Clinical trial NCT03849690
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2019-02-27; Completion date: 2019-04-15
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the effect of the proton pump inhibitor (PPI) esomeprazole on the single-dose PK of orally administered TAK-906.

Detailed description:
The drug being tested in this study is called TAK-906. TAK-906 is being tested in healthy participants to evaluate the effect of a PPI esomeprazole on the PK of TAK-906.

The study will enroll approximately 12 participants. Participants will be assigned to the following treatment sequence:

• TAK-906 25 mg; Esomeprazole 40 mg + TAK-906 25 mg

All participants will be given an oral dose of TAK-906 and Esomeprazole.

This single center trial will be conducted in the United States. The overall duration to participate in this study is 52 days. Participants will make visit to the clinic during Period 1 and Period 2 in addition to approximately 10 to 14 days after receiving their last dose of TAK-906 for a follow up assessment.

Arms: arm 1: TAK-906 25 milligram (mg), capsule, orally, once on Day 1 of Study Period 1, followed by a washout period of at least 4 days, further followed by esomeprazole 40 mg, capsule, orally, once daily on Days 1 to 5 along with TAK-906 25 mg, capsule, orally, once on Day 4 of Study Period 2.
Interventions: intervention 1: TAK-906 intervention 2: Esomeprazole
Intervention descriptions: intervention 1: TAK-906 capsules. intervention 2: Esomeprazole capsules.

Protocol documents:
Prot_000.pdf: 
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TAKEDA PHARMACEUTICALS
PROTOCOL
A Single-Sequence, Open-Label, 2-Period, Crossover Study to Evaluate the Effect of the 
Proton Pump Inhibitor Esomeprazole on the Single-Dose Pharmacokinetics of Oral 
TAK-906 in Healthy Adult Subjects
Study Identifier:
TAK-906-1006
Compound:
TAK-906
Date:
04 Feb 2019
Version/Amendment 
Number:
Final Protocol 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 2 of 68
Protocol Final
04 Feb 2019
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................14
4.1
Background for TAK-906........................................................................................14
4.2
Background for Esomeprazole .................................................................................14
4.3
Rationale for the Proposed Study.............................................................................15
4.4
Benefit/Risk Profile .................................................................................................15
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................17
5.1
Hypothesis...............................................................................................................17
5.2
Study Objectives......................................................................................................17
5.2.1
Study Primary Objective ....................................................................................17
5.2.2
Study Secondary Objective ................................................................................17
5.3
Endpoints.................................................................................................................17
5.3.1
Primary Endpoint...............................................................................................17
5.3.2
Secondary Endpoints..........................................................................................17
5.3.3
Exploratory Endpoints .......................................................................................17
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................19
6.1
Study Design ...........................................................................................................19
6.2
Dose Escalation .......................................................................................................19
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................20
6.3.1
Rationale of Study Design..................................................................................20
6.3.2
Rationale for Dose .............................................................................................20
6.3.3
Rationale for Endpoints......................................................................................20
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............20
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................20
6.5
Study Beginning and End/Completion .....................................................................21
6.5.1
Definition of Beginning of the Study..................................................................21
6.5.2
Definition of End of the Study ...........................................................................21
6.5.3
Definition of Study Completion .........................................................................21
6.5.4
Definition of Study Discontinuation...................................................................21
6.5.5
Criteria for Premature Termination or Suspension of the Study..........................21
6.5.6
Criteria for Premature Termination or Suspension of a Site................................21
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 3 of 68
Protocol Final
04 Feb 2019
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............22
7.1
Excluded Medications, Supplements, Dietary Products............................................22
7.2
Diet, Fluid, Activity.................................................................................................23
7.2.1
Diet and Fluid ....................................................................................................23
7.2.2
Activity..............................................................................................................23
7.3
Criteria for Discontinuation or Withdrawal of a Subject...........................................23
7.4
Procedures for Discontinuation or Withdrawal of a Subject......................................24
7.5
Subject Replacement................................................................................................24
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................25
8.1
Clinical Study Drug .................................................................................................25
8.1.1
TAK-906 Capsule ..............................................................................................25
8.1.2
Esomeprazole Capsule .......................................................................................25
8.1.3
Clinical Study Drug Labeling.............................................................................25
8.1.4
Clinical Study Drug Inventory and Storage ........................................................25
8.1.5
Clinical Study Drug Blinding.............................................................................25
8.1.6
Randomization Code Creation and Storage ........................................................26
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................26
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs...............................26
9.0
STUDY PROCEDURES...............................................................................................27
9.1
Administrative Procedures.......................................................................................27
9.1.1
Informed Consent Procedure..............................................................................27
9.1.2
Inclusion and Exclusion .....................................................................................27
9.1.3
Medical History/Demography ............................................................................29
9.1.4
Concomitant Medications...................................................................................29
9.2
Clinical Procedures and Assessments.......................................................................29
9.2.1
Full Physical Exam ............................................................................................29
9.2.2
Height and Weight .............................................................................................30
9.2.3
BMI ...................................................................................................................30
9.2.4
