Conditions: Healthy Volunteers
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 120
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of ascending single- and multiple-doses of TAK-020 in healthy participants.

Detailed description:
The drug being tested in this study is called TAK-020. TAK-020 is being tested to evaluate safety and tolerability of single doses and 7 days multiple doses of TAK-020 in healthy volunteers. This study will look at the PK characteristics (how the drug acts throughout the body) of the drug and safety and tolerability (lab results, vital signs, ECG, and side effects) in healthy participants who take TAK-020.

The study will enroll a total of approximately 120 participants. This study is designed to consist of 2 sequential parts: Part 1-a SRD, and Part 2-a MRD. Healthy participants for Part 1 will be enrolled into 9 cohorts. Each cohort will have 8 randomized participants with receiving a single dose of TAK-020, and 2 receiving matching placebo under fasted conditions. In Cohorts 1-9 doses of 0.1, 0.5, 2.5, 4.4, 8.8, 17.5, 35, 70 and 105 mg will be evaluated.

Healthy participants for Part 2 will be enrolled into 7 cohorts. Each cohort will have 8 randomized participants, with participants receiving one dose of TAK-020 on Day 1, followed by a washout on Day 2, then daily dosing on Days 3-9 of TAK-020 with 2 participants receiving matching placebo under fasted conditions. In Cohorts 1-4 doses of 3.75, 5.75, 13 and 25 mg will be evaluated. For Cohorts 5-7, the subsequent dose level is to be determined based on data from Part 1 and review of safety, tolerability and PK data from Part 2 Cohorts 1-4.

This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 45 days. Participants in Part 1 will make multiple visits to the clinic including a period of confinement to the clinic and will be contacted by telephone 14 days after the last dose of study drug for a follow-up assessment. Participants in Part 2 will make multiple visits to the clinic including a period of confinement to the clinic and will be observed at the clinic 17 days after the last dose of study drug for a follow-up assessment.

Arms:
arm 1: TAK-020 placebo-matching solution, orally, once on Day 1. arm 2: TAK-020 0.1 mg, solution, orally once on Day 1. arm 3: TAK-020 0.5 mg, solution, orally, once on Day 1 following review of safety, tolerability and pharmacokinetic (PK) data from Cohort 1. arm 4: TAK-020 2.5 mg, solution, orally once on Day 1 following review of safety, tolerability and PK data from Cohort 2. arm 5: TAK-020 4.4 mg, solution, orally once on Day 1 following review of safety, tolerability and PK data from Cohort 3. arm 6: TAK-020 8.8 mg, solution, orally once on Day 1 following review of safety, tolerability and PK data from Cohort 4. arm 7: TAK-020 17.5 mg, solution, orally once on Day 1 following review of safety, tolerability and PK data from Cohort 5. arm 8: TAK-020 35 mg, solution, orally once on Day 1. TAK-020 dose will be determined based on review of safety, tolerability and PK data from Cohort 6. arm 9: TAK-020 70 mg, solution, orally once on Day 1. TAK-020 dose will be determined based on review of safety, tolerability and PK data from Cohort 7. arm 10: TAK-020 105 mg, solution, orally once on Day 1. TAK-020 dose will be determined based on review of safety, tolerability and PK data from Cohort 8. arm 11: TAK-020 placebo-matching solution, orally, once on Day 1 and Days 3 to 9. arm 12: TAK-020 3.75 mg, solution, orally once on Day 1 and Days 3-9. TAK-020 dose are determined based on data from Part 1 of the study. arm 13: TAK-020 5.75 mg, solution, orally once on Day 1 and Days 3-9. TAK-020 dose will be determined based on data from Part 1 and review of safety, tolerability and PK data from Cohort 1 in Part 2. arm 14: TAK-020 13 mg, solution, orally once on Day 1 and Days 3-9. TAK-020 dose will be determined based on data from Part 1 and review of safety, tolerability and PK data from Cohort 2 in Part 2. arm 15: TAK-020 25 mg, solution, orally once on Day 1 and Days 3-9. TAK-020 dose will be determined based on data from Part 1 and review of safety, tolerability and PK data from Cohort 3 in Part 2. arm 16: TAK-020 45 mg, solution, orally once on Day 1 and Days 3-9. TAK-020 dose was determined based on data from Part 1 and review of safety, tolerability and PK data from Cohort 4 in Part 2. arm 17: TAK-020 60 mg, solution, orally once on Day 1 and Days 3-9. TAK-020 dose was determined based on data from Part 1 and review of safety, tolerability and PK data from Cohort 5 in Part 2.

Interventions: intervention 1: TAK-020 intervention 2: TAK-020 Placebo
Intervention descriptions: intervention 1: TAK-020 oral solution intervention 2: TAK-020 placebo-matching oral solution

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, Sequential-Panel, Ascending Single-and 
Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-020 in 
Healthy Volunteers 
NCT Number: TAK-020-1001
Protocol Approve Date: 27-March-2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
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
Title Page
PROTOCOL
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending Single-
and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of TAK-020 in Healthy Volunteers 
Phase 1 TAK-020 SRD/MRD Study
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, Illinois 60015
Study Number:
TAK-020-1001
IND Number:
123,875
EudraCT Number:
Not Applicable
Compound:
TAK-020
Date:
27 March 2017
Amendment 
Number:
4.0
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
17 December 2014
Initial Protocol
Not applicable
US
14 August 2015
01
Substantial
US
07 September 2016
02
Substantial
US
31 October 2016
03
Substantial
US
27 March 2017
04
Substantial
US
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.


TAK-020
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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Medical Monitor (medical advice on protocol and 
compound)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
PPD
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 Conference on 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 electronic signature of the responsible Takeda medical officer (and other signatories listed 
below), and electronic signature date, can be found on the signature page (the last page of this 
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 Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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1.3
Protocol Amendment 4 Summary of Changes 
Rationale for Amendment 4.0
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 4.0. The primary purpose of this amendment is to add an additional time point for the 
collection of the pharmacodynamic (PD) markers
to Part 2 (multiple rising dose [MRD]) of this study in 
order to explore the extended duration of the PD effects.
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 F.
Changes in Amendment 4.0
Changed name of Responsible Medical Officer.
1.
Specified doses administered for initial cohorts of Part 2.
2.
Added PD biomarkers to Follow-up Visit (Day 17).
3.
Clarified method used for PD analyses.
4.
CCI
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 4 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................11
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.............................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.1.1
Primary Objective ..............................................................................................23
5.1.2
Secondary Objectives.........................................................................................23
5.2
Endpoints.................................................................................................................23
5.2.1
Primary Endpoints .............................................................................................23
5.2.2
Secondary Endpoints..........................................................................................23
5.2.3
Exploratory Endpoints .......................................................................................24
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.1.1
Dose Escalation..................................................................................................26
6.1.2
Criteria for Stopping Dose Escalation.................................................................28
6.2
Justification for Study Design, Dose, and Endpoints ................................................29
6.3
Premature Termination or Suspension of Study or Investigational Site.....................32
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................32
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........32
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................32
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............33
7.1
Inclusion Criteria .....................................................................................................33
7.2
Exclusion Criteria ....................................................................................................33


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7.3
Excluded Medications and Dietary Products ............................................................35
7.4
Diet, Fluid, and Activity Control..............................................................................36
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................37
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................38
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................39
8.1
Study Medication and Materials...............................................................................39
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................39
8.1.1.1 Study Drug...................................................................................................39
8.1.1.2 Ancillary Materials.......................................................................................41
8.1.2
Storage...............................................................................................................41
8.1.3
Dose and Regimen .............................................................................................41
8.1.4
Overdose............................................................................................................42
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................42
8.3
Randomization Code Creation and Storage..............................................................42
8.4
Study Drug Blind Maintenance................................................................................42
8.5
Unblinding Procedure..............................................................................................43
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................43
9.0
STUDY PLAN ..............................................................................................................45
9.1
Study Procedures.....................................................................................................45
9.1.1
Informed Consent Procedure..............................................................................45
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................45
9.1.2
Demographics, Medical History, and Medication History Procedure..................45
9.1.3
Physical Examination Procedure ........................................................................45
9.1.4
Weight, Height and BMI....................................................................................46
9.1.5
Vital Sign Procedure..........................................................................................46
9.1.6
Documentation of Concomitant Medications......................................................46
9.1.7
Documentation of Concurrent Medical Conditions.............................................46
9.1.8
Procedures for Clinical Laboratory Samples.......................................................47
9.1.9
Contraception and Pregnancy Avoidance Procedure...........................................49
9.1.10 Pregnancy ..........................................................................................................50
9.1.11 ECG Procedure..................................................................................................51
9.1.11.1
Screening and Safety ECGs....................................................................51
9.1.11.2
Telemetry...............................................................................................52
9.1.12 PGx Sample Collection......................................................................................52
9.1.13 PK Sample Collection........................................................................................53


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9.1.13.1
Collection of Plasma for PK Sampling....................................................53
9.1.13.2
Collection of Urine for PK Sampling......................................................54
9.1.13.3
Bioanalytical Methods............................................................................55
9.1.14 PK Parameters ...................................................................................................55
9.1.15 PD Sample Collection........................................................................................56
9.1.15.1
......................................................................................................57
9.1.15.2
...........................................................................57
9.1.16 PD Parameters ...................................................................................................57
9.1.17 Documentation of Screen Failure .......................................................................58
9.1.18 Documentation of Randomization......................................................................58
9.2
Monitoring Subject Treatment Compliance..............................................................58
9.3
Schedule of Observations and Procedures................................................................58
9.3.1
Final Visit/Check-out.........................................................................................59
9.3.2
Early Termination..............................................................................................59
9.3.3
Follow-up Visit/Telephone Call .........................................................................60
9.4
Biological Sample Retention and Destruction ..........................................................60
9.5
Blood Volume .........................................................................................................61
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................63
10.1
Definitions...............................................................................................................63
10.1.1 PTEs..................................................................................................................63
10.1.2 AEs....................................................................................................................63
10.1.3 Additional Points to Consider for PTEs and AEs................................................63
10.1.4 SAEs..................................................................................................................65
10.1.5 Severity of PTEs and AEs..................................................................................66
10.1.6 Causality of AEs ................................................................................................66
10.1.7 Relationship to Study Procedures.......................................................................66
10.1.8 Start Date...........................................................................................................67
10.1.9 Stop Date...........................................................................................................67
10.1.10
Frequency ....................................................................................................67
10.1.11
Action Concerning Study Medication...........................................................67
10.1.12
Outcome.......................................................................................................67
10.2
Procedures...............................................................................................................68
10.2.1 Collection and Reporting of AEs........................................................................68
10.2.1.1
PTE and AE Collection Period ...............................................................68
10.2.1.2
PTE and AE Reporting ...........................................................................68
CCI
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10.2.2 Collection and Reporting of SAEs......................................................................69
10.2.3 Reporting of Abnormal LFTs.............................................................................69
10.3
Follow-up of SAEs ..................................................................................................69
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....70
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................71
12.0
DATA HANDLING AND RECORDKEEPING............................................................72
12.1
Electronic CRFs.......................................................................................................72
12.2
Record Retention .....................................................................................................72
13.0
STATISTICAL METHODS..........................................................................................74
13.1
Statistical and Analytical Plans ................................................................................74
13.1.1 Analysis Sets......................................................................................................74
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................74
13.1.3 PK Analysis .......................................................................................................75
13.1.3.1
Concentrations in Plasma and Urine .......................................................75
13.1.3.2
PK Parameters........................................................................................75
13.1.4 PD Analysis .......................................................................................................76
13.1.5 Safety Analysis ..................................................................................................76
13.1.5.1
AEs ........................................................................................................76
13.1.5.2
Clinical Laboratory Evaluation...............................................................76
13.1.5.3
Vital Signs..............................................................................................76
13.1.5.4
ECGs......................................................................................................77
13.1.5.5
Safety Biomarkers ..................................................................................77
13.2
Interim Analysis and Criteria for Early Termination ................................................77
13.3
Determination of Sample Size..................................................................................77
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................78
14.1
Study-Site Monitoring Visits ...................................................................................78
14.2
Protocol Deviations..................................................................................................78
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................79
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................80
15.1
IRB and/or IEC Approval ........................................................................................80
15.2
Subject Information, Informed Consent, and Subject Authorization .........................81
15.3
Subject Confidentiality ............................................................................................82
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................82
15.4.1 Publication and Disclosure.................................................................................82
15.4.2 Clinical Trial Registration..................................................................................83


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15.4.3 Clinical Trial Results Disclosure ........................................................................83
15.5
Insurance and Compensation for Injury....................................................................83
16.0
REFERENCES..............................................................................................................84
LIST OF IN-TEXT TABLES
Table 6.a
TAK-020 DLTs .................................................................................................29
Table 6.b
Summary of TAK-020 PK Parameters Cohorts 1 to 9 in SRD ............................30
Table 6.c
Summary of TAK-020 PK Parameters Cohorts 1 to 7 in MRD...........................30
Table 7.a
Prohibited Medications ......................................................................................36
Table 8.a
Proposed Dosing Levels and Volume of Each Cohort (SRD) .............................40
Table 8.b
Composition of TAK-020 Oral Solution, 0.1, 1, 5, 7, and 7.5 mg/mL.................40
Table 8.c
Composition of Placebo for TAK-020 Oral Solution..........................................41
Table 9.a
Clinical Laboratory Tests...................................................................................48
Table 9.b
Collection of Blood Samples for PK Analysis ....................................................54
Table 9.c
Collection of Urine Samples for PK Analysis.....................................................55
Table 9.d
Approximate Blood Volume ..............................................................................61
Table 10.a
Takeda Medically Significant AE List................................................................66
Table 14.a
Windows for PK/PD Blood Sample Collection ..................................................79
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................26
Figure 6.b
Proposed Dose Escalation Scheme .....................................................................27
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................85
Appendix B
Responsibilities of the Investigator.....................................................................89
Appendix C
Elements of the Subject Informed Consent.........................................................91
Appendix D
Investigator Consent to Use of Personal Information..........................................94
Appendix E
Collection, Storage, and Shipment of Bioanalytical/Genotyping/RNA Samples..95
Appendix F
Detailed Description of Amendments to Text.....................................................99


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc. (TDC 
Americas)
Compound:
TAK-020
Title of Protocol: A Phase 1, Randomized, Double-Blind, 
Placebo-Controlled, Sequential-Panel, Ascending Single-
and Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
TAK-020 in Healthy Volunteers 
IND No.: 123,875
EudraCT No.:
Not Applicable
Study Number: TAK-020-1001
Phase: 1
Study Design:
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple-dose study in healthy volunteers. 
The study is comprised of 2 parts, each with multiple cohorts and is presented in the Study Schematic below. The 
study population for each part will be composed of healthy subjects aged 18 to 55 years, inclusive, who weigh at least 
45 kg, and have a body mass index (BMI) between 18 and 32 kg/m2, inclusive, at Screening and Day -1.
Study Design Schematic
SRD=single-rising dose, MRD=multiple-rising dose.
Part 1: SRD
This part will comprise a maximum of 9 cohorts. Each cohort will comprise 8 randomized subjects, with 6 receiving 
TAK-020 and 2 receiving placebo in the fasted state. Sentinel dosing will be used for Cohort 1 with only 2 subjects 
dosed on the morning of Day 1 (1 receiving TAK-020 and 1 receiving placebo). The remaining subjects will be dosed 
following agreement with the investigator and Takeda after reviewing 24-hour postdose safety (adverse events [AEs], 
vital signs, 12-lead electrocardiograms [ECGs]) and tolerability data. Sentinel dosing will not be necessary for other 
cohorts, provided that exposure is observed in ≥4 subjects receiving active treatment and in agreement with the 
investigator and Takeda, otherwise sentinel dosing in the subsequent cohort will be required.
TAK-020 will be orally administered as a solution with a starting dose of 0.1 mg for Cohort 1. Dosing for the 
subsequent cohorts will only occur after review of the safety, tolerability, and minimum 24-hour pharmacokinetic 
(PK) data from the previous cohort. For each dose escalation, exposures may be increased by a maximum of 5-fold for 
Cohorts 2-4 and a maximum of 2-fold for Cohorts 5 to 9. Doses may also be decreased as appropriate.
Study Schematic for Part 1 (SRD)
Screening
Check-in
Dose
Check-out
Follow-up (a)
Day -28 to -2
Day -1
Day 1
Day 5
Day 14 (±2)
(a) A phone call is planned but individual subjects may be asked to return to the unit at this time if abnormal clinical 
safety laboratory values are obtained at Check-out or treatment emergent adverse events (TEAEs) have not resolved at 
Check-out.
Part 1: SRD
Maximum 9 Cohorts
Starting dose 0.1 mg (Cohort 1)
Cohorts 2-4: maximum exposure escalation x 
5-fold
Cohorts 5-9: maximum exposure escalation x 
2-fold
Maximum dose estimated 122 mg (with unbound 
AUC 19.8 ng*h/mL)
Part 2: MRD
Maximum 7 Cohorts
Doses to be determined from Part 1
Starting dose 3.75 mg
Cohorts 2-7: 2-fold maximum 
exposure increase per dose 
increment


