653 in Healthy 
Subjects Amendment 6, 24 March 2017.
2. Brian P. Smith, etc. (2000), Confidence Interval Criteria for Assessment of Dose 
Proportionality, Pharmaceutical Research, Vol. 17, 10:, 1278-1283.
3. Hedges, L. and Olkin, I. (1985) Statistical Methods for Meta-Analysis. New York: Academic 
Press, Page 86.


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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
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 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
Neutrophils 
(Absolute)
Both
<0.5 x LLN
>1.5 x LLN
Neutrophils 
(Relative)
Both 
<0.5 x LLN
>1.5 x LLN
Lymphocytes 
(Absolute)
Both
<0.5 x LLN
>1.5 x LLN
Lymphocytes 
(Relative)
Both 
<0.5 x LLN
>1.5 x LLN
Monocytes 
(Absolute)
Both
--
>2 x ULN
Monocytes (Relative)
Both
--
>2 x ULN
Eosinophils 
(Absolute)
Both
--
>2 x ULN
Eosinophils 
(Relative)
Both
--
>2 x ULN
Basophils (Absolute)
Both
--
>3 x ULN
Basophils (Relative) 
Both
--
>3 x ULN
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Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x 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
Direct bilirubin
Both
--
>2 ULN
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x 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
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
Both
--
>5x ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


TAK-653-1001
Page 31 of 32
Statistical Analysis Plan Final
22 August 2017
CONFIDENTIAL
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<40
>110
Systolic blood pressure
mm Hg
<85 
>160
Diastolic blood pressure
mm Hg
<45
>100
Body temperature
oC
< 35.6
>37.7


TAK-653-1001
Page 32 of 32
Statistical Analysis Plan Final
22 August 2017
CONFIDENTIAL
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms
Parameter
Unit
Lower Criteria 
Upper Criteria
Heart Rate
bpm
< 50
> 120
PR 
msec
≤ 110
≥ 220
RR 
msec
≤ 600
≥ 1440
QRS 
msec
≤ 75
≥ 110
QT Interval
msec
≤ 50
≥ 460
QTcF Interval
msec
≤ 50
>=450 or >=30 change from Baseline or 
>=60 change from Baseline


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