Vital Signs .........................................................................................................30
9.2.5
12-Lead ECG.....................................................................................................30
9.2.6
Study Drug Administration ................................................................................30
9.2.7
AE Monitoring...................................................................................................31
9.2.8
Laboratory Procedures and Assessments ............................................................31
9.2.9
Clinical Laboratory Tests...................................................................................31
9.3
PK Samples .............................................................................................................32
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 4 of 68
Protocol Final
04 Feb 2019
9.3.1
PK Measurements..............................................................................................33
9.3.2
PK Measurements..............................................................................................33
9.3.3
.................................................................................34
9.3.4
Confinement ......................................................................................................34
10.0
ADVERSE EVENTS ....................................................................................................35
10.1
Definitions and Elements of AEs .............................................................................35
10.1.1 SAEs..................................................................................................................37
10.1.2 Special Interest AEs...........................................................................................38
10.2
AE Procedures.........................................................................................................38
10.2.1 Assigning Severity/Intensity of AEs...................................................................38
10.2.2 Assigning Causality of AEs................................................................................39
10.2.3 Start Date...........................................................................................................39
10.2.4 End Date............................................................................................................40
10.2.5 Pattern of Adverse Event (Frequency)................................................................40
10.2.6 Action Taken With Study Treatment..................................................................40
10.2.7 Outcome ............................................................................................................40
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................41
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....43
11.0
STATISTICAL METHODS..........................................................................................44
11.1
Statistical and Analytical Plans ................................................................................44
11.1.1 Analysis Sets......................................................................................................44
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................44
11.1.3 PK Analysis.......................................................................................................44
11.1.4 PD Analysis.......................................................................................................45
11.1.5 Safety Analysis ..................................................................................................45
11.2
Interim Analysis and Criteria for Early Termination ................................................45
11.3
Determination of Sample Size..................................................................................45
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................47
12.1
Study-Site Monitoring Visits ...................................................................................47
12.2
Protocol Deviations..................................................................................................47
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................47
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................48
13.1
IRB and/or IEC Approval ........................................................................................48
13.2
Subject Information, Informed Consent, and Subject Authorization .........................49
13.3
Subject Confidentiality ............................................................................................50
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
34
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TAK-906
Study ID TAK-906-1006
Page 5 of 68
Protocol Final
04 Feb 2019
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................50
13.4.1 Publication and Disclosure.................................................................................50
13.4.2 Clinical Trial Registration..................................................................................51
13.4.3 Clinical Trial Results Disclosure ........................................................................51
13.5
Insurance and Compensation for Injury....................................................................51
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................52
14.1
Administrative Information......................................................................................52
14.1.1 Study Contact Information .................................................................................52
14.1.2 Investigator Agreement......................................................................................53
14.1.3 Study-Related Responsibilities...........................................................................54
14.1.4 List of Abbreviations .........................................................................................55
15.0
DATA HANDLING AND RECORDKEEPING............................................................57
15.1
CRFs (Electronic and/or Paper)................................................................................57
15.2
Record Retention .....................................................................................................57
16.0
REFERENCES..............................................................................................................59
17.0
APPENDICES...............................................................................................................60
LIST OF IN-TEXT TABLES
Table 6.a
Study Drugs Planned Dose Levels......................................................................19
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................22
Table 9.a
Primary Specimen Collections ...........................................................................33
Table 10.a
Takeda Medically Significant AE List................................................................38
LIST OF IN-TEXT FIGURES
Figure 2.a
Schematic of Study Design ................................................................................10
Figure 2.b
Schematics of Single-Sequence Design..............................................................11
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................61
Appendix B
Elements of the Subject Informed Consent.........................................................63
Appendix C
Investigator Consent to the Use of Personal Information ....................................66
Appendix D
Pregnancy and Contraception.............................................................................67
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 6 of 68
Protocol Final
04 Feb 2019
1.0
STUDY SUMMARY
Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge, Massachusetts USA 02139
Compound:
TAK-906
Study Identifier: TAK-906-1006 (CA27239)
Phase: 1
Protocol Title: A Single-Sequence, Open-Label, 2-Period, Crossover Study to Evaluate the Effect of the Proton Pump 
Inhibitor Esomeprazole on the Single-Dose Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
Study Design:
This is a single-sequence, open-label, 2-period, crossover study in 12 healthy adult subjects. The study is designed to 
investigate the effect of a proton pump inhibitor (PPI) esomeprazole on the PK of TAK-906.