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Part 2: MRD
TAK-020 will be orally administered as a solution. The dose to be used in each cohort will be selected based on data 
from Part 1 of the study and from the previous cohort in Part 2.
MRD Evaluation
The first cohort for the MRD will receive a dose of 3.75 mg, with a predicted exposure at steady state estimated to be 
below the no-observed adverse-effect level (NOAEL) rat (63 ng*h/mL). The cohort may be initiated when the 
acceptable safety and tolerability have been collected in the SRD. The predicted steady state exposure in the first MRD 
cohort will be approximately 10-fold lower than the highest predicted steady state exposure determined from the SRD 
data. The MRD will comprise a maximum of 7 cohorts, each cohort with 8 subjects randomized with 6 receiving 
TAK-020 and 2 receiving placebo. In each successive cohort after the first, the dose increments will increase the 
predicted exposures by no more than 2-fold. The predicted steady state exposure in the MRD will not exceed the 
maximum exposure observed in the SRD.
Study Schematic for Part 2 (MRD)
Screening
Check-in
Dose
Washout
Dose
Check-out
Follow-up (a)
Day -28 to -2
Day -1
Day 1
Day 2
Days 3-9
Day 10
Day 17 (±2)
(a) All subjects will return to the unit and complete hematology, serum chemistry, renal biomarkers and 
pharmacodynamic (PD) tests, vital signs, concomitant medications, and adverse event (AE) assessment.
Primary Objective:
To characterize the safety and tolerability of TAK-020 following single and multiple oral doses in healthy subjects. 
Secondary Objectives:
To characterize the PK of TAK-020 following single and multiple oral doses. 
To characterize the PD of TAK-020 following single and multiple oral doses. 
Subject Population: Healthy subjects aged 18-55, inclusive.
Number of Subjects:
Part 1: Maximum 9 cohorts with 8 subjects per cohort
TAK-020: 6, Placebo: 2
Part 2: Maximum 7 cohorts with 8 subjects per cohort
TAK-020: 6, Placebo: 2
Estimated Total Part 1: 72 subjects randomized
Estimated Total Part 2: 56 subjects randomized
Number of Sites:
Estimated total: 1 site in United States
Dose Level(s):
Starting dose 0.1 mg once daily (QD) to approximately 
122 mg QD solution 
Route of Administration:
Oral
Duration of Treatment:
Part 1: single dose, QD
Part 2: single dose, QD for maximum 8 days
Period of Evaluation:
Screening = up to 28 days
Part 1 treatment = approximately 14 days (includes 
Follow-up phone call)
Part 2 treatment = approximately 17 days (includes 
Follow-up return to unit)
Total Part 1 = approximately 42 days
Total Part 2 = approximately 45 days


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Main Criteria for Inclusion:
The subject is a healthy adult male or female aged 18 to 55 years, inclusive, and weighs at least 45 kg and has a BMI 
between 18 and 32 kg/m2.
All subjects must be able to comply with the protocol and willing to sign the informed consent prior to undergoing any 
study-related procedures to be eligible for this study.
Main Criteria for Exclusion:
Subject has a known hypersensitivity to any component of the formulation of TAK-020, Captisol or related 
compounds. Subject has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, 
renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or 
allergic skin rash. There is any finding in the subject’s medical history, physical examination, or safety laboratory tests 
giving reasonable suspicion of a disease that would contraindicate taking TAK-020, or a similar drug in the same 
class, or that might interfere with the conduct of the study. Subject has abnormal Screening or Day -1 laboratory values 
that suggest a clinically significant underlying disease or subject with the following lab abnormalities or any of the 
following: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.2× the upper limit of normal 
(ULN), positive screen test for drugs of abuse, positive blood screen for hepatis B surface antigen (HBsAg), hepatitis 
C virus (HCV), or human immunodeficiency virus-1 or -2 antibodies, or a positive test for tuberculosis (TB) 
(QuantiFERON). In addition, subjects may not use any excluded medications, supplement, or food product outlined in 
Table 7.a.
Main Criteria for Evaluation and Analyses:
PK
Plasma and urine samples will be taken at the following time points in the first cohort. Based on emerging data in each 
cohort, the time points may be modified but will not exceed the number of samples presented and will not be taken 
after 96 hours in the SRD and 48 hours in the MRD.
Part 1 (SRD)
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
1
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, 48, 72, and 96 hours postdose
Urine
1
Predose (-12-0), and 0-6, 6-12, 12-24, 24-48, 48-72, and 72-96 hour postdose 
intervals
Part 2 (MRD)
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
1
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, and 48 hours postdose
Plasma
9 
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 
12, 16, and 24 hours postdose
Urine
1
Predose (-12-0), and 0-6, 6-12, 12-24 hour postdose intervals
Urine
9 
Predose (-12-0), and 0-6, 6-12, 12-24 hour postdose intervals
The following plasma PK parameters will be determined: area under the plasma concentration-time curve from time 0 
to 24 hours (AUC24); area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval (AUCτ); area under the plasma concentration-time curve from time 0 to time of last 
quantifiable concentration (AUCt), area under the plasma concentration-time curve from time 0 to infinity (AUC∞);
accumulation ratio (R, calculated as AUCτ at steady state/AUC∞ after a single dose); accumulation ratio based on 
AUC (Rac(AUC)), calculated as AUCτ at steady state or AUCτ after a single dose); maximum observed plasma 
concentration (Cmax); maximum observed steady-state plasma concentration during a dosing interval (Cmax,ss);
apparent clearance after extravascular administration (CL/F); terminal elimination rate constant (λz); terminal 
disposition phase half –life (t1/2z); lag time (Tlag, time from TAK-020 administration to first quantifiable 


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concentration); time to first occurrence of Cmax (tmax); and apparent volume of distribution during the terminal
disposition phase after extravascular administration (Vz/F). 
The following urine PK parameters will be determined: amount of drug excreted in urine from time 1 to time 2 (Aet1-2, 
calculated as Cur×Vur), Aet, amount of drug excreted in urine during a dosing interval (τ) at steady state (Aeτ), fe, and 
renal clearance (CLR).
Pharmacodynamics:
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Safety:
Safety parameters will include TEAEs, clinical laboratory results, physical examination findings, ECG findings, and 
vital signs measurements. Standard safety assessments for phase 1 studies will be collected as provided in Section 9.0
Study Plan.
Laboratory tests: 
Standard laboratory tests will be assessed as provided in Table 9.a Clinical Laboratory Tests. 
Pharmacogenomics:
Deoxyribonucleic acid (DNA) samples will be used to evaluate drug metabolic enzyme and transporter 
polymorphisms that may contribute to the variability in the PK of TAK-020. The sampling of whole blood for 
pharmacogenomic (PGx) and genotyping analysis is mandatory; every subject must sign the informed consent in order 
to participate in this study. Also, since PGx is an evolving science, many genes and their functions are not yet fully 
understood. 
Maximum total volume of blood drawn:
Part 1 (SRD): 300 mL; Part 2 (MRD): 413 mL
Statistical Considerations:
Safety Analysis
AEs will be presented in listings, and TEAEs will be summarized. Individual results of laboratory tests (hematology, 
chemistry, and urinalysis) will be listed and Baseline, postdose, and change from Baseline to postdose laboratory data 
will be summarized. Individual results of vital signs will be listed and observed values and changes from Baseline in 
vital signs will be summarized. Individual results of quantitative ECG parameters from the 12-lead safety ECGs will 
be listed and observed values and changes from Baseline in quantitative ECG parameters will be summarized. The 
subjects who meet predefined markedly abnormal values (MAV) criteria for laboratory tests, vital signs and ECG 
parameters will be summarized and listed. All summaries will be performed by pooled placebo, each TAK-020 dose 
level, and TAK-020 overall across cohorts as appropriate for single and multiple doses of Parts 1 and 2. Physical 
examination findings will be presented in data listings.
PK Analysis 
Concentrations of TAK-020 in plasma will be summarized by dose level over each scheduled sampling time using 
descriptive statistics. Individual plasma concentration data vs time will be presented in a data listing.
Amount of TAK-020 excreted in urine will be summarized by dose level over each scheduled sampling interval using 
descriptive statistics. Individual urine concentration data along with volume versus time intervals will be presented in 
a data listing.
PK parameters of TAK-020 will be summarized by dose level using descriptive statistics. All PK parameter data will 
be listed.
The above summaries will be performed separately for Part 1 (SRD) and Part 2 (MRD). 
Power model will be used to assess dose proportionality of single and multiple dosing in healthy subjects for Cmax and 
AUC.
Analysis of variance (ANOVA) will be used to assess time dependency for Part 2 multiple dosing. In the model, the 
natural log-transformed AUCs and Cmax will be used as response variable and dose level, Day and the interaction of 
dose level by Day will be fixed factors. 
Pharmacodynamic Analysis
 
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summarized.
The above summaries will be performed separately for Part 1 (SRD) and Part 2 (MRD).
The relationship between dose, TAK-020 concentrations, PK parameters, and PD response will be explored and 
PK/PD models developed if deemed appropriate.
Interim Analysis and Criteria for Early Termination 
No formal interim analyses will be performed.
Sample Size Justification: The sample sizes chosen of 8 subjects per cohort (6 active: 2 placebo) in Part 1 and 2 is 
considered to be sufficient for evaluation of safety, tolerability, PK and the PD of TAK-020 in 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 
Clinical Study Supplier List template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator 
PPD


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3.3
List of Abbreviations
λz
terminal elimination rate constant
AE
adverse event
Aet1-t2
amount of drug excreted in urine from time 1 to time 2
Aet
amount of drug excreted in urine from time 0 to time t
Aeτ
amount of drug excreted in urine during a dosing interval (τ) at steady state
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC24
area under the plasma concentration-time curve from the time 0 to time 24 hours
AUCτ
area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval
AUCt
area under the plasma concentration-time curve from time 0 to time t 
AUC∞
area under the plasma concentration-time curve from time 0 to infinity 
BA
bioavailability 
BCR
B cell receptor
BMI
body mass index
bpm
beats per minute 
BTK
Bruton’s tyrosine kinase
CI
confidence interval
CIA
collagen-induced arthritis 
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
CS
clinically significant
Cur t1-t2
concentration of drug excreted in urine from time 1 to time 2
%CV
percentage coefficient of variation
CYP
cytochrome P-450
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
EC90
90% effective concentration
ECG
electrocardiogram
eCRF
case report form electronic
ED50
median effective dose
eGFR
estimated glomerular filtration rate
Emax
maximum drug-induced effect
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FDA
Food and Drug Administration
fe
fraction of drug excreted in urine
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HED
human equivalent dose 
hERG
human ether-à-go-go–related gene
IC50
50% inhibitory concentration
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activation motifs 
IUD
intrauterine device
K2EDTA
potassium ethylenediamine-tetraacetic acid
LFT
liver function test
LOAEL
low-observed-adverse-effect-level
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple rising dose
MSS
most sensitive species
NCS
not clinically significant
NOAEL
no observed adverse effect level
OTC
over-the-counter
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PGx
pharmacogenomic(s)
PI
principal investigator
PK
pharmacokinetic
PT
preferred term
PTE
pretreatment event
QD
once daily
QTcF
QT interval with Fridericia correction method
R
accumulation ratio (index)
RA
rheumatoid arthritis
Rac(AUC)
accumulation ratio (based on AUC) 
RNA
ribonucleic acid


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SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SRD
single rising dose
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TB
tuberculosis 
TEAE
treatment emergent adverse event
tmax
time of first occurrence of Cmax.
tmax(E)
time to Emax
tlag
lag time
ULN
upper limit of normal
Vur t1-t2
volume of urine excreted from time 1 to time 2
Vz/F
apparent volume of distribution during the terminal phase after extravascular administration 
WHODRUG
World Health Organization Drug Dictionary
3.4
Corporate Identification 
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-020 is an orally available small molecule irreversible inhibitor of Bruton’s tyrosine kinase 
(BTK) for the treatment of autoimmune diseases. BTK is expressed in multiple cell types 
(including B cells, neutrophils, basophils, monocytes, mast cells and osteoclasts) and the function 
of BTK in these cell types may be clinically relevant in a variety of autoimmune diseases [1-4]. 
BTK plays a critical role in B-cell receptor activation, which results in proliferation and 
phenotypic differentiation of immature B cells into antibody-secreting cells [2,3]. It also plays an 
essential role in Fcγ and Fcε receptor signaling by mediating activation of immunoreceptor 
tyrosine-based activation motifs (ITAM) in multiple cell types [1,2,5]. Inhibiting B cell activation 
and ITAM signaling are 2 of the main mechanisms through which TAK-020 is proposed to 
contribute to clinical efficacy in the treatment of autoimmune disease. 
The initiation of rheumatoid arthritis (RA) involves the presentation of self-antigens, leading to the 
activation of T and B lymphocytes. Activation of the adaptive immune response results in cytokine 
secretion and autoantibody production, which promotes inflammation [6]. Therapies directly or 
indirectly targeting B cells have been developed in an attempt to attenuate disease progression. 
Whereas current therapies for RA primarily target a single factor contributing to RA pathogenesis, 
BTK is an appealing therapeutic target because of its function in multiple signaling pathways 
downstream of the B cell receptor (BCR) and FcεRs. 
TAK-020 engages the target rapidly and remains covalently bound, even after plasma 
concentrations are undetectable, with proven efficacy in a rat collagen-induced arthritis (CIA) 
model with median effective dose (ED50) of 0.31 mg/kg/day. The high selectivity of TAK-020
reduces potential off-target effects and it is anticipated to improve the benefit risk profile of this 
compound compared with competitors (eg, ibrutinib). 
TAK-020 is poorly soluble, but using a Captisol formulation, appears well-absorbed across 
nonclinical species, with the predicted fraction absorbed in humans estimated as 98% from oral 
dosing solution. In nonclinical studies, TAK-020 was absorbed rapidly and extensively after oral 
administration, with peak plasma concentrations generally occurring within 2 hours postdose. 
Terminal disposition phase half-life (t1/2z) of TAK-020 after oral administration was 4.4-7.3 hours 
in rats and 3.8-6.7 hours in dogs. The oral bioavailability (BA) of TAK-020 in animals was low 
(12.6%-21.8% in rats and 8.17% to16.5% in dogs). Absorption could be modulated by 
P-glycoprotein (P-gp), since TAK-020 is likely to be a P-gp substrate based on results obtained 
from a study using LLC-PK1-MDR1 cells. 
TAK-020 is mainly metabolized by CYP3A4, CYP2C19, and CYP1A2, and is also metabolized to 
a minor extent by CYP2D6, CYP2C8, and CYP2C9 (TAK-020-10222, TAK-020-10223). 
TAK-020 has inhibitory effects on CYP2C19 activity with 50% inhibitory concentration (IC50) of 
10 μmol/L without preincubation and 6.3 μmol/L with pre-incubation (TAK-020-10133). 
TAK-020 has little or no time-dependent inhibitory effects on the other cytochrome P-450 (CYP)
activities (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A4/5) up to 30 μmol/L 


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(TAK-020-10133). TAK-020 is a weak inducer for CYP1A2 and CYP3A4 (TAK-020-10134). 
TAK-020 was found to be an inducer for CYP2B6.
A comprehensive series of nonclinical safety studies (Good Laboratory Practice [GLP]) was
conducted with TAK-020 to support early human studies. No safety concerns were identified in 
safety pharmacology assessments (human ether-à-go-go–related gene [hERG], 
electrocardiography, cardiovascular, respiratory, central nervous system [CNS]), genetic 
toxicology studies (Ames, in vitro micronucleus, in vivo micronucleus), or an in vivo 
phototoxicity study. In addition, daily repeated-dose toxicology studies of 28 days in duration have 
been conducted in rats and dogs. The oral dose levels were 5, 25, and 75 mg/kg in the rat study and 
5, 20, and 75 mg/kg in the dog study. The no-observed–adverse-effect level (NOAEL) in the rat 
study was 5 mg/kg (AUC=63 ng*h/mL, sexes combined). The NOAEL in the dog study was 
20 mg/kg (AUC=518 ng*h/mL, sexes combined). At the low-observed-adverse-effect-level 
(LOAEL) the combined sex AUC in rat and dog were 431 ng*h/mL and 6418 ng*h/mL, 
respectively. 
For further information on TAK-020, please refer to the Investigator’s Brochure for TAK-020.
4.2
Rationale for the Proposed Study
The nonclinical pharmacology, toxicology, and pharmacokinetic (PK) studies support the 
proposed escalating single and multiple dose study of TAK-020 in healthy subjects.
The study will characterize the safety, tolerability, PK, and pharmacodynamic (PD) of TAK-020
in healthy subjects.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 
To characterize the safety and tolerability of TAK-020 following single and multiple oral doses in 
healthy subjects.
5.1.2
Secondary Objectives 

To characterize the PK of TAK-020 following single and multiple oral doses. 

To characterize the PD of TAK-020 following single and multiple oral doses. 
5.2
Endpoints
5.2.1
Primary Endpoints 
The primary safety endpoints include the number and percentage of subjects who:

Experience at least 1 treatment-emergent adverse event (TEAE).

Meet the Takeda Development Center, Inc. (TDC) markedly abnormal values (MAV) criteria 
for safety laboratory tests at least once postdose.

Meet the TDC MAV criteria for vital sign measurements at least once postdose.

Meet the TDC MAV criteria for safety electrocardiogram (ECG) parameters at least once 
postdose.
5.2.2
Secondary Endpoints
The secondary endpoints will be the following PK parameters of TAK-020:

Maximum observed plasma concentration (Cmax).

Time of first occurrence of Cmax (tmax).

Area under the plasma concentration-time curve from time 0 to the time t (AUCt).

Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).

Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval (AUCτ).

Terminal disposition phase half-life (t1/2z).

Apparent clearance after extravascular administration (CL/F). 

Apparent volume of distribution during the terminal phase after extravascular administration 
(Vz/F). 