The study will include a Screening Visit, Study Period 1 (Days 1 to 3), followed by at least a 4-day washout (from the 
time of TAK-906 dose on Day 1), Study Period 2 (Days 1 to 6), and finally a Follow-up Visit. 
In Study Period 1, subjects will be confined from the day prior to dosing (Day -1), at the time indicated by the Clinical 
Research Unit (CRU), until after the 48-hour blood draw (Day 3). In Study Period 2, subjects will come to the CRU on 
the mornings of Day 1 and Day 2, at the time indicated by the CRU, for dosing and/or study procedures as appropriate. 
Subjects will be confined from morning of Day 3, at the time indicated by the CRU, until after the 48-hour blood draw 
on Day 6. At any time, a subject may be required to remain at the CRU for longer at the discretion of the Investigator.
On Day 1 of Study Period 1, subjects will receive a single oral dose of TAK-906. On Days 1 through 5 of Study 
Period 2, subjects will receive esomeprazole dose once daily (QD). On Day 4 of Study Period 2, a single oral dose of 
TAK-906 will be administered 1 hour following the esomeprazole dose. Serial blood samples will be collected 
predose and for 48 hours after each TAK-906 dose to determine the pharmacokinetics (PK) of TAK-906. 
There will be a washout of at least 4 days between dosing in Study Period 1 and first dosing in Study Period 2. 
All subjects who received at least one dose of study drug (including subjects who terminate the study early) will return 
to the Clinical Research Unit (CRU) approximately 10-14 days after the last dose of TAK-906 for follow-up 
procedures, and to determine if any adverse event (AE) has occurred since the last study visit. 

Study Primary Objective:

To evaluate the effect of the PPI esomeprazole on the single-dose PK of orally (PO) administered TAK-906.

Secondary Objectives:

To evaluate the safety and tolerability of a single PO dose of TAK-906 in the presence and absence of the PPI 
esomeprazole.
Study Subject Population: Males and females (with no childbearing potential) aged 18 to 55 years, inclusive, at the 
Screening Visit. Body mass index (BMI) ≥18.0 and ≤30.0 kg/m2 at screening.
Planned Number of Subjects:
12
Planned Number of Sites:
1
Dose Levels:
Study Period 1 (Treatment A): 
25 mg TAK-906 (1 x 25 mg TAK-906 capsule) 
Study Period 2 (Treatment B):
40 mg esomeprazole (1 x 40 mg NEXIUM® capsule, or 
generic equivalent) 
25 mg TAK-906 (1 x 25 mg TAK-906 capsule)
Route of Administration:
Oral
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 7 of 68
Protocol Final
04 Feb 2019
Duration of Treatment:
On Day 1 of Study Period 1, subjects will receive a 
single oral dose of TAK-906.
On Days 1 through 5 of Study Period 2, subjects will 
receive QD doses of esomeprazole. On Day 4 of Study 
Period 2, subjects will receive a single oral dose of 
TAK-906 1 hour following esomeprazole dose. 
Planned Study Duration:
Approximately 50 days including Screening Period
Main Criteria for Inclusion:
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study: 
1.
Healthy, adult, male or female, 18-55 years of age, inclusive, at screening.
2.
Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first 
dosing and throughout the study, based on screening urine cotinine test.
3.
Body mass index (BMI) ≥18.0 and ˂ 30.0 kg/m2 at screening. 
4.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs or electrocardiographs (ECGs), as deemed by the Investigator or designee.
5.
For a male or female of non-childbearing potential, use acceptable birth control methods as indicated in Appendix 
D.
6.
A male subject who is nonsterilized and sexually active with a female partner of childbearing potential must agree 
to use a barrier method of contraception from the signing of informed consent form (ICF) throughout the duration 
of the study and through to the follow up (ie, 10-14 days after the last dose of TAK-906) (refer to Appendix D).
7.
If male, must agree not to donate sperm from the first dosing until follow-up visit (ie, 10-14 days after the last dose 
of TAK-906) (refer to Appendix D).
8.
Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the 
protocol.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant endocrine, gastrointestinal (including motility disorder and intestinal 
obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiration, genitourinary, or major 
neurological (including stroke and chronic seizures) or any other clinically significant abnormalities or disease in 
the opinion of the Investigator or designee.
3.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study or 
poses an additional risk to the subject by their participation in the study.
4.
History of cancer (malignancy).
5.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing. 
6.
History or presence of hypersensitivity or idiosyncratic reaction to TAK-906 or related compounds, or to 
esomeprazole or PPIs (see NEXIUM® US product insert [USPI]).
7.
Female subjects of childbearing potential.
8.
Female subjects with a positive pregnancy test or who is lactating.
9.
Positive urine drug or alcohol results at screening or first check-in. 
10. Positive urine cotinine at screening. 
11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 8 of 68
Protocol Final
04 Feb 2019
12. QTcF interval is >450 msec or ECG findings are deemed abnormal with clinical significance by the Investigator 
or designee at screening.
13. Estimated creatinine clearance <90 mL/min at screening. 
14. Unable to refrain from or anticipates the use of:
!
Any drug, including prescription and non-prescription medications (including PPIs, antacids, and 
H2-antagonist), herbal remedies, or vitamin supplements within 14 days prior to the first dosing and 
throughout the study. Thyroid hormone replacement medication may be permitted if the subject has been on 
the same stable dose for the immediate 3 months prior to first study drug administration. After first dosing, 
acetaminophen (up to 2 g per 24 hours) may be administered at the discretion of the Investigator or designee.
!
Any drugs known to significantly affect the absorption, distribution, metabolism, or elimination of study 
drugs (TAK-906 or esomeprazole) within 28 days prior to the first dosing and throughout the study. 
Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack of PK/pharmacodynamic 
interaction with study drug.
15. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 
30 days prior to the first dosing and throughout the study.
16. Donation of blood or significant blood loss (eg, approximately 500 mL) within 56 days prior to the first dosing.
17. Plasma donation within 7 days prior to the first dosing.
18. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-day window or 
5 half-lives will be derived from the date of the last blood collection or dosing, whichever is later, in the previous 
study to Day 1 of Study Period 1 of the current study.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:
The following plasma PK parameters for TAK-906 on Day 1 in Study Period 1 and on Day 4 in Study Period 2:
!
Cmax: Maximum observed concentration.
!
AUClast: Area under the concentration-time curve from time 0 to time of the last quantifiable concentration.
!
AUCinf: Area under the concentration-time curve from time 0 to infinity.
The secondary endpoints include the following:
!
Treatment emergent adverse event (TEAE) assessments.
!
Vital signs.
!
12-lead ECG.
!
Clinical laboratory testing (hematology, serum chemistry and urine analysis).
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TAK-906
Study ID TAK-906-1006
Page 9 of 68
Protocol Final
04 Feb 2019
Statistical Considerations:
For evaluation of potential effect of esomeprazole on TAK-906 PK, an ANOVA will be performed on the 
ln-transformed Cmax, AUClast, and AUCinf. The ANOVA model will include treatment as fixed effect and subject as a 
random effect. Each ANOVA will include calculation of least-squares means (LSM) as well as the difference between 
treatment LSM. The geometric mean of the relative bioavailability of the TAK-906 with esomeprazole regimen 
relative to the TAK-906 regimen alone and the associated 90% CIs will be determined by exponentiation of the 
appropriate estimates for the difference between regimens in the log-transformed parameters.
Sample Size Justification:
A total of twelve (12) subjects will be enrolled in this study. This sample size will provide at least 80% power to 
conclude the Cmax of TAK-906 will not decrease more than 50% in the presence of esomeprazole, assuming that the 
intra-subject %CV for Cmax of TAK-906 will not exceed 45% and a true ratio of 0.8. Lower intra-subject variability 
was observed for AUC in previous studies; therefore, the power is expected to be greater for AUC.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 10 of 68
Protocol Final
04 Feb 2019
2.0
STUDY SCHEMATIC
Figure 2.a
Schematic of Study Design
Screening
Study Period 1 a
Within Day -28 to -2 
for screening; first 
dosing in Study 
Period 1 
Day -1
Day 1
Days 2 - 3
Check-in
TAK-906 Dosing 
Plasma sampling for TAK-906 PK and safety monitoring for at least 48 hours 
postdose
< - - - - - - - - - - - -  Confinement b, c - - - - - - - - - - - - >
a There will be a washout of at least 4 days between dosing in Study Period 1 and first dosing in Study Period 2.
b A subject may be required to remain at the CRU for longer at the discretion of the Investigator or designee.
c Subjects will start the confinement on Day -1 of Study Period 1 and be released from CRU after Day 3 study 
assessments are complete. In Study Period 2, subjects will return to the CRU on the morning of Days 1 and 2 for 
dosing and/or study procedures as appropriate. Subjects will be confined from morning of Day 3 of Study Period 2, at 
the time indicated by the CRU, until after 48-hour blood draw on Day 6. 