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!
Total amount of drug excreted in urine from time 0 to time t (Aet).
!
Fraction of drug excreted in urine (fe).
!
Renal clearance (CLR).
5.2.3
Exploratory Endpoints 
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple-dose study in 
healthy volunteers. The study is comprised of 2 parts, each with multiple cohorts and is presented 
in the Study Schematic below. The study population for each part will be composed of healthy 
subjects aged 18 to 55 years, inclusive, who weigh at least 45 kg, and have a body mass index 
(BMI) between 18 and 32 kg/m2, inclusive, at Screening and Day -1.
SRD=single-rising dose, MRD=multiple-rising dose.
Part 1: SRD
This part will comprise a maximum of 9 cohorts. Each cohort will comprise of 8 randomized 
subjects, with 6 receiving TAK-020 and 2 receiving placebo in the fasted state. Sentinel dosing 
will be used for Cohort 1 with only 2 subjects dosed on the morning of Day 1 (1 receiving 
TAK-020 and 1 receiving placebo). The remaining subjects will be dosed following agreement 
with the investigator and Takeda after reviewing 24-hour postdose safety (adverse events [AEs], 
vital signs, 12-lead ECGs) and tolerability data. Sentinel dosing will not be necessary for other 
cohorts provided that exposure is observed in ≥4 subjects receiving active treatment and in 
agreement with the investigator and Takeda, otherwise sentinel dosing in the subsequent cohort 
will be required.
TAK-020 will be orally administered as a solution with a starting dose of 0.1 mg for Cohort 1. 
Dosing for the subsequent cohorts will only occur after review of the safety, tolerability, and 
minimum 24-hour PK data from the previous cohort. For each dose escalation, exposures may be 
increased by a maximum of 5-fold for Cohorts 2-4 and a maximum of 2-fold for Cohorts 5 to 9. 
Doses may also be decreased as appropriate.
Part 2: MRD
TAK-020 will be orally administered as a solution. The dose to be used in each cohort will be 
selected based on data from Part 1 of the study and from the previous cohort in Part 2. 
2) MRD Evaluation
The first cohort for the MRD will receive a dose of 3.75 mg, with a predicted exposure at steady 
state estimated to be below the NOAEL rat (63 ng*h/mL). The cohort may be initiated when the 
Part 1: SRD
Maximum 9 Cohorts
Starting dose 0.1 mg (Cohort 1)
Cohorts 2-4: maximum exposure escalation x 
5-fold
Cohorts 5-9: maximum exposure escalation x 
2-fold
Maximum dose estimated 122 mg (with unbound 
AUC 19.8 ng*h/mL)
Part 2: MRD
Maximum 7 Cohorts
Doses to be determined from Part 1
Starting dose 3.75 mg
Cohorts 2-7: 2-fold maximum 
exposure increase per dose 
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acceptable safety and tolerability have been collected in the SRD. The predicted steady state 
exposure in the first MRD cohort will be approximately 10-fold lower than the highest predicted 
steady state exposure determined from the SRD data. The MRD will comprise a maximum of 7 
cohorts, each cohort with 8 subjects randomized with 6 receiving TAK-020 and 2 receiving 
placebo. In each successive cohort after the first, the dose increments will increase the predicted 
exposures by no more than 2-fold. The predicted steady state exposure in the MRD will not exceed 
the maximum exposure observed in the SRD.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
Study Schematic for Part 1
Screening
Check-in
Dose
Check-out
Follow-up (a)
Day -28 to -2
Day -1
Day 1
Day 5
Day 14 (±2)
(a) A phone call is planned but individual subjects may be asked to return to the unit at this time if abnormal clinical 
safety laboratory values are obtained at Check-out or TEAEs have not resolved at Check-out.
Study Schematic for Part 2
Screening
Check-in
Dose
Washout
Dose
Check-out
Follow-up (a)
Day -28 to -2
Day -1
Day 1
Day 2
Days 3-9
Day 10
Day 17 (±2)
(a) All subjects will return to the unit and complete hematology, serum chemistry, renal biomarkers and 
pharmacodynamic tests, vital signs, concomitant medications, and AE assessment.
6.1.1
Dose Escalation
The dose escalation scheme is shown in Figure 6.b. All decisions concerning dose escalation will
be made by Takeda (at a minimum, the clinical science representative(s) and pharmacovigilance 
physician) and the principal investigator (PI). Additionally, Takeda and the PI 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.
The AUC24 will be calculated for each subject and subsequently the geometric mean of AUC24 will 
be determined for each cohort (excluding placebo). Dose escalation will proceed to a dose level 
that is predicted to give a TAK-020 unbound AUC of (19.8 ng*h/mL) approximately 2-fold higher 
than the unbound AUC of the rat LOAEL. 
There will be a minimum period of 5 days between each dose escalation to allow for review of 
safety, tolerability and PK data. The blind of the PK data will remain intact during these reviews 
by using an alias number as the subject identifier instead of randomization sequence number for 
each subject.
For each dose level administered/completed cohort, the PI and Takeda will carefully review the 
available blinded safety, tolerability and blinded PK data (if data is available in time for the 
planned review). They will determine whether dosing should stop or continue (and, if continue, at 
what dose, including whether to repeat the previous dose), whether additional sequential dosing 


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should be implemented in future cohorts or whether the blind should be broken to identify whether 
the subjects received TAK-020 or placebo. In the next cohort (Part 1), exposures may be increased 
by a maximum of 5-fold as long as the predicted exposure will be below that at the NOAEL in the 
most sensitive nonclinical species, which is the rat (63 ng·hr/mL, sexes combined). For doses with 
exposure above the NOAEL doses may be increased to give a maximum of 2-fold increase in 
exposure. Doses may also be decreased as appropriate. In cohorts in the next part of the study 
(Part 2), the doses may be increased as long as the maximum exposure multiplier is below 2-fold.
The predicted steady state exposure in the MRD will not exceed the maximum exposure observed 
in the SRD.
All AEs reported during the Treatment Period, both within and across cohorts, up to the time of 
discharge on Day 5 (Part 1) and Day 10 (Part 2) will be evaluated to assess the need for subject 
and/or study termination in accordance with the prespecified criteria for 
discontinuation/termination (Section 6.3.1).
Following assessment of the AE data and pre-defined 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 PI will decide if and how it is appropriate for the 
study to proceed.
If agreement regarding a dose escalation decision cannot be reached between the PI and Takeda, 
the study will be stopped.
Figure 6.b
Proposed Dose Escalation Scheme
Part 1 SRD
Cohort 1
(a)
Cohort 2
(a)
Cohort 3
(a)
Cohort 4
(a)
Cohort 5
(a)
Cohort 6
(a)
Cohort 7
(a)
Cohort 8
(a)
Cohort 9 
(a)
0.1 mg 
TAK-020 or 
placebo
Completed
0.5 mg 
TAK-020 or 
placebo
Completed
2.5 mg 
TAK-020 or 
placebo
Completed
4.4 mg 
TAK-020 or 
placebo
Completed
8.8 mg 
TAK-020 or 
placebo
Completed
17.5 mg 
TAK-020 or 
placebo
Completed
35 mg 
TAK-020 or 
placebo
Completed
70 mg 
TAK-020 or 
placebo
Completed
105 mg 
TBD 
TAK-020 or 
placebo
(a) Dosing with TAK-020 will progress to the next cohort after review of the safety, tolerability and PK data from the 
previous cohort and the agreement of the PI and Takeda of the next proposed dose. 
TBD =to be determined for actual dose level when PK data from the previous cohort is available.
Part 2 MRD
Part 2
MRD 
Evaluation
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Cohort 5
Cohort 6
Cohort 7
3.75 mg 
TAK-020 or 
placebo
5.75 mg
TAK-020 or 
placebo
13 mg 
TAK-020 or 
placebo
25 mg 
TAK-020 or 
placebo
X mg TBD 
TAK-020 or 
placebo
X mg TBD 
TAK-020 or 
placebo
X mg TBD 
TAK-020 or 
placebo
TBD=to be determined for actual dose level when PK data from the previous cohort is available.


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6.1.2
Criteria for Stopping Dose Escalation
Two or more subjects in any single cohort or across more than 1 cohort experience any of the 
1.
Takeda Medically Significant List events (as outlined in Table 10.a).*
Two or more subjects in any single cohort experience alanine aminotransferase (ALT) and/or 
2.
aspartate aminotransferase (AST) elevations > 3 x upper limit of normal (ULN), irrespective of 
total bilirubin increase or other lab changes.
Two or more subjects in any single cohort or across more than 1 cohort experience ALT and/or 
3.
AST elevations >5 × ULN in the absence of a concomitant bilirubin increase.*
One or more subjects in any single cohort or across more than 1 cohort experience ALT and/or 
4.
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”).
Two or more subjects in any single cohort or across more than 1 cohort experience ALT and/or 
5.
AST elevations >3 ×ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).*
Within each dose level, if 2 subjects develop a dose limiting toxicity (DLT) listed in Table 6.a
6.
that is confirmed by repeat test if applicable, the subject(s) will be unblinded prior to any 
dose-escalation safety review meeting. If the unblinded subjects have received TAK-020, no 
further dosing will occur in that dose level and no further dose escalation beyond that dose 
level will be allowed.
Two or more subjects in the same cohort experience the same toxicity graded at least as 
7.
moderate (≥ Grade 2) and requiring discontinuation of investigational drug.
* Please note that 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 date.

In addition to Takeda’s standard criteria for study termination, the following stopping criteria 
will also be implemented in this study for individual subjects:
–
Within each dose level, if at least 1 subject develops a DLT listed in Table 6.a, and 
confirmed by repeat test, if applicable, the subject will be unblinded prior to any
dose-escalation safety review meeting. If the unblinded subject has received TAK-020, no 
further dosing will occur in that subject. 


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Table 6.a
TAK-020 DLTs
Toxicity
Definition
Leukopenia
Total leukocyte count <2500 cells/mm3 (2.5×109/L)
Neutropenia
Absolute neutrophil count <1500/mm3 (1.5 x 109/L)
Thrombocytopenia
Platelet count <75 x109/L
Lymphopenia
Lymphocyte count <1000 cells/mm3 (1.0×109/L)
Liver enzymes
ALT or AST >3× ULN
Renal changes
Serum Creatinine>1.3×ULN
Or
eGFR decrease by 30% from Baseline
Abnormal coagulation
INR >2×ULN
aPTT >2×ULN
prothrombin time >2×ULN
QT interval with Fridericia correction 
method (QTcF)
QTcF >500 msec or a change from Baseline in QT/QTcF of >60 ms.
Severe infection
Serious infection requiring hospitalization, intravenous (IV) antibiotics (more 
than 1 dose), systemic antifungal or antiviral intervention
aPTT=activated partial thromboplastin time, eGFR= estimated glomerular filtration rate.
6.2
Justification for Study Design, Dose, and Endpoints
Study Design
Parts 1 and 2
This study will be performed in healthy subjects rather than the target subject population 
(ie, diseased patients) in order to collect safety and tolerability information that will not be biased 
by common comorbidities. The study is double-blind in order to avoid subjective bias in the 
assessment of safety, tolerability, and pharmacological effects of the study medication. Placebo 
will be administered as a control in order to establish the frequency or magnitude of changes in 
clinical endpoints that may occur in the absence of active treatment. Sentinel dosing is intended to 
be used in the first cohort in Part 1, but it may also be used in other cohorts if exposure is observed 
in fewer than 3 subjects or by agreement with Takeda and the investigator.
Dose and Dose Regimen
The starting dose of 0.1 mg was based on both the Food and Drug Administration (FDA) guidance 
[7] and PK/PD modeling which predicted 20% BTK occupancy, which is considered to represent a 
minimum anticipated biological effect level.
Currently doses of 0.1, 0.5, 2.5, 4.4, 8.8, 17.5, 35, 70, and 105 mg have been tested in the SRD and 
3.75, 5.75, 13 and 25 mg in the MRD and were shown to be safe and well tolerated. Draft PK data 
are summarized in Table 6.b and Table 6.c for the SRD and MRD, respectively.


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Table 6.b
Summary of TAK-020 PK Parameters Cohorts 1 to 9 in SRD
Cohort (Dose)
Cmax
(ng/mL)
Tmax*
(hr)
AUC24
(ng*h/mL)
AUCt
(ng*h/mL)
AUC∞
(ng*h/mL)
Half-life
(hr)
*Median value.
Table 6.c
Summary of TAK-020 PK Parameters Cohorts 1 to 7 in MRD
Cohort (Dose)
Cmax
(ng/mL)
Tmax*
(hr)
AUC24
(ng*h/mL)
AUCt
(ng*h/mL)
AUC∞
(ng*h/mL)
Half-life
(hr)
Accumulation 
Index
*Median value.
Accumulation index=D9AUC24/D1AUC∞
.
TBD=to be determined.
Furthermore, plasma protein binding of TAK-020 in humans is higher than in the rat, (98.9% and 
98.0% respectively) resulting in lower exposures to unbound (free) TAK-020 in humans at a given 
total exposure. Therefore unbound exposure estimates have been used to refine the dose 
escalation.
CCI


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The exposure at the maximum proposed dose would not exceed 1808 ng*h/mL (total) and 
19.9 ng*h/mL (unbound) which is 2.19-fold unbound exposure at the LOAEL, and corresponds to 
a safety factor of 0.43.
As the PK t1/2z for this compound remains short, PK washout would be expected within 24-hours 
and time dependency of PK could be evaluated without the need for any additional washout period 
following Day 1 in the MRD study Part 2. Further, due to the short t1/2z, no accumulation in plasma 
PK is expected during the MRD. PD washout following Day 1 in MRD was not considered 
necessary for evaluation.
The following safety variables will be used to describe the safety and tolerability of TAK-020:

Physical examination findings.

TEAEs.

Clinical laboratory test results.

Vital sign measurements and weight.

12-lead ECGs.
Background safety information – anticipated risks
Risk factors relating to mode of action and nature of target
Based on information from patients with inherited BTK deficiency, immunosuppression with low 
serum immunoglobulins, low circulating B-cells and opportunistic infections could be observed 
with >99% BTK inhibition by TAK-020.
TAK-020 nonclinical studies
Nonclinical toxicology studies were conducted with TAK-020 in rats and dogs. The rat was 
identified as the most sensitive toxicology species. Target organ toxicity in a GLP 4-week rat 
toxicology study administered doses in excess of the NOAEL (AUC>63 nghr/mL, sexes 
combined) was seen in the liver and kidney. Liver toxicity was seen in rats at an AUC of greater or 
equal to 431 ng·hr/mL (sexes combined), and kidney toxicity seen at an AUC of 2030 ng·hr/mL. 
Reversibility was not tested in the 4-week GLP rat study, however in a 2-week rat study, liver 
changes were fully reversible after a 2-week recovery period. In the absence of nonclinical 
information on reversibility, the kidney changes will be considered not reversible. Markers of 
kidney injury will be monitored in this study.
Safety profile of other BTK inhibitors
Based on first-in-human (FIH) safety data from BTK inhibitor CC-292 in healthy volunteers, 
grade 1 liver function test increase, hemoglobin decrease, blood glucose increase and diarrhea may 
be observed with TAK-020. CC-292 was well tolerated in the study with healthy volunteers, 
(assumed body weight 60 kg), who received 0.5 mg/kg (30 mg) to 7.0 mg/kg (420 mg) CC-292.
Based on the US prescribing information of BTK inhibitor ibrutinib, cytopenias, hemorrhage, 
renal toxicity, atrial fibrillation and serious infections were seen in patients with hematological 


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malignancies. No information is available about ibrutinib use in healthy volunteers for 
comparison.
These potential risks can be monitored clinically or with serial laboratory tests and were taken into 
consideration when setting the stopping rules and dose limiting toxicities in the proposed 
TAK-020 FIH study.
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 medication 
that indicates a change in the known risk/benefit profile for TAK-020, 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 meets predefined dose escalation stopping rules within or between cohorts and the 
sponsor and PI jointly decide not to study additional cohort(s) at a lower dose per 
Section 6.1.2.
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(s)
In the event that the sponsor, an institutional review board (IRB)/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 suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization or first dose or 
other. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
In the opinion of the investigator, the subject is capable of understanding and complying with 
1.
protocol requirements.
The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
2.
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.
The subject is a healthy adult male or female.
3.
The subject is aged 18 to 55 years, inclusive, at the time of informed consent and first study 
4.
medication dose.
[Previous criterion deleted.]
5.
The subject weighs at least 45 kg and has a BMI between 18.0 and 32.0 kg/m2, inclusive at 
6.
Screening and Day -1. 
[Previous criterion deleted.]
7.
A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
8.
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 12 weeks after last dose.
A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
9.
partner agrees to use adequate contraception* from signing of informed consent throughout the 
duration of the study and until the next menstrual period or 30 days after last dose, whichever is 
first. If the next menstrual period is delayed, a pregnancy test will be required for exclusion of 
pregnancy. See section 8.1.10 for Pregnancy Follow-up. 
*Definitions and acceptable methods of contraception are defined in Section 9.1.9
Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.10 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
The subject has received any investigational compound within 30 days prior to Screening.
1.
The subject is an immediate family member, study site employee, or in a dependent 
2.
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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Subject has a known hypersensitivity to any component of the formulation of TAK-020, 
3.
Captisol or related compounds.
The subject has a positive urine drug result for drugs of abuse at Screening or Check-in 
4.
(Day -1).
The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
5.
abuse (defined as 4 or more alcoholic beverages per day) within 1 year prior to the Screening 
visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. One unit is 
equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine.
Subject has taken any excluded medication, supplements, or food products listed in Table 7.a
6.
Prohibited Medications and Dietary Products. 
If female, the subject is pregnant or lactating or intending to become pregnant before, during or 
7.
within 1 month after exit from this study (30 days post last dose); or intending to donate ova 
during such time period.
If male, the subject intends to donate sperm during the course of this study or for 12 weeks 
8.
thereafter. 
Subject has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic 
9.
disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma 
hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the subject’s 
medical history, physical examination, or safety laboratory tests giving reasonable suspicion of 
a disease that would contraindicate taking TAK-020, or a similar drug in the same class, or that 
might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer 
disease, seizure disorders, and cardiac arrhythmias.
Subject has current or recent (within 6 months) gastrointestinal disease that would be expected 
10.
to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic 
ulcer disease, erosive esophagitis frequent [more than once per week] occurrence of heartburn, 
or any surgical intervention [eg, cholecystectomy]).
Subject has a history of cancer, except basal cell carcinoma which has been in remission for at 
11.
least 5 years prior to Day 1.
12. 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).
13. The subject has poor peripheral venous access.
14. 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 30 days prior to Day 1. 
15. Vaccination with any live vaccine within 4 weeks of study drug administration.


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16. Subject has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry of 
any subject with an abnormal (not clinically significant) ECG must be approved, and 
documented by signature by the PI medically qualified subinvestigator.
17. Subject has QTcF >450 msec for men and women or PR outside the range of 120 to 220 msec 
confirmed upon repeat testing within a maximum of 30 minutes, at the Screening Visit or 
Check-in (Day -1).
18.
Subject has abnormal Screening or Day -1 laboratory values that suggest a clinically 
significant underlying disease or subject with the following lab abnormalities:
a) ALT or AST >1.2× the ULN.
b) Positive screen test for drugs of abuse.
c) Positive blood screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), or 
human immunodeficiency virus-1 or -2 antibodies.
d) A positive test for tuberculosis (TB) (QuantiFERON).
7.3
Excluded Medications and Dietary Products
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points
specified until completion of all study activities.


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Table 7.a
Prohibited Medications
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 
Hormonal Contraceptives
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 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
P-gp substrates or inhibitors
OTC=over-the-counter. 
(a) Occasional use of acetaminophen (2 g/day) is allowed or other OTC medication as approved by Takeda’s Medical 
Monitor or designee on a case-by-case basis during the 7 days prior to Day -1. Acetaminophen may be allowed from 
Day 1 in exceptional circumstances but its use should be carefully monitored.
(b) Inclusive of but not limited to H1N1 and other flu vaccinations.
Subjects must be instructed not to take any medications including OTC products, without first 
consulting with the investigator.
Use of concomitant medications will not be allowed during the study except for those approved by 
Takeda on a case-by-case basis, unless deemed necessary in a medical emergency or treatment of 
adverse events. Concomitant medications will include all medications the subject has taken from 
Screening to Follow-up.
If the subject reports taking any medication or if administration of any medication becomes 
necessary during the course of this study, the Takeda Medical Monitor or designee must be 
notified. All medications must be recorded in the source documents as well as on the appropriate 
electronic case report form (eCRF) along with dosage information, dates of administration, and 
reasons for use.
7.4
Diet, Fluid, and Activity Control 
Subjects will be confined to the clinic for the duration of each treatment period: Part 1, Day -1 
through Day 5, Part 2, Day -1 through Day 10.


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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). On dosing days, breakfast will not be served. For Part 1 of the study, the meals served on 
the day of dosing should be identical for each cohort in the study. For Part 2 of the study, meals 
served on the PK assessment days (Days 1 and 9) should be identical for each cohort, Meals on 
other days should be standardized to ensure comparability if options are provided (consistent 
protein, carbohydrates, and fat content).
The study menu should be recorded and submitted to the study file with a copy provided to the 
sponsor prior to the start of the study. The meal start and stop times and percentage of the meal 
consumed will be recorded in the source and appropriate eCRF for all meals served on PK 
assessment days, Day 1 for Part 1 of the study (SRD), and Days 1 and 9 for Part 2 of the study 
(MRD).
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 arm of the study, Part 1, TAK-020 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.
During the MRD arm of the study, Part 2, TAK-020 and placebo will be administered on Days 1 
and 3 through 9 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. The dosing regimen and diet should be 
consistent on each day of the study.
Subjects will remain upright (seated, standing, or ambulatory) for 1 hour following the dose 
administration, except as necessitated by the occurrence of an adverse event or study procedures 
(eg, obtaining 12-lead ECG). Subjects will refrain from strenuous exercise throughout the entire 
course of the study.
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 
medication should be recorded in the eCRF using the following categories. For screen failure 
subjects, refer to Section 9.1.17.
Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
1.
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.

Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical Follow-up
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 


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normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time
during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or INR 
>1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
2.
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
Lost to Follow-up. The subject did not return to the clinic and attempts to contact the subject 
3.
were unsuccessful. Attempts to contact the subject must be documented.
Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
4.
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 (ie, withdrawal due to an 
AE).
Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
5.
Pregnancy. The subject is found to be pregnant. 
6.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
Other.
7.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. Discontinued or withdrawn subjects. Subjects that are discontinued from 
the study due to non-safety reasons may be replaced at the discretion of the sponsor.


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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 medication refers to all or any of the drugs defined below.
8.1.1.1
Study Drug
TAK-020 Drug Substance
TAK-020 drug substance is manufactured by Albany Molecular Research, Inc., 21 Corporate 
Circle, Albany, NY 12203. The drug substance is packaged in an appropriate container with a 
single panel label that contains, but will not be limited to the following information: protocol 
number, lot number, US caution statement, and name and address of the sponsor.
A pharmacy manual will be provided to the unblinded pharmacist at site.
TAK-020 Oral Solution
The TAK-020 drug substance will be compounded at the clinical site pharmacy into TAK-020 oral 
solution. Compounding instructions will be provided to the pharmacy. The composition of the oral 
solution can be found below (Table 8.b). The oral solution will be filled into amber glass bottles 
and labeled at the pharmacy. The bottle size will be based upon the volume of dose required. The 
planned dose for Cohort 1 is 0.1 mg, but dose for subsequent doses have not been defined. They 
will be determined following review of the safety, tolerability and PK data from the previous 
cohort. The current estimates for the doses to be used in subsequent cohorts are provided in 
Table 8.a. The dose may be adjusted by volume for subsequent cohorts based upon the previous 
cohort PK results.
The actual volume of solution given to a subject will be recorded on the eCRF.


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Table 8.a
Proposed Dosing Levels and Volume of Each Cohort (SRD)
Cohort
TAK-020
Dose Level
Volume of 
TAK-020 Solution
(0.1 mg/mL)
Volume of 
TAK-020 Solution
(1 mg/mL)
Volume of 
TAK-020 Solution
(5 mg/mL)
Volume of 
TAK-020 Solution
(7 mg/mL)
1
0.1 mg
1 mL
2
0.5 mg
5 mL
3
2.5 mg
2.5 mL
4
4.4 mg
4.4 mL
5
8.8 mg
8.8 mL
6
17.5 mg
3.5 mL
7
35 mg
7 mL
8
70 mg
10 mL
9
105 mg (TBD)
15 mL
TBD=to be determined following review of safety, tolerability and PK data from the previous cohort.
Table 8.b
Composition of TAK-020 Oral Solution, 0.1, 1, 5, 7, and 7.5 mg/mL
Component
Amount per 
mL*
0.1 mg/mL 
solution
1 mg/mL 
solution
5 mg/mL 
solution
7 mg/mL 
solution
7.5 mg/mL 
solution
TAK-020 (free base)
0.1 mg
1.0 mg
5.0 mg
7.0 mg
7.5 mg
Sodium hydroxide, NF 
grade
1.2 mg
1.2 mg
1.2 mg
1.2 mg
1.2 mg
Captisol, NF grade
200 mg
200 mg
200 mg
200 mg
200 mg
Phosphoric acid, NF 
grade
1.64 mg
1.64 mg
1.64 mg
1.64 mg
1.64 mg
Sterile water for 
irrigation, USP
q.s. to 1 mL
q.s. to 1 mL
q.s. to 1 mL
q.s. to 1 mL
q.s to 1 mL
NF= National Formulary, q.s.= quantity sufficient, USP= United States Pharmacopeia.
*The concentration may be prepared within the range of 0.1 mg/mL TAK-020 and 7.5 mg/mL TAK-020 to 
accommodate the dosing needs.
Placebo for TAK-020 Oral Solution
The placebo for TAK-020 Oral Solution will be compounded at the clinical site pharmacy. The 
placebo solution will contain the same concentration of excipients as the active solution without 
the active drug substance. Compounding instructions will be provided to the pharmacy. The 
composition of the oral solution can be found below (Table 8.c). The oral solution will be filled 
into amber glass bottles and labeled by the pharmacy. The bottle and filled volumes of the placebo 
oral solution will be identical to the corresponding dose level volumes of the TAK-020 Solution, 
as listed in Table 8.a.


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Table 8.c
Composition of Placebo for TAK-020 Oral Solution
Component
Amount per mL
TAK-020 (free base)
0 mg
Sodium hydroxide, NF grade
1.2 mg
Captisol, NF grade
200 mg
Phosphoric acid, NF grade
1.64 mg
Sterile water for irrigation, USP
q.s. to 1 mL
NF= National Formulary, q.s.= quantity sufficient, USP= United States Pharmacopeia.
8.1.1.2
Ancillary Materials 
Amber glass bottles will be used for dosing medication. The packaging for TAK-020 oral solution 
may use 5, 20, or 50 mL bottles. These will be provided by either the clinical site or Takeda based 
upon availability. If provided by Takeda, unused bottles will be accounted for and disposed of as 
directed by Takeda or a Takeda designee.
8.1.2
Storage
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All study medication must be stored under 
the conditions specified on the label, and remain in the original container until dispensed.
TAK-020 drug substance must be stored per the label at controlled room temperature 25°C (77°F), 
with excursions permitted between 15°C to 30°C (59°F to 86°F). All TAK-020 compounded 
solution must be stored under the condition specified in the compounding worksheet at 2°C to 8°C 
(36°F to 46°F). A do not use beyond date of 14 days after compounding will be assigned. Bottles 
containing TAK-020 compounded solution may be stored at controlled room temperature for up to 
24 hours prior to dosing. A daily temperature log of the drug storage area must be maintained 
every working day.
8.1.3
Dose and Regimen
In Cohorts 1 to 9, doses of 0.1, 0.5, 2.5, 4.4, 8.8, 17.5, 35, 70, and 105 mg have been evaluated. The 
investigator or investigator’s designee will instruct the subject on dosing procedures. All dosing 
will occur while subjects are in the clinic under the supervision of the PI or designee. On dosing 
days, subjects will be given TAK-020 or placebo oral solution. A separate pharmacy manual will 
describe how each dose regimen will be formulated.
Study drug will be administered at the same time on each dosing day (approximately 0800 hours). 
After initial administration, the dosing bottle shall be rinsed twice with about half the volume of 
the bottle with water. The rinse will be administered to the subject. The exact time of dose will be 
recorded in the source documents and on the appropriate eCRF.


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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 AEs.
Serious 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
For each dosing cohort, subjects will be assigned to receive a 4-digit randomization sequence 
number. The number will be assigned by the clinic site personnel in sequential order. A separate 
randomization schedule will be provided for Part 1, and Part 2.
Part 1 (SRD), the randomization sequence number will be from X001 to X008 for Cohort X, 
for example: 1001 to 1008 for Cohort 1, and 2001 to 2008 for Cohort 2, etc.
Part 2 (MRD), randomization sequence number will be from X101 to X108 for Cohort X, for 
example: 1101 to 1108 for Cohort 1, and 2101 to 2108 for Cohort 2, etc.
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 PK and PD 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 which is 
assigned at the time the informed consent is obtained and which is used for all other procedures to 
identify the subjects throughout the study.
8.3
Randomization Code Creation and Storage 
The randomization schedule will be generated by TDC Americas’ Quantitative 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
Study Drug Blind Maintenance 
The investigational drug blind is maintained through a randomization schedule held by the 
site-designated unblinded pharmacist or designee. 


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The investigator will receive the subject’s investigational drug blind information in the form of a 
sealed envelope, which will reveal the subject’s study treatments if opened. During regularly 
scheduled monitoring visits, a study monitor from the sponsor or a designee will perform an 
inventory of blinded sealed envelopes.
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 or by opening the sealed envelope for that subject.
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 (TAK-020), 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 
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.


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The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator or designee. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot 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 
and following dosing to ensure all subjects received the correct dose of study medication. 
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 
(TAK-020) 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 and/or retest date, date and amount 
dispensed, including signature of the person dispensing the drug, including the 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.
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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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 is located in Appendix A.
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 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
Pharmacogenomic Informed Consent Procedure 
Pharmacogenomics informed consent is a component of the overall study informed consent. The 
requirements are described in Section 15.2.
The pharmacogenomic (PGx) sample collection is mandatory.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, height, weight, caffeine consumption, alcohol use, reproductive status 
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 stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the pretreatment assessment immediately prior to the 
start of investigational drug) 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) nervous system; 
(10) lymph nodes; and (11) other. 


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Any abnormal change from the initial Screening physical examination must be assessed as not 
clinically significant (NCS) or clinically significant (CS) by the investigator and recorded in the 
source document and eCRF.
Any clinically significant change, as determined by the investigator, from the baseline physical 
examination will be recorded as an AE or pretreatment event in source documentation and on the 
Pretreatment Event/AE eCRF.
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 it 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. 
9.1.5
Vital Sign Procedure
Vital signs will include body temperature oral measurement, respiratory rate, sitting blood 
pressure (after 5 minutes resting) and pulse (beats per minute [bpm]). 
Vital signs should be measured at the same time of the day across visits if possible. When vital 
signs are scheduled at the same time as blood draws, the blood draw will take priority and vital 
signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. 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 medication (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. 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 


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examination abnormalities noted at screening examination. The condition (ie, diagnosis) should be 
described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 140 mL, and the approximate total volume of 
blood for the study is 300 mL for Part 1 and 413 mL for Part 2. Laboratory samples will be taken 
following a minimum 10-hour overnight fast on the days stipulated in the Schedule of Study 
Procedures Appendix A.
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry 
Urinalysis
RBC
WBC with differential 
[both % and absolute 
count]
Hemoglobin
Hematocrit
Platelets
prothrombin time /INR
aPTT
Fibrinogen
Alanine aminotransferase
Albumin
Albumin: Globulin ratio
Alkaline phosphatase
Amylase
Aspartate aminotransferase
Total bilirubin
Total protein
C-reactive protein
Cholesterol
Creatinine (eGFR) [8]
Cystatin -C
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase
Glutamate dehydrogenase
Lactate dehydrogenase
Potassium
Sodium
Glucose
Chloride
Quantitative IgA, IgG and IgM
Triglycerides
Bicarbonate
Calcium
Lipase
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Renal Biomarkers:
Kidney Injury Molecule-1 
(KIM-1)/ TIM-1 (T Cell 
Immunoglobulin Mucin 1) 
Cystatin C
Neutrophil 
Gelatinase-Associated 
Lipocalin (NGAL)
Urine Albumin
Urine Protein
Microscopic Analysis 
(performed only if urine 
evaluations are abnormal): 
RBC/high power field
WBC/high power field
Epithelial cells, casts etc
Diagnostic Screening:
Serum
Urine 
Hepatitis panel, including HBsAg and anti-HCV, 
(and/or HCV RNA), HIV-1 and HIV-2 screening, 
TB screening (QuantiFERON)
Drug screen, including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, alcohol, 
and cotinine.
Female subjects only:
hCG (for pregnancy)
FSH if menopause is suspected
aPTT= activated partial thromboplastin time, eGFR= estimated glomerular filtration rate, FSH= follicle-stimulating 
hormone, hCG=human chorionic gonadotropin, HIV= human immunodeficiency virus, Ig= immunoglobulin, RBC= 
red blood cells, RNA=ribonucleic acid, WBC= White blood cells.
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. If the laboratory is unable to electronically 
transfer data, the study site coordinator or designee is responsible for transcribing laboratory 
results to the eCRF. The investigator will maintain a copy of the laboratory accreditation and the 
reference ranges for the laboratory used.


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Laboratory reports must be signed and dated by the PI or subinvestigator indicating that the report 
has been reviewed and any abnormalities have been assessed for clinical significance.
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
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 12 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use double 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 last 
dose of study medication, or until after the next menstrual period, female subjects of childbearing 
potential* who are sexually active with a nonsterilized male partner** must use adequate 
contraception. In addition they must be advised not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as 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 medication 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.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception for female subjects are: 
Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):

Cap (plus spermicidal cream or jelly) PLUS 
male condom and spermicide.

Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom and spermicide.

Copper T PLUS condom or spermicide.


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Contraception allowed in female partners of male subjects (hormonal contraception is allowed in 
female partners):
Barrier methods (each time the 
subject has intercourse):
Intrauterine devices 
(IUDs):
Hormonal contraceptives:

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom 
or spermicide.

Progesterone T PLUS 
condom or spermicide.

Implants.

Hormone shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS male 
condom and spermicide.
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.
During the course of the study, regular serum hCG pregnancy tests will be performed for all female 
subjects and also both male and female subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm donation as part of the study procedures (Appendix A). In 
addition to a negative serum hCG pregnancy test at Screening, subjects also must have a negative 
serum hCG pregnancy test on Day -1 and at Check-out (Day 5 for Part 1 or Day 10 for Part 2) or 
Early Termination. If after Study Exit the expected menstruation is delayed, female subjects and 
female partners of male subjects must do a pregnancy test and inform the investigator 
immediately, if the pregnancy test is positive. See Section 9.1.10 for Pregnancy reporting and 
Follow-up until outcome.
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-020) should be immediately discontinued. In addition, any 
pregnancies in the female 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 medication, eg, after Day 1 or within 
12 weeks of the last dose of active study medication, 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. 


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If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable).
All reported pregnancies 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.
9.1.11 ECG Procedure 
9.1.11.1 Screening and Safety ECGs
A triplicate 12-lead ECG printed in standard format, will be collected at Screening, Check-in 
(Day -1), Day 1 predose (0 hours) and at 1, 4, 12, 24, 48, 72, and 96 hours postdose or at Early 
Termination in Part 1 (SRD) and at Screening, Check-in (Day -1), Day 1 predose (0 hours) and at 
1, 4, 12, 24 hours postdose, and also on Dosing Days 3, 5, 9, and 10 at predose (0 hours), or at 
Early Termination for Part 2 (MRD). 
The investigator will interpret the Safety ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded.
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, 
RR interval, QRS interval, PR interval, QT interval, and QT (corrected) (Fridericia’s and Bazett’s 
corrections).
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject safety and will 
be provided in an appropriate format with the clinical study report.
Ad hoc 12-lead ECGs will also be required, if a subject complains of palpitations, dizziness, 
sudden onset of breathlessness, chest tightness or any other symptoms of arrhythmia, between 
Day 1 (postdose) and Study Exit/Early Termination. Pulse checked immediately, and if it is 
greater than 80 bpm, a 12-lead ECG, blood pressure and pulse will be measured and recorded. The 
ECG, blood pressure and pulse measurements shall be reviewed by the Investigator, who will use 
clinical judgment regarding further monitoring and management.
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 signed by the physician or archival quality
paper can be utilized for ECG printouts, with a 25 year (or more) guarantee from the manufacturer 
(assuming appropriate storage conditions are satisfied). If a photocopy is made, it will be filed with 
the original ECG in the source.
When an ECG is scheduled at the same time as blood draws or vital signs, then the blood draws 
and vital signs will take priority and the ECG will be obtained within 0.5 hour before or after the 


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scheduled blood draw/vital sign assessment. If an ECG coincides with a meal, ECG will take 
precedence followed by the meal.
9.1.11.2 Telemetry
On Day 1 of Part 1 (SRD) and Days 1 and 9 of Part 2 (MRD), cardiac monitoring (telemetry) will 
be performed for approximately 2 hours prior to dosing through to approximately 12 hours 
postdose.
The site will use their standard telemetry system for monitoring rhythm and other ECG 
characteristics from approximately 2 hours prior to dosing through to approximately 12 hours 
postdose in each period. Subjects should remain sitting or supine for at least 5 minutes before each 
reading at each PK time point.
The data will be sent to Takeda who will engage a cardiac expert for reading the data, if required. 
Reporting of this data and any subsequent analysis will be reported separately.
Of interest are the ten (10) second triplicate ECGs that will be extracted at PK time-points for 
manual reading and precise ECG reading including QT interval measurement. The following 
parameters will be measured from the subject’s ECG trace: heart rate, QT interval, PR interval, 
QRS interval, RR interval and QTcF and QTcB corrections. The effect of increasing 
concentrations of TAK-020 on these parameters will be explored.
9.1.12 PGx Sample Collection
When sampling of whole blood for PGx analysis occurs, every subject must sign informed 
consent/be consented in order to participate in the study.
Deoxyribonucleic acid (DNA) and RNA form the basis for the genes that make the body produce 
proteins such as enzymes, drug transporters or drug targets, and may be evaluated for the genetic 
contribution how the drug is broken down, or how the drug affects the body. This is called a “PGx
research study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to TAK-020.