Treatment Study Period 2 a
Study exit
Follow-up b
Days 1-2
Day 3
Day 4 
Day 5
Day 
6
Day 6 of 
Treatment 
Study 
Period 2
10-14 days 
after last 
dosing
Check-in
Esomeprazole 
dosing 
Esomeprazole 
dosing
Esomeprazole dosing 
TAK-906 Dosing 
Esomeprazole 
dosing
Plasma sampling for TAK-906 PK and safety 
monitoring for at least 48 hours postdose
Outpatient visit
< - - - - - - - - - - - - Confinement c, d - - - - - - - - - - - - >
a There will be a washout of at least 4 days between dosing in Study Period 1 and first dosing in Study Period 2.
b All subjects who received at least one dose of study drug (including subjects who terminate the study early) will 
return to the CRU approximately 10-14 days after the last dose of TAK-906 for follow-up procedures, and to 
determine if any AE has occurred since the last study visit
c A subject may be required to remain at the CRU for longer at the discretion of the Investigator or designee.
d In Study Period 2, subjects will return to the CRU on the morning of Days 1 and 2 for dosing and/or study procedures 
as appropriate. Subjects will be confined from morning of Day 3 of Study Period 2, at the time indicated by the CRU, 
until after 48-hour blood draw on Day 6. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 11 of 68
Protocol Final
04 Feb 2019
Figure 2.b
Schematics of Single-Sequence Design
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 12 of 68
Protocol Final
04 Feb 2019
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES 
Screening
Study Period 1 (a)
Study Period 2
Follow-up
Procedures/Assessments
Day -28 to -2
Day
Day
10-14 days after last dose of 
TAK-906
-1
Predose
(Day 1)
1
2
3
1
2
3
4
5
6
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
------------------------------------Continuous Monitoring------------------------------------
Clinical Procedures/Assessments
Full physical examination
X
X (b)
X
Height
X
Weight
X
BMI
X
12-Lead Safety ECG
X
X (c), (b)
X (c)
X
X (c)
X (h)
X
Supine vital signs (heart rate, systolic 
blood pressure and diastolic blood 
pressure)
X
X (c),(b)
X (c)
X
X (c)
X (h)
X
Vital signs (respiratory rate, oral [at the 
floor of the mouth]/tympanic 
temperature)
X
X
TAK-906 administration(d)
X
X
Esomeprazole administration (e)
X
X
X
X
X
AE monitoring
------------------------------------Continuous Monitoring------------------------------------
Laboratory Procedures/Assessments
Hematology
X
X
X (b)
X (h)
X
Urinalysis
X
X
X (b)
X (h)
X
Chemistry
X
X
X (b)
X (h)
X
Serum Pregnancy Test (♀only)
X
X
Serum FSH (PMP ♀only)
X
Urine drug screen
X
X
X
Urine alcohol test (f)
X
X
X
Urine cotinine test
X
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TAK-906
Study ID TAK-906-1006
Page 13 of 68
Protocol Final
04 Feb 2019
CONFIDENTIAL
Screening
Study Period 1 (a)
Study Period 2
Follow-up
Procedures/Assessments
Day -28 to -2
Day
Day
10-14 days after last dose of 
TAK-906
-1
Predose
(Day 1)
1
2
3
1
2
3
4
5
6
Hepatitis screen 
X
Human immunodeficiency virus (HIV) 
X
Pharmacokinetics Evaluations
Blood for plasma TAK-906 (g)
X--------------------------X
X---------X
Other
Confinement 
X--------------X
X--------------X
Returns (i)
X
X
Meals fasting 
X
X
X
X
X
X
X
(a) There will be a minimum 4-day washout between Study Periods 1 and 2, starting from administration of TAK-906 on Day 1 of Study Period 1.
(b) Day 1 predose assessment may be done within approximately 24 hours prior to study drug administration.