Finding out more information about how TAK-020 works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to TAK-020.

Identifying variations in genes related to the biological target of TAK-020.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of TAK-020 and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
DNA samples will be used to evaluate drug metabolizing enzymes and transporter polymorphisms 
that may contribute to the variability in PK of TAK-020. Since PGx is an evolving science, many 
genes and their functions are not yet fully understood. Future data may suggest a role of these 


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genes in drug response, which may lead to additional hypothesis-generating exploratory research 
and diagnostic development on stored samples.
Part 1- PGx Sample Collection
One whole blood sample (6 mL) for DNA isolation will be collected from each subject in the study 
before dosing on Day 1, into a plastic potassium ethylenediamine-tetraacetic acid (K2EDTA) 
spray-coated tube. 
Two whole blood samples (2.5 mL per sample) will be collected for RNA analysis from each 
subject in the study predose on Day 1 and at 24 hours postdose, in a PAXgene tube. 
Part 2 - PGx Sample Collection
One 6-mL whole blood sample for DNA isolation will be collected before dosing on Day 1 from 
each subject in the study, into plastic K2EDTA spray-coated tubes. 
Two whole blood samples (2.5 mL per sample) will be collected before dosing on Days 1, 3, and 9 
for RNA isolation from each subject in the study, into a PAXgene tubes. 
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible.
The DNA samples will be used to evaluate common variations in genes which encode drug 
metabolizing enzymes and transporters. This could be helpful in understanding why there are 
differences in TAK-020 kinetics between subjects.
Each PGx sample for a study subject should be identifiable on the requisition form with a 7-digit 
subject ID (the 4-digit site number plus the 3-digit subject number).
The PGx samples will be shipped to Covance at the address listed in Appendix E of this protocol.
The samples will be stored for no longer than 15 years after completion of the TAK-020 study 
and/or until the drug development of TAK-020 is no longer actively pursued by Takeda or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Takeda. “Stored samples” are defined as samples 
that are key-coded (the samples are stripped of all personal identifying information but a key links 
the samples to the clinical data collected from the sample donor) and are used in the analysis of 
investigational drug or related drugs.
Detailed instructions for the handling and shipping of samples will be compiled in a laboratory 
manual and provided to the site.
9.1.13 PK Sample Collection
9.1.13.1 Collection of Plasma for PK Sampling
Blood samples (one 6-mL sample per scheduled time) for pharmacokinetic analysis of TAK-020
will be collected into chilled Vacutainers containing K2EDTA according to the schedule in 
Appendix A. Instructions for sample processing and shipment are provided in Appendix E.


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Serial blood samples for determination of TAK-020 will be collected according to Table 9.b. 
Plasma samples will be taken at the following time points in the first cohort. Based on emerging
data in each cohort, the time points may be modified but will not exceed the number of samples 
presented and will not be taken after 96 hours in the SRD and 48 hours in the MRD.
Table 9.b
Collection of Blood Samples for PK Analysis
Part 1 (SRD)
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
1
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, 48, 72, and 96 hours postdose
Part 2 (MRD)
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
1
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 
12, 16, 24, 36, and 48 hours postdose
Plasma
9
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 
12, 16, and 24 hours postdose
The actual time of sample collection will be recorded on the source document and eCRF.
Sampling time points may be adjusted based on the preliminary emerging PK data collected from 
prior cohort(s), but the total number of samples collected per subject should not exceed the 
planned number. 
Placebo samples will not be analyzed by the bioanalytical laboratory except 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 protocol 
compliance that no additional subjects could have been on active treatment. 
9.1.13.2 Collection of Urine for PK Sampling
Serial urine samples for determination of TAK-020 will be collected according to Table 9.c. Urine
samples will be taken at the following time points in the first cohort. Based on emerging data in 
each cohort, the time points may be modified but will not exceed the number of samples presented 
and will not be taken after 96 hours in the SRD and 48 hours in the MRD.


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Table 9.c
Collection of Urine Samples for PK Analysis
Part 1 (SRD)
Sample Type
Dosing Day
Time Postdose (hours)
Urine
1
Predose (-12-0), and 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 hour postdose intervals
Part 2 (MRD)
Sample Type
Dosing Day
Time Postdose (hours)
Urine
1
Predose (-12-0), and 0-6, 6-12, 12-24 hour postdose intervals
Urine
9
Predose (-12-0), and 0-6, 6-12, 12-24 hour postdose intervals
Instructions for sample processing and shipment are provided in Appendix E.
Urine samples for subjects randomized to placebo will not be analyzed.
9.1.13.3 Bioanalytical Methods
Plasma and urine concentrations of TAK-020 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry.
Part of the archival plasma and urine samples will be sent to TDC Japan/Development Research 
Center for potential analysis of unknown metabolite characterization, if appropriate.
9.1.14 PK Parameters 
The pharmacokinetic parameters of TAK-020 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. 
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The following plasma PK parameters will be determined: 
Symbol/Term
Definition
Plasma/Blood/Serum
AUC24
Area under the plasma/blood/serum concentration-time curve from the time 0 to time 24 
hours. 
AUCτ
Area under the plasma/blood/serum concentration-time curve during a dosing interval, where 
tau (τ) is the length of the dosing interval.
AUCt
Area under the plasma/blood/serum concentration-time curve from time 0 to time of the last 
quantifiable concentration
AUC∞
Area under the plasma/blood/serum concentration-time curve from time 0 to infinity, 
calculated as AUC∞=AUCt+Clast/λz
R
Accumulation ratio (index) calculated as AUCτ at steady state/AUC∞ after a single dose.
Rac(AUC)
Accumulation ratio (based on AUC), calculated as AUCτ at steady state/AUCτ after a single 
dose.
Cmax
Maximum observed plasma/blood/serum concentration.
Cmax,ss
Maximum observed steady-state plasma/blood/serum concentration during a dosing interval.
CL/F
Apparent clearance after extravascular administration, calculated as =Dose/AUC∞after a 
single dose and as Dose/AUCτ after multiple dosing (at steady state).
λz
Terminal elimination 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.
t1/2z
Terminal disposition phase half-life, calculated as ln(2)/λz.
tlag
Lag time.
tmax
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal phase after extravascular administration, 
calculated as (CL/F)/λz.
The following urine PK parameters of TAK-020 will be determined:
Urine
Aet1-t2
Amount of drug excreted in urine from time 1 to time 2, calculated as Cur×Vur, where Cur is the 
concentration of drug excreted in urine and Vur is the volume of urine excreted.
Aet
Total amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval (τ) at steady state.
fe
Fraction of drug excreted in urine, calculated as (Aet/dose)×100. Molecular weight adjustment 
needed for metabolites.
CLR
Renal clearance, calculated as Ae0-24/AUC24.
9.1.15 PD Sample Collection 
Sampling times for sampling collection are shown in the tables below.


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Instructions for sample processing and shipment are provided in Appendix E.
9.1.15.1
9.1.15.2 BTK Occupancy Assay
9.1.16 PD Parameters 
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9.1.17 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. 

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. 
9.1.18 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.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study medication, 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 medication 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).


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9.3.1
Final Visit/Check-out 
Final Visit for Part 1 will be on Day 5 and Part 2 will be on Day 10. The following procedures will 
be performed and documented:
!
Physical exam.
!
Vital signs.
!
Weight.
!
Concomitant medications.
!
Clinical lab tests.
!
Serum pregnancy test (female subjects only).
!
!
12-lead ECG.
!
PK blood collection.
!
PK urine collection.
!
PD blood collection.
!
AE assessment.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.2
Early Termination
The reason for discontinuation must be documented in the source document and eCRF. The 
following procedures will be performed and documented:
!
Physical exam.
!
Vital signs.
!
Weight.
!
Concomitant medications.
!
Clinical lab tests.
!
Serum pregnancy test (female subjects only).
!
!
12-lead ECG.
!
PK blood collection.
!
PK urine collection.
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
PD blood collection.

AE assessment.
The PK/PD sample collection should be collected at the Early Termination Visit, if possible and 
relatively close to a protocol-specified time point. For example, collect samples if early 
withdrawal is due to an AE, and/or if several hours elapsed since last blood draw.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.3
Follow-up Visit/Telephone Call 
Subjects with unresolved SAEs, CS laboratory abnormalities, ECG or physical exam findings or at 
the PI’s discretion should be seen for a Follow-up visit on Day 14 (±2 days) in Part 1 for 
appropriate repeat procedure(s). A Follow-up phone call will be made to all other subjects on 
Day 14 (±2 days) in Part 1 for an assessment of AEs and concomitant medications. In Part 2, all 
subjects will return the clinical site on Day 17 (±2 days) for laboratory tests (Hematology, Serum 
Chemistry, Urinary renal biomarkers, and PD tests), assessment of vital signs, AEs and 
concomitant medications.
9.4
Biological Sample Retention and Destruction 
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.12,
Pharmacogenomic Sample Collection. The genetic material will be preserved and retained at 
Covance for up to but not longer than 15 years or as required by applicable law. The sponsor has 
put into place a system to protect the subjects’ personal information to ensure optimal 
confidentiality and defined standard processes for sample and data collection, storage, analysis, 
and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The samples will be initially stored at Covance. The Sponsor and 
researchers working with the Sponsor will have access to the samples collected and any test 
results. All samples collected during the study will be stored securely with limited access and the 
Sponsor will require anyone who works with the samples to agree to hold the research information 
and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers; the samples are stripped of all personal identifying information but a key linking 
the samples to clinical analysis data exists. This link means that the subject may be identified but 
only indirectly. The code numbers will be kept secure by or on behalf of the Sponsor.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify sponsor 
of consent withdrawal.


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9.5
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.d.
Table 9.d
Approximate Blood Volume
Part 1
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total Volume 
(mL)
Day -28
to -2
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5 (a)
Safety laboratory 
samples
29 (b)
19 (c)
1
1
1
1
1
1
124
PK samples
6
--
--
13
2
1
1
1
108
PD samples
4
--
--
8
2
1
1
1
52
PGx - DNA
6
--
--
1
--
--
--
6
PGx - RNA
2.5
--
--
2
2
--
--
--
10
Blood volume (mL)
29
19
140
44
29
10
29
300
(a) If abnormal labs at Check Out are outside markedly abnormal values (to be provided by Takeda in the final study 
protocol), repeat labs on Day 14 (±2) until resolution and report as a TEAE.
(b) Screening Visit only.
(c) Days -1 to 5.
Part 2
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Day -2
8 to -2Day -1 Day 1 Day 2 Day 3 Day 4 Day 5
Days
6 to 8 Day 9
Day 
10 (a)
Follow-
up
Safety 
laboratory 
samples
29 (b)
19 (c)
1
1
1
1
1
--
1
--
--
1
1
162
PK samples
6
--
--
13
2
--
--
--
--
13
1
174
PGx - DNA
6
--
--
1
--
--
--
--
--
--
--
6
PGx - RNA
2.5
--
--
2
--
2
--
--
--
2
--
15
Blood volume 
(mL)
29
19
130
37
26
0
19
0
105
29
23
417
(a) If abnormal labs at Check Out are outside markedly abnormal values (to be provided by Takeda in the final study 
protocol), repeat labs on Day 17 (±2) until resolution and report as a TEAE.
(b) Screening Visit only.
(c) Days -1 to 10.
The maximum volume of blood at any single day is approximately 140 mL, and the approximate 
total volume of blood for the study is 300 mL for Part 1 and 417 mL for Part 2.
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Direct venipuncture is the preferred method of blood collection. Any other method of blood 
collection will need to be approved by the sponsor before use.
If a catheter with a normal saline flush is used, the total blood volume does not include discarded 
blood from predraws (assuming approximately 1 mL of blood is discarded each time a sample is 
collected from a catheter). Should a catheter be used, the total blood volume taken during the study 
must not exceed 500 mL.


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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 
medication; 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 medication 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 a PTE(s) or as an 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 retest 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 medication) or 
an AE (worsening or complication occurs after start of study medication). 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 medication, 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 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /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.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered 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 
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.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome /malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
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 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.
10.1.6 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which 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.
10.1.7 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.


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10.1.8 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.
10.1.9 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.
10.1.10
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11
Action Concerning Study Medication 

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.
10.1.12
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 which are considered as 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.


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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 continue until the subject is first administered study medication on 
Day 1 or until screen failure. For subjects who discontinue prior to study medication 
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 
medication on Day 1. Routine collection of AEs will continue until the Follow-up telephone call at 
14 (±2) days for Part 1 and the Follow-up visit at 17 (±2) days for Part 2 after last dose of study 
medication.
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.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All 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.
1.
Start and stop date {and time}.
2.
Frequency.
3.
Severity.
4.
Investigator’s opinion of the causal relationship between the event and administration of study 
5.
medication(s) (related or not related) (not completed for PTEs).
Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
6.
the suspected procedure.
Action concerning study medication (not applicable for PTEs).
7.
Outcome of event.
8.


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Seriousness.
9.
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 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 medication(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 LFTs
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. Concerning ALT/AST 
increases, please also see Section 6.1.2 Criteria for Stopping Dose Escalation.
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, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited report 
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of 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 his or her IRB or 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(s) and pharmacovigilance physician) 
and the PI will review the safety and tolerability data, pharmacokinetic data for each cohort prior to 
dosing any additional cohort. The decision for the next subsequent dose must be agreed by all 
representatives of Takeda and the PI. If any one person has concerns regarding subsequent dosing,
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 
Drug Dictionary (WHODRUG).
12.1
Electronic CRFs 
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 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 to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. All 
new additions are to be made with the date and signature.
The PI 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 PI must review the data change for completeness and accuracy, and must sign and 
date. 
The 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), 


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and query responses/ electronic copy of eCRFs, including the audit trail, and detailed records of 
drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the subject’s chart to ensure long-term 
legibility. Furthermore, International Conference on 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 unblinding of subject’s 
treatment assignment and 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
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous demographic variables and baseline characteristics variables (eg. age, height, weight, 
and BMI) for pooled placebo, each TAK-020 dose level, TAK-020 overall, and total overall. The 
number and percentage of subjects in each class of the categorical demographic variables and 
baseline characteristics variables (eg. gender, ethnicity, and race) will be tabulated for pooled 
placebo group, each TAK-020 dose level, TAK-020 overall, and total overall. Individual subject 
demographic and baseline characteristics data will be listed. Placebo data will be pooled across the 
cohorts. Part 1 and Part 2 data will be summarized separately.
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.


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13.1.3 PK Analysis
13.1.3.1 Concentrations in Plasma and Urine
Concentrations of TAK-020 in plasma will be summarized by dose level over each scheduled 
sampling time using descriptive statistics. Individual plasma concentration data vs time will be 
presented in a data listing.
Amount of TAK-020 excreted in urine will be summarized by dose level over each scheduled 
sampling interval using descriptive statistics. Individual urine concentration data along with 
volume vs time intervals will be presented in a data listing.
PK concentration data in Part 1 and Part 2 will be summarized separately.
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 PK parameters for TAK-020
by dose level and population. In addition, geometric mean and coefficient of variation will be 
computed for Cmax and AUCs. All PK parameter data will be listed.
Power model will be used to assess dose proportionality for Cmax and AUC in each part. 
The power model will be assumed as described by the following equation:
Where β0 is the intercept, β1 is the slope and ɛ is the random error.
The 90% confidence interval (CI) of the slope estimate will be presented. 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).
Analysis of variance (ANOVA) will be performed for Tmax and λz after a single or multiple dose 
administration to evaluate the effect of dose on Tmax for SRD and MRD parts and λz for SRD part.
ANOVA will be used to assess time dependency for Part 2 (MRD). The natural log-transformed 
AUCs and Cmax will be used as response variable and dose level, Day and the interaction of dose 
level and Day will be fixed factors. Within the frame work of ANOVA, 90% CIs for the ratio of 
AUCs and Cmax central values between Days 9 and 1 will be presented.
Detailed analysis methodologies will be presented in SAP as necessary. 