(c) Measured predose and at 1, 2, 4, 8, and 48 hours postdose (times relative to TAK-906 dose). Subjects should have rested in a supine position for at least 5 minutes before the 
measurements. 
(d) Both doses of TAK-906 (Day 1 of Study Period 1 and Day 4 of Study Period 2) will be administered after an overnight fast of at least 10 hours and subjects will be required to fast 
for at least 4 hours postdose. For Study Period 2, TAK-906 will be administered 1 h after esomeprazole dose on Day 4. 
(e) Esomeprazole will be administered once daily at the same time each day and 1 hour prior to TAK-906 on Day 4. On Days 1 to 3 and Day 5, subjects will be required to fast for at 
least 1 hour prior to esomeprazole dosing and to remain fasting for at least 2 hours postdose.
(f) An alcohol breath test may be performed at the discretion of the Investigator.
(g) Blood samples for TAK-906 assay will be collected on Day 1 of Study Period 1 and Day 4 of Study Period 2 predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours 
postdose (times relative to TAK-906 dose). The 16-hour postdose on Day 1 of Study Period 1 and Day 4 of Study Period 2 will be either on Day 1 or Day 2 of Period 1 and Day 4 or 
Day 5 of Study Period 2, depending on the time of dosing on Day 1 of Study Period 1 and Day 4 of Study Period 2, respectively.
(h) To be performed on Day 6 of Study Period 2 or prior to early termination from the study. 
(i) Subjects will return to the CRU every morning on Days 1 and 2 of Study Period 2 to receive the esomeprazole dosing (± 1 hour of Day 1 dosing). 
Abbreviations: ♀= Female, AE = Adverse events, BMI = Body mass index, CRU = Clinical research unit, DNA = Deoxyribose nucleic acid, ECG = Electrocardiogram, 
HIV = Human immunodeficiency virus, PMP = Postmenopausal, PK = Pharmacokinetics.
CCI
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TAK-906
Study ID TAK-906-1006
Page 14 of 68
Protocol Final
04 Feb 2019
4.0
INTRODUCTION
4.1
Background for TAK-906
The intended indication for TAK-906 is to treat patients with gastroparesis, a disorder of the 
stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. 
Symptoms are chronic with episodic symptom exacerbation [1]. These symptoms may commonly 
include nausea, vomiting, early satiety, abdominal pain, and postprandial fullness. The prevalence 
of gastroparesis in the United States (US) is estimated to be approximately 24.2 per 100,000 [2]. In 
cases of chronic gastroparesis, diabetic (29%), postsurgical (13%), and idiopathic (36%) etiologies 
comprise the majority of cases in the tertiary referral setting [3].
TAK-906 is a peripherally selective (ie, very limited penetration of the blood brain barrier [BBB]) 
dopamine D2/D3 receptor antagonist. It demonstrated suitable PK and PD activity in a phase 1 
study and other completed studies. Therefore TAK-906 is expected to reduce nausea and vomiting, 
without the side effects which restrict the use. Because of its low BBB penetration and a weak 
human ether-a-go-go-related gene (hERG) channel affinity indicative of a low potential cardiac 
risk, TAK-906 is anticipated to have an improved safety profile, compared to other D2/D3 
antagonist (eg, metoclopramide and domperidone). 
The solubility of TAK-906 is pH dependent (decreases with the increase of pH), and it is classified 
as a Biopharmaceutical Classification System class IV drug. Studies of in vitro metabolism 
suggest that TAK-906 is mainly metabolized by CYP2C8 and CYP3A4/5,
 
 The relative contribution ratio of CYP and non-CYP toward in vitro
metabolism of TAK-906 using human hepatic S9 cell line was 43.3% and 56.7%, respectively. 
TAK-906 is also a substrate of P-glycoprotein (P-gp), organic anion-transporting polypeptide 
(OATP)1B1 and OATP1B3. 
TAK-906 shows rapid absorption and rapid elimination. Median Tmax was 1.1 hours postdose. The 
half-life (T½) following a single PO dose averaged approximately 4 hours when administered in 
the fasted state. Following administration of single PO doses of TAK-906 maleate between 5 and 
300 mg, exposure to TAK-906 increased in a manner generally proportional to dose increment. 
Food had a significant impact on reducing the exposure to TAK-906 in healthy subjects. 
Coadministration of itraconazole 200 mg for 5 days with TAK-906 maleate increased TAK-906 
mean Cmax by approximately 2.0-fold and AUCinf by approximately 1.3-fold. TAK-906 is not 
classified as a sensitive CYP3A4 substrate.
Refer to the Investigator’s Brochure (IB) for detailed background information on TAK-906 [4]. 
4.2
Background for Esomeprazole
Esomeprazole, the S-enantiomer of omeprazole, is a PPI that inhibits gastric acid secretion by 
suppressing H+ ion formation through inhibition of the H+/K+ ATPase enzyme system at the 
secretory surface of gastric parietal cells. Esomeprazole is indicated for the treatment of heartburn 
and other symptoms associated with gastroesophageal reflux disease and, in combination with 
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TAK-906
Study ID TAK-906-1006
Page 15 of 68
Protocol Final
04 Feb 2019
clarithromycin and amoxicillin, for the eradication of Helicobacter pylori. The recommended adult 
dosages are 20 mg to 40 mg QD, administered at least one hour before meals [5]. 
After oral administration of esomeprazole capsule formulation, Cmax occurs at approximately 
1.5 hours (Tmax). At repeated QD dosing with 40 mg, the systemic bioavailability is approximately 
90% compared to 64% after a single dose of 40 mg [5]. The administration of food with 
esomeprazole reduces AUC and Cmax by 43 to 53% and 33 to 53%, respectively; however this does 
not have a significant influence on the effect of esomeprazole on intra-gastric acidity [6]. 
Esomeprazole is 97% bound to plasma proteins [5]. Esomeprazole is acid-labile and rapidly 
degrades under acidic conditions, but is very stable in alkaline media. Esomeprazole has been 
shown to be optically stable and the degree of inversion to be negligible [5]. 
Esomeprazole is extensively metabolized in the liver (to a lesser extent than racemic omeprazole), 
primarily by CYP2C19 and CYP3A to form the hydroxy, desmethyl, and sulfone metabolites. 
None of the identified metabolites exhibit any of the significant anti-secretory effects displayed by 
the parent drug [5]. 
Elimination of the drug is rapid with a terminal elimination half-life of about 1.3 hours. 
Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the 
urine, and 20% in feces. Less than 1% of the parent drug is excreted unchanged in the urine [5]. 
The most common adverse reactions associated with esomeprazole administration are: headache, 
abdominal pain, constipation, diarrhea, flatulence, nausea, and dry mouth [5]. 
4.3
Rationale for the Proposed Study
The solubility of TAK-906 is pH dependent (decreases with the increase of pH). PPIs are 
commonly used by gastroparesis patients to relieve symptoms of gastroesophageal reflux such as 
heartburn or regurgitation that frequently overlap with gastroparesis. This group of agents 
suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase pump in gastric 
parietal cells, thereby increasing gastric pH for a sustained time, and thus may alter the 
bioavailability of drugs with pH-dependent solubility when used together.
Esomeprazole is widely prescribed. It is known to have a strong anti-secretory effect, suppressing 
the production of gastric acid from parietal cells, and increasing pH. Esomeprazole is expected to 
lack the potential to interact directly with TAK-906, for example through CYP3A4 metabolic 
interaction [7]. In addition, esomeprazole has a good safety and tolerability profile, and was found 
to be well tolerated in healthy volunteers [8].
4.4
Benefit/Risk Profile
The dose of TAK-906 administered in this study is not anticipated to induce any potential risk or 
benefit to subjects participating in this study. Based on the first-in-human phase 1 study, a single 
dose of 25 mg TAK-906 is expected to be well tolerated. 
The dose of esomeprazole administered in this study is not anticipated to induce any potential risk 
or benefit to subjects participating in this study, and it is administered according to the dosing 
recommendations found in the full prescribing information for NEXIUM® [5].
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 16 of 68
Protocol Final
04 Feb 2019
The safety monitoring practices employed by this protocol (ie, 12-lead ECG, vital signs, clinical 
laboratory tests, AE questioning, and physical examination) are adequate to protect the subjects’ 
safety and should detect all TEAEs.
There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1006
Page 17 of 68
Protocol Final
04 Feb 2019
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
NA
5.2
Study Objectives
5.2.1
Study Primary Objective
!
To evaluate the effect of the PPI, esomeprazole, on the single-dose PK of PO administrated
TAK-906.
5.2.2
Study Secondary Objective
!
To evaluate the safety and tolerability of a single PO dose of TAK-906 in the presence and
absence of the PPI, esomeprazole.
5.3
Endpoints
5.3.1
Primary Endpoint
The primary endpoint of the study is:
The following plasma PK parameters for TAK-906 on Day 1 in Study Period 1 and on Day 4 in 
Study Period 2
!