)
log(
)
log(
1
0
Dose
r
PKParamete








)
ln(
)
25
.1
ln(
1
,
)
ln(
)
80
.0
ln(
1
r
r


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13.1.4 PD Analysis
Descriptive statistics will be used to summarize PD parameters. 
The relationship between dose, TAK-020 concentrations, PK parameters, and PD response will be 
explored and PKPD models developed if deemed appropriate.
Detailed analysis methodologies will be presented in SAP as necessary.
13.1.5 Safety Analysis
The safety summary tables presented under this section will be summarized by placebo group, 
each TAK-020 dose level and TAK-020 overall for single and multiple doses of Part 1 and Part 2 if 
not specified otherwise. Placebo data will be pooled across the cohort of each Part. The subjects 
who meet pre-defined MAV criteria for laboratory tests, vital signs and ECG parameters will be 
summarized and listed.
13.1.5.1 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 included in the summary tables. All AEs will be in the listings. 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.
13.1.5.2 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet TDC’s 
markedly abnormal criteria will be summarized and listed. Baseline, postdose, and change from 
Baseline to postdose laboratory data will be summarized by placebo and TAK-020 dose level. All 
clinical laboratory data will be listed. 
13.1.5.3 Vital Signs
Individual results of vital signs that meet TDC’s markedly abnormal criteria will be summarized 
and listed. Baseline, postdose, and changes from Baseline in vital sign measurements will be 
CCI
CCI


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summarized by placebo and TAK-020 dose level. All vital sign data will be provided in the data 
listings. 
13.1.5.4 ECGs
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet TDC’s 
markedly abnormal criteria will be summarized and listed. Baseline, postdose, and changes from 
Baseline in quantitative ECG parameters will be summarized by placebo and TAK-020 dose level. 
Shift tables will be generated for the investigator’s ECG interpretations that changed from 
Baseline to the postdose assessments. All ECG data will be provided in the data listings.
The relationship between telemetry ECG parameters (change from Baseline) and TAK-020
concentration will be assessed.
The analysis end points and baseline choice of the triplicate ECG will be defined in detail in SAP.
13.1.5.5 Safety Biomarkers
Renal biomarkers will be summarized, and the relationship between serum eGFR or serum 
creatinine and renal biomarkers will be explored. 
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned. Section 6.1.1 describes the blinded safety and PK review which 
will take place after completion of each cohort and prior to the next dose escalation stage in the 
study.
13.3
Determination of Sample Size
The sample sizes chosen of 8 subjects per cohort (6 active: 2 placebo) in Part 1 and 2 is considered 
to be sufficient for evaluation of safety, tolerability, PK and the PD of TAK-020 in 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 (contract research organization) and by the IRB or 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 medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, 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. 
The investigator should document all protocol deviations.
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 by entering it into the significant deviation eCRF.


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Protocol Deviation Forms are to be entered for pharmacokinetic/pharmacodynamic samples 
collected outside of the following intervals:
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 postdose
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, 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 B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or 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 IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives notification 
no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify sponsor 
of consent withdrawal.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical 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.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the 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 


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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 
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 www.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
1. Krupa A, Fudala R, Florence JM, Tucker T, Allen TC, Standiford TJ, et al. Bruton's tyrosine 
kinase mediates FcgammaRIIa/Toll-like receptor-4 receptor crosstalk in human neutrophils. 
Am J Respir Cell Mol Biol 2013;48(2):240-9.
2. Kawakami Y, Kitaura J, Hata D, Yao L, Kawakami T. Functions of Bruton's tyrosine kinase in 
mast and B cells. J Leukoc Biol 1999;65(3):286-90.
3. Luo W, Mayeux J, Gutierrez T, Russell L, Getahun A, Muller J, et al. A balance between B cell 
receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining 
optimal Ets1 levels. J Immunol 2014;193(2):909-20.
4. Bonami RH, Sullivan AM, Case JB, Steinberg HE, Hoek KL, Khan WN, et al. Bruton's 
tyrosine kinase promotes persistence of mature anti-insulin B cells. J Immunol 
2014;192(4):1459-70.
5. Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, et al. The Bruton 
tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple 
effector cells. Arthritis Res Ther 2011;13(4):R115.
6. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358(9285):903-11.
7. 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.
8. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130(6):461-70.


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Appendix A
Schedule of Study Procedures
Part 1 (SRD)
Screening
Check-in
Treatment
Check-out
Early 
Termination
Follow-up
Study Day:
Days -28 
to -2
Day -1
Day
1
Day 
2
Day 
3
Day 
4
Day 5
(a)
Day 14 
(±2) (b)
Confinement 
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
X
Medication history
X
Physical examination
X
X(c)
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
Weight, height, and BMI (e)
X
X
X
X
Concurrent medical conditions
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
Clinical laboratory tests (g)
X
X
X
X
X
X
Hepatitis panel
X
HIV screening
X
TB screening
X
Pregnancy test (hCG) (h)
X
X
X
X
Urine drug/alcohol/cotinine 
screen 
X
X
ECG (j)
X
X
X
X
X
X
X
X
Telemetry (k)
X
PGx DNA sample collection (l)
X
PGx RNA sample collection 
(m)
X
X
PK blood collection (n)
X
X
X
X
X
X
PK urine collection (o)
X
X
X
X
X
X
Dispense study medication
X
PTE assessment (q)
X
X
X
AE assessment
X
X
X
X
X
X
X
Footnotes are on the next page.
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(a) Conduct procedures for subjects discontinued early. The PK sample collection should be collected at the Early Termination
Visit, if possible. For example, collect samples if early withdrawal is due to an AE, and/or if several hours elapsed since last blood 
draw. 
(b) The Follow-up Visit will occur by telephone on Day 14 (±2) unless abnormal, clinically significant findings were observed upon 
discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s discretion.
(c) The physical examination can be conducted within 24 hours prior to study drug administration.
(d) Vital signs (oral temperature, sitting pulse, and blood pressure) will be collected at Screening and Check-in (Day -1), Day 1 
predose (0 hours) and at 1, 4, 12, 24, 48, 72, 96 hours postdose or Early Termination.
(e) Height will only be collected at Screening.
(f) Record all medications (other than study drug) from Screening and throughout the study.
(g) Clinical laboratory tests (hematology, serum chemistries, and urinalysis) will be collected at Screening, Day -1, Days 2 and 3, 
and prior to check-out (Day 5) or Early Termination. Laboratory samples will be taken following a minimum 10-hour overnight 
fast.
(h) Pregnancy test (hCG) will be performed for all female subjects.
(i) 
y 
(j) Triplicate 12-lead ECGs printed in standard format, will be collected at Screening, Check-in (Day -1), Day 1 predose (0 hours) 
and at 1, 4, 12, 24, 48, 72 and 96 hours postdose or Early Termination. For ad hoc ECGs, as required, see Section 9.1.11.
(k) Telemetry will be performed approximately 2 hours predose until 12 hours postdose on Day 1. Ten (10) sec triplicate ECGs will 
be extracted at PK time-points for manual reading and precise ECG reading including QT interval measurement.
(l) One blood sample (6 mL) will be collected prior to dosing on Day 1.
(m) Two whole blood samples (2.5 mL per sample) will be collected on Days 1 (predose) and 24 hours postdose. 
(n) Blood samples for PK analysis will be collected on Day 1 at predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 
1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose.
(o) Urine samples for PK analysis will be collected on Day 1 at predose (-12-0) and 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 hour 
postdose intervals.
(p) Blood samples for PD analysis will be collected on Day 1 at predose (within 30 minutes prior to dosing) and at 0.5, 1, 2, 4, 8, 12, 
16, 24, 36, 48, 72 and 96 hours postdose.
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1.
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Part 2 (MRD)
Screening
Check-in
Treatment
Washout
Treatment
Check-out
Early 
Termination
Follow-up
Visit
Study Day:
Days -28 
to -2
Day -1
Day 1
Day 2
Day 3-9
Day 10
(a)
Day 17 
(±2) (b)
Confinement 
X
X
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics and 
medical history
X
X
Medication history
X
Physical examination
X
X (c)
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
Weight, height, and 
BMI (e)
X
X
X
X
Concurrent medical 
conditions
X
X
Concomitant 
medications (f)
X
X
X
X
X
X
X
X
Clinical laboratory 
tests (g)
X
X
X
X
X
X
X (s)
Hepatitis panel
X
HIV screening
X
TB screening
X
Pregnancy test (hCG) 
(h)
X
X
X
X
Urine 
drug/alcohol/cotinine 
screen 
X
X
ECG (i)
X
X
X
X
X
X
X
Telemetry (j)
X
X
PGx DNA sample 
collection (k)
X
PGx RNA sample 
collection (l)
X
X
PK blood collection 
(m)
X
X
X
X
X
PK urine collection 
(n)
X
X
X
X
X
Dispense study 
medication
X
X
PTE assessment (r)
X
X
X
AE assessment
X
X
X
X
X
X
Footnotes are on the next page.
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(a) Conduct procedures for subjects discontinued early. The PK sample collection should be collected at the Early Termination
Visit, if possible. For example, collect samples if early withdrawal is due to an AE, and/or if several hours elapsed since last blood 
draw]. 
(b) All subjects will return to the unit and complete Hematology and Serum Chemistry tests, vital signs, concomitant medications, 
and AE assessment.
(c) The physical examination can be conducted within 24 hours prior to study drug administration.
(d) Vital signs (oral temperature, sitting pulse, and blood pressure) will be collected at Screening and Check-in (Day -1) and on 
Day 1 at predose (0 hours) and 1, 4, 12, 24 hours postdose, then twice daily until Study Exit (Day 10) or Early Termination and once 
during the Follow-up visit.
(e) Height will only be collected at Screening.
(f) Record all medications (other than study drug) from Screening and throughout the study.
(g) Clinical laboratory tests (hematology, serum chemistries, and urinalysis) will be collected at Screening, Day -1, Days 2, 3, 5, 8 
and prior to check-out (Day 10) or Early Termination. Laboratory samples will be taken following a minimum 10-hour overnight 
fast
(h) Pregnancy test (hCG) will be performed for all female subjects.
(i) Triplicate 12-lead ECGs printed in standard format, will be collected at Screening, Check-in (Day -1), Day 1 predose (0 hours) 
and at 1, 4, 12, and 24 hours postdose, Days 3, 5, 9, 10 at predose (0 hours) or Early Termination. For ad hoc ECGs, as required, see 
Section 9.1.11.
(j) Telemetry will be performed approximately 2 hours predose until 12 hours postdose on Days 1 and 9 only. Ten (10) sec triplicate 
ECGs will be extracted at PK time-points for manual reading and precise ECG reading including QT interval measurement.
(k) One blood sample (6 mL) will be collected prior to dosing on Day 1.
(l) Two whole blood samples (2.5 mL per sample) will be collected at predose on Days 1, 3 and 9. 
(m) Blood samples for PK analysis will be collected at predose on Day 1 (within 30 minutes prior to dosing) and at 0.25, 0.5, 0.75, 
1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours postdose and at predose on Day 9 (within 30 minutes prior to dosing) and at 0.25, 0.5, 
0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose.
(n) Urine samples for PK analysis will be collected on Day 1 and Day 9 at predose (-12-0), and 0-6, 6-12, 12-24 hour postdose 
intervals.
(o) 
(p)
(q)
(r) PTEs will be collected from signing of informed consent up until dosing on Day 1
(s) Hematology and Serum Chemistry only.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
Conduct the study in accordance with the protocol.
1.
Personally conduct or supervise the staff that will assist in the protocol.
2.
Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
3.
screening assessments, are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
4.
these obligations.
Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
5.
21 Code of Federal Regulations (CFR) Part 56 ICH, and local regulatory requirements.
Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
6.
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
Ensure that requirements for informed consent, as outlined in 21 CFR Part 50 ICH and local 
7.
regulations, are met.
Obtain valid informed consent from each subject who participates in the study, and document 
8.
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
Prepare and maintain adequate case histories of all persons entered into the study, including 
9.
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 
documents.
Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
10.
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Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
11.
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
12.
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
A statement that the study involves research.
1.
An explanation of the purposes of the research.
2.
The expected duration of the subject’s participation.
3.
A description of the procedures to be followed, including invasive procedures.
4.
The identification of any procedures that are experimental.
5.
The estimated number of subjects involved in the study.
6.
A description of the subject’s responsibilities.
7.
A description of the conduct of the study.
8.
A statement describing the treatment(s) and the probability for random assignment to each 
9.
treatment.
A description of the possible side effects of the treatment that the subject may receive.
10.
A description of any reasonably foreseeable risks or discomforts to the subject and, when 
11.
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 
12.
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 
13.
advantageous to the subject and their important potential risks and benefits.
A statement describing the extent to which confidentiality of records identifying the subject 
14.
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
For research involving more than minimal risk, an explanation as to whether any compensation 
15.
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.
16.
The anticipated expenses, if any, to the subject for participating in the study.
17.
An explanation of whom to contact for answers to pertinent questions about the research 
18.
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
A statement that participation is voluntary, that refusal to participate will involve no penalty or 
19.
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 


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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 
20.
orderly termination of participation by the subject.
A statement that the subject or the subject’s legally acceptable representative will be informed 
21.
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
A statement that results of PGx analysis will not be disclosed to an individual, unless 
22.
prevailing laws require the sponsor to do so.
The foreseeable circumstances or reasons under which the subject’s participation in the study 
23.
may be terminated.
A written subject authorization (either contained within the informed consent form or provided 
24.
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
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25. 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 until the next menstrual period or 
30 days after last dose, whichever is first. Regular pregnancy tests will be performed 
throughout the study for all female subjects. If a subject is found to be pregnant during study, 
study medication 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
26.
Screening, throughout the duration of the study and for 12 weeks after last dose. If the partner 
or wife of the subject is found to be pregnant during the study, the investigator will offer the 
subject the choice to receive unblinded treatment information. 
A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
27.
accessible website, such as www.ClinicalTrials.gov. 


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


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Appendix E
Collection, Storage, and Shipment of Bioanalytical/Genotyping/RNA Samples 
Instructions for Processing of Plasma Samples for Pharmacokinetic Analysis of TAK-020
1. Collect 6 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All TAK-020 blood 
samples should be collected into vacutainers containing K2EDTA.
2. Gently invert the vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. 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 manufacturer’s instruction 
for proper centrifugation force and time.
4. 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 should include protocol number (TAK-020-1001), sample matrix (ie, 
plasma) randomization sequence number, Part (ie. 1 or 2), profile day and nominal time, and 
either “SET 1” (for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20°C or lower until shipment to 
, Whitesboro, 
NY, USA. No more than 45 to 60 minutes will elapse between blood collection and freezing 
the plasma sample.
Instructions for Processing of Urine Samples for PK Analysis of TAK-020
1. 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 of 2% Tween 80 to 
prevent absorption to containers.
2. At the end of each void, mix the urine, transfer to a graduated cylinder and measure and record 
the volume. For the urine sample in the graduated cylinder, measure “X” amount of 2% Tween 
80 solution (2% Tween 80 by volume in water) into a separate graduated cylinder (where “X” 
equals 1 part in 10 of the urine volume in the cylinder).
3. Pour 3/4 of the “X” amount of Tween 80 solution into the graduated cylinder containing the 
subject’s urine collection. Mix and transfer to the collection jug for the time period.
4. With the remaining Tween 80 solution, rinse the collection container and combine with the 
sample in the collection jug for the time period.
5. Store the collection jug refrigerated during the collection period. Record the total volume of 
urine sample collected.
6. Mix well and measure the urine volume within 2 hours of the end of the collection period.
7. Transfer approximately10 mL aliquots of urine in duplicate into appropriate polypropylene 
containers. Containers should be filled to between 60% and 90% of nominal volume. Labeling 
should include protocol number (TAK-020-1001), Part (ie, 1 or 2), sample matrix (ie, urine), 
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randomization number, nominal day, nominal collection time interval, and either “SET 1” (for 
original sample), or “SET 2” (for duplicate sample).
8. Cap the labeled storage tubes and immediately freeze the urine samples and store at 
approximately -70°C or lower in an upright position until shipment to 
 
, Whitesboro, NY, USA.
Shipping of Plasma and Urine Samples 
The following instructions are recommended unless they differ from the site’s standard operating 
procedures for labeling, packaging, or shipping of PK samples.
1. Biological samples (ie, plasma or urine) 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 sequence number, sample matrix 
(ie, plasma or urine), 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 3 through 6 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 medication (TAK-020), protocol number (TAK-020-1001), 
investigator’s name, sample type (ie, plasma or urine), subject randomization sequence 
number, Part (ie. 1 or 2), nominal 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 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.
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CONFIDENTIAL
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 and Urine Samples for TAK-020
Project Leader 1
12. 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)
13. 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.
14. Obtain the airway bill number and a receipt of shipment from the carrier.
15. After shipping of the TAK-020 samples, please notify 
 at 
 by email 
) and copy 
 (
to notify them 
of next day delivery. When emailing, provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
Instructions for Processing and shipping of Blood Samples for PD Analysis
Occupancy Assay)
Sample tube requirements and processing instructions for the PD assays will be compiled in a 
laboratory manual and provided to the site.
CCI
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Protocol Incorporating Amendment No. 4.0
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CONFIDENTIAL
Instructions for processing and shipping of plasma samples for DNA and RNA PGx
Sample tube requirements and processing instructions for the PGx samples will be compiled in a 
laboratory manual and provided to the site.
The storage provider has validated procedures in place for transport, delivery, retention, retrieval, 
and destruction of the specimens, and will appropriately retain the specimens for up to but not 
longer than 15 years as required by applicable law. 


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Study No. TAK-020-1001
Page 99 of 101
Protocol Incorporating Amendment No. 4.0
27 March 2017
CONFIDENTIAL
Appendix F
Detailed Description of Amendments to Text 
The primary section(s) of the protocol affected by the changes in Amendment No. 04 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Changed name of Responsible Medical Officer.
The primary change occurs in Section 1.1, Contacts
Initial wording:
New wording:
Rationale for Change:
This change reflects a staffing change at Takeda
has replaced
as Responsible Medical Officer for the study and as a Protocol Signatory.
Section 1.2, Approval also contains this change.
Change 2: Specified doses administered for initial cohorts of Part 2.
The primary change occurs in Section 6.1.1 Dose Escalation
Initial wording:
Part 2
MRD 
Evaluation
Cohort 
1∀
Cohort 
2∀
Cohort 
3∀
Cohort 
4∀
Cohort 
5∀
Cohort 
6∀
Cohort 7
3.75 mg 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
New wording:
Part 2
MRD 
Evaluation
Cohort 
1∀
Cohort 
2∀
Cohort 
3∀
Cohort 
4∀
Cohort 
5∀
Cohort 
6∀
Cohort 7
3.75 mg 
TAK-020
or placebo
X 5.75 mg 
TBD
TAK-020
or placebo
X 13 mg 
TBD
TAK-020
or placebo
X 25 mg 
TBD
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
X mg TBD 
TAK-020
or placebo
Rationale for Change:
The actual doses were based on PK data that is now available.
Section 6.2, Justification for Study Design, Dose, and Endpoints also contains this change.
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CONFIDENTIAL
Change 3: Added PD biomarkers to Follow-up Visit (Day 17).
The primary change occurs in Section 9.1.15, PD Sample Collection.
Initial wording:
New wording:
Rationale for Change:
 
CCI
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Study No. TAK-020-1001
Page 101 of 101
Protocol Incorporating Amendment No. 4.0
27 March 2017
CONFIDENTIAL
Sections that also contain this change are:
!
Section 2.0, STUDY SUMMARY.
!
Section 9.3.3, Follow-up Visit/Telephone Call.
!
Section 9.5, Blood Volume.
!
Appendix A, Schedule of Study Procedures, Part 2 MRD.
Change 4: Clarified method used for PD analyses.
This change occurs in Section 13.1.4 PD Analysis
Initial wording:
PD data in Part 1 and Part 2 will be summarized separately. All PD results will 
be included in the listing.
New wording:
PD data in Part 1 and Part 2 will be summarized 
separately. All PD results will be included in the listing.
Rationale for Change:
The change was made to clarify the methods used to analyze the data.
CCI
CCI
CCI


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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.
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
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.
Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending Single-and 
Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-020 in 
Healthy Volunteers 
Approve Date: 22-May-2017
NCT Number: TAK-020-1001


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-020-1001
TAK-020 SRD/MRD Study
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending 
Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of TAK-020 in Healthy Volunteers
PHASE 1
Version: Final
Date: 22 May 2017
Prepared by:
Based on:
Protocol Version: Amendment 4
Protocol Date: 27 March 2017
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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TAK-020-1001
Page 2 of 31
Statistical Analysis Plan Final
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CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


TAK-020-1001
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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 Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
Exploratory Endpoints ...............................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.1.3
Definition of Study Visit Windows ....................................................................12
7.1.4
Conventions for Missing Adverse Event Dates...................................................13
7.1.5
Conventions for Missing Concomitant Medication Dates...................................13
7.1.6
Conventions for Missing Data............................................................................13
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Medication History and Concomitant Medications...................................................14
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................15
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................15
7.9.1
Pharmacokinetic Analysis ..................................................................................15
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................20
7.11
Safety Analysis........................................................................................................20


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7.11.1 Adverse Events ..................................................................................................20
7.11.2 Clinical Laboratory Evaluations .........................................................................21
7.11.3 Vital Signs .........................................................................................................21
7.11.4 12-Lead ECGs ...................................................................................................22
7.11.5 Other Observations Related to Safety.................................................................22
7.12
Interim Analysis ......................................................................................................23
7.13
Changes in the Statistical Analysis Plan...................................................................23
8.0
REFERENCES..............................................................................................................24
LIST OF IN-TEXT TABLES
Table 4.a
Schematic of Study Design ..................................................................................8
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................16
Table 7.b
Collection of Urine Samples for Pharmacokinetic Analysis................................16
Table 7.c
Plasma and Urine PK Parameters .......................................................................17
Table 7.d
Pharmacodynamic Sample Collection ................................................................19
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................25
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values .................29
Appendix C
Criteria for Identification of Markedly Abnormal Vital Signs Parameters...........30
Appendix D
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters ......31


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3.0
LIST OF ABBREVIATIONS
ADaM
Analysis Data Model
AE
adverse event
Aet
total amount of drug excreted in urine from time 0 to time t
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUCt
area under the plasma concentration-time curve from time 0 to the time of last 
quantifiable concentration
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCτ
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) 
is the length of the dosing interval
BMI
body mass index
CI
confidence interval
CL/F
apparent clearance after extravascular administration
CLR
renal clearance
Cmax
maximum observed plasma concentration
CPAP
Clinical Pharmacology Analysis Plan
%CV
coefficient of variation
CV
conventional units
ECG
electrocardiogram
Emax
maximum observed effect
fe
fraction of drug excreted in urine
LLOQ
lower limit of quantification
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple rising dose
NOAEL
no observed adverse effect level
PD
pharmacodynamics
PK
pharmacokinetics
PT
preferred term
PTE
pretreatment event
SD
standard deviation
SI
International System of Units
SOC
system organ class
SRD
single rising dose
TDC
Takeda Development Center
TEAE
treatment-emergent adverse event
tmax
time to reach maximum observed plasma concentration
CCI
CCI
CCI
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tmax(E)
time to reach maximum observed effect
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal phase after extravascular 
administration
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of this study is to characterize the safety and tolerability of TAK-020 
following single and multiple oral doses in healthy subjects.
4.2
Secondary Objectives
The secondary objectives of this study are:

To characterize the pharmacokinetics (PK) of TAK-020 following single and multiple oral 
doses.

To characterize the pharmacodynamics (PD) of TAK-020 following single and multiple oral 
doses.
4.3
Additional Objectives
Not applicable.
4.4
Study Design
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple-dose study 
in healthy volunteers. The study is comprised of 2 parts, each with multiple cohorts and is 
presented in the Study Schematic below. The study population for each part will be composed of 
healthy subjects aged 18 to 55 years, inclusive, who weigh at least 45 kg, and have a body mass 
index (BMI) between 18 and 32 kg/m2, inclusive, at Screening and Day -1.
SRD=single-rising dose, MRD=multiple-rising dose.
Part 1: Single-Rising Dose (SRD)
This part will comprise a maximum of 9 cohorts. Each cohort will comprise of 8 randomized 
subjects, with 6 receiving TAK-020 and 2 receiving placebo in the fasted state. Sentinel dosing 
will be used for Cohort 1 with only 2 subjects dosed on the morning of Day 1 (1 receiving TAK-
020 and 1 receiving placebo). The remaining subjects will be dosed following agreement with 
the investigator and Takeda after reviewing 24-hour postdose safety (adverse events [AEs], vital 
signs, 12-lead electrocardiograms [ECGs]) and tolerability data. Sentinel dosing will not be 
necessary for other cohorts provided that exposure is observed in ≥4 subjects receiving active 
Part 1: SRD
Maximum 9 Cohorts
Starting dose 0.1 mg (Cohort 1)
Cohorts 2-4: maximum exposure escalation x 5-fold
Cohorts 5-9: maximum exposure escalation x 2-fold
Maximum dose estimated 122 mg (with unbound 
AUC 19.8 ng*h/mL)
Part 2: MRD
Maximum 7 Cohorts
Doses to be determined from Part 1
Starting dose 3.75 mg
Cohorts 2-7: 2-fold maximum 
exposure increase per dose increment


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treatment and in agreement with the investigator and Takeda, otherwise sentinel dosing in the 
subsequent cohort will be required.
TAK-020 will be orally administered as a solution with a starting dose of 0.1 mg for Cohort 1. 
Dosing for the subsequent cohorts will only occur after review of the safety, tolerability, and 
minimum 24-hour PK data from the previous cohort. For each dose escalation, exposures may be 
increased by a maximum of 5-fold for Cohorts 2-4 and a maximum of 2-fold for Cohorts 5-9. 
Doses may also be decreased as appropriate.
Part 2: Multiple-Rising Dose (MRD)
TAK-020 will be orally administered as a solution. The dose to be used in each cohort will be 
selected based on data from Part 1 of the study and from the previous cohort in Part 2.
The first cohort for the MRD will receive a dose of 3.75 mg, with a predicted exposure at steady 
state estimated to be below the no observed adverse effect level (NOAEL) rate (63 ng*h/mL). 
The predicted steady state exposure in the first MRD cohort will be approximately 10-fold lower 
than the highest predicted steady state exposure determined from the SRD data. The MRD will 
comprise a maximum of 7 cohorts, each cohort with 8 subjects randomized with 6 receiving 
TAK-020 and 2 receiving placebo. In each successive cohort after the first, the dose increments 
will increase the predicted exposures by no more than 2-fold. The predicted steady state 
exposure in the MRD will not exceed the maximum exposure observed in the SRD.
A schematic of the study design is included as Table 4.a. A schedule of assessments is listed in 
Appendix A.
Table 4.a
Schematic of Study Design
Study Schematic for Part 1
Screening
Check-in
Dose
Check-out
Follow-up (a)
Day -28 to -2
Day -1
Day 1
Day 5
Day 14 (±2)
(a) A phone call is planned but individual subjects may be asked to return to the unit at this time if abnormal clinical 
safety laboratory values are obtained at Check-out or TEAEs have not resolved at Check-out.
Study Schematic for Part 2
Screening
Check-in
Dose
Washout
Dose
Check-out
Follow-up (a)
Day -28 to -2
Day -1
Day 1
Day 2
Days 3-9
Day 10
Day 17 (±2)
(a) All subjects will return to the unit and complete hematology and serum chemistry tests, vital signs, concomitant 
medications, and AE assessment.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary safety endpoints include the number and percentage of subjects who:
!
Experience at least 1 treatment-emergent adverse event (TEAE).
!
Meet the Takeda Development Center (TDC) markedly abnormal values (MAV) criteria for
safety laboratory tests at least once postdose.
!
Meet the TDC MAV criteria for vital sign measurements at least once postdose.
!
Meet the TDC MAV criteria for safety ECG parameters at least once postdose.
5.2
Secondary Endpoints
The secondary endpoints will be the following PK parameters of TAK-020:
!
Maximum observed plasma concentration (Cmax).
!
Time to reach Cmax (tmax).
!
Area under the plasma concentration-time curve from time 0 to the time of last quantifiable
concentration (AUCt).
!
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
!
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the
length of the dosing interval (AUCτ).
!
t1/2z.
!
Apparent clearance after extravascular administration (CL/F).
!
Apparent volume of distribution during the terminal phase after extravascular administration
(Vz/F).
!
Total amount of drug excreted in urine from time 0 to time t (Aet).
!
Fraction of drug excreted in urine (fe).
!
Renal clearance (CLR).
5.3
Exploratory Endpoints
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CCI


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6.0
DETERMINATION OF SAMPLE SIZE
The sample sizes chosen of 8 subjects per cohort (6 active: 2 placebo) in Part 1 and 2 is 
considered to be sufficient for evaluation of safety, tolerability, PK and the PD of TAK-020 in 
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
Data for SRD and MRD will be summarized separately over all randomized subjects in each 
study part. Continuous data will be summarized using descriptive statistics, including the number 
of subjects (N), mean, standard deviation (SD), median, minimum and maximum. The 
coefficient of variation (%CV) and geometric mean will be included in the summary of 
continuous data where indicated. Categorical data will be summarized using the number and 
percentage of subjects (N[%]) for each category. Missing values will be categorized separately 
where deemed appropriate and necessary.
In general, the presentation of decimal points will follow the following rules as appropriate: 
minimum and maximum values will be presented using the same number of decimal places as 
the recorded data. Means and medians will be presented to 1 more decimal place than the 
recorded data. SD will be presented to 2 more decimal places than the recorded data. The 
confidence interval (CI) for a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate. Percentages will be presented to 1 decimal place (eg, 
80.3%). All p-values will be rounded to 3 decimal places. If a p-value is less than 0.001, it will 
be reported as “<0.001”; if a p-value is greater than 0.999, it will be reported as “>0.999”.
All study-related raw data, including derived data, will be presented in data listings.
When no data are available for a table or appendix, an empty page with the title will be produced 
with suitable text (eg, “There were no subjects with markedly abnormal values of laboratory 
parameters.”).
The Baseline value for a variable is defined as the last observation collected before the first dose 
of study medication, unless stated otherwise. 
Analysis datasets and summary displays will be prepared using SAS version 9.2 or later.
7.1.1
Study Definitions
There are no study-specific definitions.
7.1.2
Definition of Study Days
Study day will be calculated relative to the date of first dose of study medication for each 
subject. Study Day 1 is defined as the date on which a subject takes the first dose of study 
medication, as recorded on the CRF dosing page. Study days prior to the date of first dose of 
study medication will be calculated as: date of assessment (or event) - date of first dose of study 
medication. Study days after the date of first dose of study medication will be calculated as: date 
of assessment (or event) - date of first dose of study medication + 1.
7.1.3
Definition of Study Visit Windows
There will be no visit windowing.


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7.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.
7.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.
7.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 
Plasma concentrations that are below the lower limit of quantification (< LLOQ) will be treated 
as zero in the summarization of concentration values and derivation of PK parameters.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

All randomized subjects will consist of all subjects who are randomized to a treatment.

The safety analysis set will consist of all subjects who are randomized to a treatment and 
receive 1 dose of study drug. Subjects in this analysis set will be used for demographic, 
baseline characteristics and safety summaries.

The PK analysis 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. Subjects in this analysis set 
will be used for all PK summaries and statistical analyses.

The PD analysis set will consist of all subjects who receive study drug and have at least 1 
predose and postdose PD measurement. Subjects in the analysis set will be used for all PD 
summaries and statistical analyses.
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 all 
randomized subjects will be presented in the subject listings.
7.3
Disposition of Subjects
Disposition of all screen failure subjects will be summarized according to the primary reason for 
screen failure. Additionally, disposition information for screen failures will be listed.
Disposition of all randomized subjects will be summarized by pooled placebo, each TAK-020 
dose level and TAK-020 overall. The categories will include:

Subjects who were randomized, but not treated, if applicable.

Subjects who completed study drug.

Subjects who prematurely discontinued study drug.

Subjects who completed all study visits.


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
Subjects who prematurely discontinued study visits.
Primary reasons for discontinuing study drug and/or visits, as entered on the eCRF, will be 
summarized.
Disposition information for randomized subjects will be listed. The status of the blind for 
randomized subjects will also be listed. A listing of inclusion/exclusion criteria not met will be 
provided for randomized subjects who did not meet at least one entrance criterion.
Significant protocol deviations captured on the eCRF will be listed and summarized.
7.4
Demographic and Other Baseline Characteristics
Demographic characteristics, including age at informed consent, gender, ethnicity and race will 
be summarized and listed for screen failure subjects, along with the reason(s) for failure.
Demographic and study baseline characteristics, including age at informed consent, gender, 
ethnicity, race, baseline height (cm), baseline weight (kg), baseline BMI (kg/m2), smoking 
history, alcohol history, caffeine/xanthine history and female reproductive status will be 
summarized for all subjects in the safety analysis set by pooled placebo, each TAK-020 dose 
level, TAK-020 overall and total overall. Subjects who identify themselves as belonging to more 
than 1 race on the eCRF will be classified as multiracial for summaries and each race selected 
will be listed. In addition, demographic and baseline characteristics will be summarized for all 
subjects in the safety analysis set (i.e. SRD and MRD combined) by pooled placebo, TAK-020 
and overall.
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that stopped prior to the signing
of informed consent. Concurrent medical conditions are defined as significant conditions that are 
present or ongoing at or after the signing of informed consent.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 19 or higher) coding system.
Medical history and concurrent medical conditions will be listed separately by site and subject 
number.
There will be no summary or inferential analysis of medical history and concurrent medical 
conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medications are recorded on 
the eCRF and include any medications, other than the study drug, taken at any time between 
informed consent and on or prior to the last dose of study drug.


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Medication history and concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHODrug) version 01MAR2016 Expanded or higher.
Separate listings for medication history and concomitant medications will be produced by site 
and subject number.
There will be no summary or inferential analysis of medication history and concomitant 
medications.
7.7
Study Drug Exposure and Compliance
Each subject will be given a single dose in SRD and multiple doses in MRD as per the study 
design. Since all doses of study medication will be administered during confinement, study drug 
compliance will not be summarized. Dosing administration as well as study drug concentration 
data will be provided by subject and visit for SRD and MRD in the listings.
There will be no inferential analysis of study drug exposure.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The schedule of blood samples for PK analysis of TAK-020 is listed in Table 7.a and the 
schedule of urine samples is listed in Table 7.b.
Plasma concentrations of TAK-020 will be summarized by treatment over each scheduled 
sampling time using descriptive statistics. The amount of TAK-020 excreted in urine will also be 
summarized by treatment over each scheduled sampling interval using descriptive statistics.
Plasma concentrations and the amount of study drug excreted in urine will be summarized 
separately for the SRD and MRD portions of the study. Subjects randomized to placebo will not 
be included in these summarizes but will be listed. Individual plasma concentrations and urine 
amounts will be listed separately.


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Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis
Part 1 (SRD)
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
1 
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 
10, 12, 16, 24, 36, 48, 72, and 96 hours postdose
Part 2 (MRD)
Sample Type
Dosing Day
Time Postdose (hours)
Plasma
1 
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 
10, 12, 16, 24, 36, and 48 hours postdose
Plasma
9 
Predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 
10, 12, 16, and 24 hours postdose
Table 7.b
Collection of Urine Samples for Pharmacokinetic Analysis
Part 1 (SRD)
Sample Type
Dosing Day
Time Postdose (hours)
Urine
1
Predose (-12-0), and 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 hour postdose intervals
Part 2 (MRD)
Sample Type
Dosing Day
Time Postdose (hours)
Urine
1
Predose (-12-0), and 0-6, 6-12, 12-24 hour postdose intervals
Urine
9 
Predose (-12-0), and 0-6, 6-12, 12-24 hour postdose intervals
PK parameters of TAK-020 are listed in Table 7.c and will be determined from the 
concentration-time profiles for all evaluable subjects. 


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Table 7.c
Plasma and Urine PK Parameters
The following plasma PK parameters will be determined: 
Symbol/Term
Definition
Plasma/Blood/Serum
AUC24
Area under the plasma concentration-time curve from the time 0 to time 24 hours. 
AUCτ
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval.
AUCt
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∞=AUCt+Clast/λz
R
Accumulation ratio (index) calculated as AUCτ at steady state/AUC∞ after a single dose.
Rac(AUC)
Accumulation ratio (based on AUC), calculated as AUCτ at steady state/AUCτ after a single 
dose.
Cmax
Maximum observed plasma concentration.
Cmax,ss
Maximum observed steady-state plasma concentration during a dosing interval.
CL/F
Apparent clearance after extravascular administration, calculated as =Dose/AUC∞after a 
single dose and as Dose/AUCτ after multiple dosing (at steady state).
λz
Terminal elimination 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.
t1/2z
Terminal disposition phase half-life, calculated as ln(2)/λz.
tlag
Lag time.
tmax
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal phase after extravascular 
administration, calculated as (CL/F)/λz.
The following urine PK parameters of TAK-020 will be determined:
Urine
Aet1-t2
Amount of drug excreted in urine from time 1 to time 2, calculated as Cur×Vur, where Cur is the 
concentration of drug excreted in urine and Vur is the volume of urine excreted.
Aet
Total amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval (τ) at steady state.
fe
Fraction of drug excreted in urine, calculated as (Aet/dose)×100. Molecular weight adjustment 
needed for metabolites.
CLR
Renal clearance, calculated as Ae0-24/AUC24.
Specific or additional PK parameters may be added as appropriate per the Clinical Pharmacology 
Analysis Plan (CPAP).
PK parameters of TAK-020 will be summarized by treatment using descriptive statistics. In 
addition, geometric mean and coefficient of variation will be computed for Cmax and AUCs. PK 


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parameters will be summarized separately for the SRD and MRD portions of the study. 
Individual PK parameters will be listed.
Dose proportionality will be tested for Cmax and AUCs of both SRD and MRD using a power 
model. The power fit will be assumed as described by the following equation:
ln( 	
	
) =  +  ln() + 
where  is the intercept,  is the slope and  is the random error. The 90% CI for 1 will be 
presented and dose proportionality would be declared when this CI lies entirely within the 
critical region1 +
 (.)
 () , 1 +
 (. !)
 () ", where 
 is the ratio of the highest and lowest dose in the 
study. This criterion implies that the 90% CI for the ratio of the central values of the 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].
For SRD, the effect of dose on Tmax and λz will be evaluated using analysis of variance 
(ANOVA) with treatment as a fixed effect. Means and standard deviations will be presented for 
all treatments along with a p-value of overall treatment effect. A similar analysis will be 
completed for Tmax within the MRD portion of the study. This analysis will be done separately 
for Day 1 and Day 9.
ANOVA will be used to assess time dependency for Part 2 (MRD). The natural log-transformed 
AUCs and Cmax will be used as response variable and dose level, Day and the interaction of 
dose level and Day will be fixed factors. Within the frame work of ANOVA, 90% CIs for the 
ratio of AUCs and Cmax central values between Day 9 and Day 1 will be presented.
7.9.2
Pharmacodynamic Analysis
Sampling times for collection of
samples are listed in Table 7.d.
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Table 7.d
Pharmacodynamic Sample Collection
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7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
Safety analyses include evaluations of AEs, clinical laboratory results, vital signs results and
12-lead ECG results. All summaries of safety data are based on subjects included in the Safety 
Analysis Set. The safety data will be summarized by placebo, each TAK-020 dose level and 
TAK-020 overall, where appropriate, for the SRD and MRD portions of the study. Placebo data 
will be pooled across the cohorts in each part.
7.11.1 Adverse Events
A TEAE is defined as any AE, regardless of relationship to study drug, which occurs on or after 
the first dose of study drug and no more than 30 days after receiving the last dose of study drug
(onset date – date of last dose + 1 ≤ 30). A TEAE may also be an event or condition reported 
prior to the date of first dose, which worsens in intensity after administration of study drug. A 
PTE is defined as any adverse event that occurs or worsens after the subject has signed informed 
consent and before the first dose of study drug.
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA, 
version 19 or higher.
Summary tables will be generated for AEs. TEAEs and PTEs will be presented by pooled 
placebo, each TAK-020 dose level and TAK-020 overall. The following summary tables will be 
generated separately for SRD and MRD:

Overview of TEAEs, including number of subjects and events.

TEAEs by SOC and PT, including number of subjects and events.

Subject mappings for TEAEs by SOC and PT.

TEAEs by PT.

Non-Serious TEAEs by SOC and PT.

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.


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If a subject has more than 1 AE that codes to the same level of a MedDRA term, the subject will 
be counted only once for that level, where applicable, using the most extreme incidence (related 
or more severe in intensity). 
All AEs will be presented in the data listings. 
7.11.2 Clinical Laboratory Evaluations
All clinical laboratory evaluations (hematology, chemistry and urinalysis) will be summarized. 
Renal safety biomarkers will be summarized separately.
Clinical laboratory tests will be summarized using descriptive statistics (N, mean, median, SD, 
minimum, and maximum) for baseline, post-baseline, and change from baseline values by 
treatment regimen and study visit for both SRD and MRD using the Safety Analysis Set. 
Unscheduled laboratory assessments that are collected post first dose of study drug will be 
excluded from the summary statistics. Only the scheduled safety laboratory results within 7 days 
of the last dose of study drug will be included in the summary. Note that urinalysis parameters 
with character results, such as protein and nitrite, will only be listed.
Individual results for hematology and chemistry laboratory tests that meet the Takeda predefined 
laboratory markedly abnormal value (MAV) criteria in Appendix B will be presented in a data 
listing. If a subject has a MAV for a particular laboratory parameter at a visit, all visits for that 
subject for that parameter will be listed. The number and percentage of subjects with at least 1 
postdose MAV during treatment will be summarized for each laboratory parameter by pooled 
placebo, each TAK-020 dose level and TAK-020 overall. The mapping of subjects who meet the 
MAV criteria will also be presented. All postdose observations, including those at unscheduled 
visits, will be considered to determine if a subject had a MAV during treatment.
Clinical laboratory tests will be summarized using Takeda Standard International System of 
Units (SI) units. For test results not in SI units, the conversion to SI units will be done in ADaM 
datasets using the known conversion factors. All laboratory test parameters will be displayed in 
individual subject data listings using both SI and conventional units (CV).
Clinical laboratory results for all subjects in the safety analysis set will be summarized separately 
for the SRD and MRD portions of the study.
7.11.3 Vital Signs
Vital signs measurements include systolic and diastolic blood pressure, pulse, body temperature 
and respiratory rate. Each vital signs measurement will be summarized using descriptive 
statistics (N, mean, SD, median, minimum and maximum) for baseline, postdose, and change 
from baseline to postdose values. Summaries will be presented separately for SRD and MRD by 
pooled placebo and each TAK-020 dose level.
Individual results for vital sign measurements that meet the Takeda predefined vital signs MAV 
criteria in Appendix C will be presented in a data listing. If a subject has a MAV for a particular 
vital sign parameter at a visit, all visits for that subject for that parameter will be listed. The 
number and percentage of subjects with at least 1 postdose markedly abnormal vital sign 


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measurement during treatment will be summarized by pooled placebo, each TAK-020 dose level 
and TAK-020 overall. The mapping of the subjects who meet the MAV criteria will also be 
created. All postdose observations, including those at unscheduled visits, will be considered to 
determine if a subject had a MAV during treatment.
All vital sign measurements will be listed by subject in the data listings and markedly abnormal 
values will be flagged.
Vital signs results for all subjects in the safety analysis set will be summarized separately for the 
SRD and MRD portions of the study.
7.11.4 12-Lead ECGs
Triplicate 12-lead ECGs will be collected at the scheduled 12-lead ECG measurement visits and 
time points. The average of the triplicate values will be used as analysis endpoint in summaries.
ECG measurements include heart rate, RR interval, PR interval, QRS interval, QT interval, 
QTcF interval (Fredericia’s method) and QTcB interval (Bazett’s method). Each ECG
measurement will be summarized with descriptive statistics (N, mean, SD, median, minimum 
and maximum) for baseline, postdose, and change from baseline to postdose values. Summaries 
will be presented separately for SRD and MRD by pooled placebo and each TAK-020 dose level.
Individual results for 12-lead ECG measurements that meet the Takeda predefined 12-lead ECG 
MAV criteria in Appendix D will be presented in a data listing. If a subject has a MAV for a 
particular ECG parameter at a visit, all visits for that subject for that parameter will be listed. The 
number and percentage of subjects with at least 1 postdose markedly abnormal ECG 
measurement during treatment will be summarized by pooled placebo, each TAK-020 dose level
and TAK-020 overall. If any ECG result in a set of triplicate ECG measurements meets the 
MAV criteria, the subject will be counted as having a MAV ECG result. The mapping of the 
subjects who meet the MAV criteria will be also be created. All postdose observations, including 
those at unscheduled visits, will be considered to determine if a subject had a MAV during 
treatment
A shift table showing the number of subjects with status changes from baseline to postdose 
(normal, abnormal not clinically significant and abnormal clinically significant) according to 
investigator interpretations will be created.
All ECG measurements will be listed by subject in the data listings and markedly abnormal 
values will be flagged.
ECG results for all subjects in the safety analysis set will be summarized separately for the SRD 
and MRD portions of the study.
7.11.5 Other Observations Related to Safety
Cardiac monitoring telemetry will be performed at different scheduled times from approximately 
2 hours predose until 12 hours postdose on Day 1 for SRD and both Day 1 and Day 9 for MRD. 
Ten second triplicate ECG parameters will be summarized using descriptive statistics for 


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baseline, postdose and change from baseline to postdose using the average of the triplicate 
values. All cardiac monitoring telemetry results will be listed by subject in the data listings and 
markedly abnormal values will be flagged.
Liver function test results will be presented in the data listings. No summary tables will be 
provided.
Physical examination findings will be presented in the data listings. No summary tables will be 
provided.
Pharmacogenomic sample collection data will be presented in the data listings. No summary 
tables will be provided.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
Not applicable.


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8.0
REFERENCES
1. Protocol: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, 
Ascending Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of TAK-020 in Healthy Volunteers, Protocol
Amendment 3, 31 October 2016.
2. Brian P. Smith, etc. (2000): Confidence Interval Criteria for Assessment of Dose 
Proportionality. Pharmaceutical Research; Vol. 17, No. 10: 1278-1283.


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Appendix A
Schedule of Study Procedures
Part 1 (SRD)
Screening
Check-in
Treatment
Check-out
Early 
Termination
Follow-up
Study Day:
Days -28 
to -2
Day -1
Day
1
Day 
2
Day 
3
Day 
4
Day 5
(a)
Day 14 
(±2) (b)
Confinement 
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
X
Medication history
X
Physical examination
X
X(c)
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
Weight, height, and BMI (e)
X
X
X
X
Concurrent medical conditions
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
Clinical laboratory tests (g)
X
X
X
X
X
X
Hepatitis panel
X
HIV screening
X
TB screening
X
Pregnancy test (hCG) (h)
X
X
X
X
Urine drug/alcohol/cotinine 
screen 
X
X
ECG (j)
X
X
X
X
X
X
X
X
Telemetry (k)
X
PGx DNA sample collection (l)
X
PGx RNA sample collection 
(m)
X
X
PK blood collection (n)
X
X
X
X
X
X
PK urine collection (o)
X
X
X
X
X
X
Dispense study medication
X
PTE assessment (q)
X
X
X
AE assessment
X
X
X
X
X
X
X
Footnotes are on the next page.
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(a) Conduct procedures for subjects discontinued early. The PK sample collection should be collected at the Early Termination
Visit, if possible. For example, collect samples if early withdrawal is due to an AE, and/or if several hours elapsed since last 
blood draw. 
(b) The Follow-up Visit will occur by telephone on Day 14 (±2) unless abnormal, clinically significant findings were observed 
upon discharge. In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s discretion.
(c) The physical examination can be conducted within 24 hours prior to study drug administration.
(d) Vital signs (oral temperature, sitting pulse, and blood pressure) will be collected at Screening and Check-in (Day -1), Day 1 
predose (0 hours) and at 1, 4, 12, 24, 48, 72, 96 hours postdose or Early Termination.
(e) Height will only be collected at Screening.
(f) Record all medications (other than study drug) from Screening and throughout the study.
(g) Clinical laboratory tests (hematology, serum chemistries, and urinalysis) will be collected at Screening, Day -1, Days 2 and 3, 
and prior to check-out (Day 5) or Early Termination. Laboratory samples will be taken following a minimum 10-hour overnight 
fast.
(h) Pregnancy test (hCG) will be performed for all female subjects.
(j) Triplicate 12-lead ECGs printed in standard format, will be collected at Screening, Check-in (Day -1), Day 1 predose (0 hours) 
and at 1, 4, 12, 24, 48, 72 and 96 hours postdose or Early Termination.
(k) Telemetry will be performed approximately 2 hours predose until 12 hours postdose on Day 1. Ten (10) sec triplicate ECGs 
will be extracted at PK time-points for manual reading and precise ECG reading including QT interval measurement.
(l) One blood sample (6 mL) will be collected prior to dosing on Day 1.
(m) Two whole blood samples (2.5 mL per sample) will be collected on Days 1 (predose) and 24 hours postdose. 
(n) Blood samples for PK analysis will be collected on Day 1 at predose (within 30 minutes prior to dosing), and at 0.25, 0.5, 
0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose.
(o) Urine samples for PK analysis will be collected on Day 1 at predose (-12-0) and 0-6, 6-12, 12-24, 24-48, 48-72, 72-96 hour 
postdose intervals.
(p) Blood samples for PD analysis will be collected on Day 1 at predose (within 30 minutes prior to dosing) and at 0.5, 1, 2, 4, 8, 
12, 16, 24, 36, 48, 72 and 96 hours postdose.
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1.
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Part 2 (MRD)
Screening
Check-in
Treatment
Washout
Treatment
Check-out
Early 
Termination
Follow-up
Visit
Study Day:
Days -28 
to -2
Day -1
Day 1
Day 2
Day 3-9
Day 10
(a)
Day 17 
(±2) (b)
Confinement 
X
X
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics and 
medical history
X
X
Medication history
X
Physical examination
X
X (c)
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
Weight, height, and 
BMI (e)
X
X
X
X
Concurrent medical 
conditions
X
X
Concomitant 
medications (f)
X
X
X
X
X
X
X
X
Clinical laboratory 
tests (g)
X
X
X
X
X
X
X (s)
Hepatitis panel
X
HIV screening
X
TB screening
X
Pregnancy test 
(hCG) (h)
X
X
X
X
Urine 
drug/alcohol/cotinine 
screen 
X
X
ECG (i)
X
X
X
X
X
X
X
Telemetry (j)
X
X
PGx DNA sample 
collection (k)
X
PGx RNA sample 
collection (l)
X
X
PK blood collection 
(m)
X
X
X
X
X
PK urine collection 
(n)
X
X
X
X
X
Dispense study 
medication
X
X
PTE assessment (r)
X
X
X
AE assessment
X
X
X
X
X
X
Footnotes are on the next page.
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(a) Conduct procedures for subjects discontinued early. The PK sample collection should be collected at the Early Termination
Visit, if possible. For example, collect samples if early withdrawal is due to an AE, and/or if several hours elapsed since last 
blood draw]. 
(b) All subjects will return to the unit and complete Hematology and Serum Chemistry tests, vital signs, concomitant 
medications, and AE assessment.
(c) The physical examination can be conducted within 24 hours prior to study drug administration.
(d) Vital signs (oral temperature, sitting pulse, and blood pressure) will be collected at Screening and Check-in (Day -1) and on 
Day 1 at predose (0 hours) and 1, 4, 12, 24 hours postdose, then twice daily until Study Exit (Day 10) or Early Termination and 
once during the Follow-up visit.
(e) Height will only be collected at Screening.
(f) Record all medications (other than study drug) from Screening and throughout the study.
(g) Clinical laboratory tests (hematology, serum chemistries, and urinalysis) will be collected at Screening, Day -1, Days 2, 3, 5, 
8 and prior to check-out (Day 10) or Early Termination. Laboratory samples will be taken following a minimum 10-hour 
overnight fast
(h) Pregnancy test (hCG) will be performed for all female subjects.
(i) Triplicate 12-lead ECGs printed in standard format, will be collected at Screening, Check-in (Day -1), Day 1 predose (0 hours) 
and at 1, 4, 12, and 24 hours postdose, Days 3, 5, 9, 10 at predose (0 hours) or Early Termination.
(j) Telemetry will be performed approximately 2 hours predose until 12 hours postdose on Days 1 and 9 only. Ten (10) sec 
triplicate ECGs will be extracted at PK time-points for manual reading and precise ECG reading including QT interval 
measurement.
(k) One blood sample (6 mL) will be collected prior to dosing on Day 1.
(l) Two whole blood samples (2.5 mL per sample) will be collected at predose on Days 1, 3 and 9. 
(m) Blood samples for PK analysis will be collected at predose on Day 1 (within 30 minutes prior to dosing) and at 0.25, 0.5, 
0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours postdose and at predose on Day 9 (within 30 minutes prior to dosing) and at 
0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose.
(n) Urine samples for PK analysis will be collected on Day 1 and Day 9 at predose (-12-0), and 0-6, 6-12, 12-24 hour postdose 
intervals.
(o)
(p) 
(q) 
(r) PTEs will be collected from signing of informed consent up until dosing on Day 1
(s) Hematology and Serum Chemistry only.
CCI
CCI
CCI
CCI
CCI
CCI
CCI


TAK-020-1001
Page 29 of 31
Statistical Analysis Plan Final
22 May 2017
CONFIDENTIAL
Appendix B
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
Fibrinogen
Both
< 0.8 × LLN 
> 1.2 × ULN
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x 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
CPK
Both
--
>5x ULN
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
Lipase
Both
--
>3x ULN
Triglycerides
Both
--
>2.5x ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CPK=creatine phosphokinase, GGT=-glutamyl 
transferase, LLN=lower limit of normal, ULN=upper limit of normal.


TAK-020-1001
Page 30 of 31
Statistical Analysis Plan Final
22 May 2017
CONFIDENTIAL
Appendix C
Criteria for Identification of Markedly Abnormal Vital Signs Parameters
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
< 35.6
>37.7


TAK-020-1001
Page 31 of 31
Statistical Analysis Plan Final
22 May 2017
CONFIDENTIAL
Appendix D
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcB Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤80 milliseconds
≥180 milliseconds


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