Cmax: Maximum observed concentration.
!
AUClast: Area under the concentration-time curve from time 0 to time of the last quantifiable
concentration.
!
AUCinf: Area under the concentration-time curve from time 0 to infinity.
5.3.2
Secondary Endpoints 
Secondary endpoints include: 
!
TEAE assessments.
!
Vital signs.
!
12-lead ECG.
!
Clinical laboratory testing (hematology, serum chemistry, and urine analysis).
5.3.3
Exploratory Endpoints
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-906
Study ID TAK-906-1006
Page 18 of 68
Protocol Final
04 Feb 2019
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-906
Study ID TAK-906-1006
Page 19 of 68
Protocol Final
04 Feb 2019
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a single-sequence, open-label, 2-period crossover study in 12 healthy adult subjects. The 
study is designed to investigate the effect of a PPI esomeprazole on the PK of TAK-906. 
The study will include a Screening Visit, a Study Period 1 (Days 1 to 3), followed by at least a 
4-day washout from the time of TAK-906 dose, a Study Period 2 (Days 1 to 6), and a Follow-up 
Visit. 
Screening of subjects will occur within 28 days prior to the first dosing.
In Study Period 1, subjects will be confined from the day prior to dosing (Day -1), at the time 
indicated by the CRU, until after the 48-hour blood draw (Day 3). In Study Period 2, subjects will 
come to the CRU on the mornings of Day 1 to Day 2, at the time indicated by the CRU, for dosing 
and/or study procedures as appropriate. Subjects will be confined from morning of Day 3, at the 
time indicated by the CRU, until after the 48-hour blood draw on Day 6. At any time, a subject may 
be required to remain at the CRU for longer at the discretion of the Investigator.
On Day 1 of Study Period 1, subjects will receive a single oral dose of TAK-906. On Days 1 
through 5 of Study Period 2, subjects will receive esomeprazole dose QD. On Day 4 of Study 
Period 2, a single oral dose of TAK-906 will be administered 1 hour following the esomeprazole 
dose. Serial blood samples will be collected predose and for 48 hours after each TAK-906 dose to 
determine the PK of TAK-906.
There will be a washout of at least 4 days between dosing in Study Period 1 and first dosing in 
Study Period 2.
All subjects who received at least one dose of study drug (including subjects who terminate the 
study early) will return to the CRU approximately 10-14 days after the last dose of TAK-906 for 
follow-up procedures, and to determine if any AE has occurred since the last study visit. 
Please refer to Section 2.0 for study schematics.
The planned dose levels of TAK-906 and esomeprazole to be used are outlined in Table 6.a. 
Table 6.a
Study Drugs Planned Dose Levels 
Dose
Route of 
Administration
Study Period 1 (Treatment A)
TAK-906
25 mg
Oral capsule
Study Period 2 (Treatment B)
TAK-906
25 mg
Oral capsule
Esomeprazole
40 mg
Oral capsule
6.2
Dose Escalation
NA
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TAK-906
Study ID TAK-906-1006
Page 20 of 68
Protocol Final
04 Feb 2019
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
This is a single-sequence, open-label, 2-period crossover study.
An open-label design was employed in this study, since the primary objective is to assess PK and it 
is unnecessary to be blinded.
Since esomeprazole may have a prolonged effect on acid secretion due to its irreversible binding to 
H+/K+ ATPase pump, a single-sequence design in which esomeprazole is administered in Study 
Period 2 was selected to ensure that there is no carryover pharmacodynamic effect on gastric acid 
secretion for the reference treatment (TAK-906 alone).
The washout period between TAK-906 doses in each period is considered sufficient to ensure 
minimal carryover effects of the TAK-906.
6.3.2
Rationale for Dose 
TAK-906: Based on the first-in-human phase 1 study, administration of single PO doses of 
TAK-906 maleate ranging from 5 to 300 mg have been well-tolerated in healthy men and women. 
Overall, the incidence of TEAEs was low in the study. There were no SAEs or severe AEs reported 
during the study, and no subjects discontinued due to an AE. Based on the results of the clinical 
studies, 25 mg dose of TAK-906 is expected to be the clinically efficacious dose that is well below 
the maximum tested dose of 300 mg.
Esomeprazole: A dose of 40 mg esomeprazole daily is within the recommended dose as 
prescribed in the labeling [5]. In addition, multiple doses will ensure maximum inhibition of acid 
secretion by esomeprazole [6]. The maximum recommended dose of esomeprazole (40 mg per 
day) was selected to ensure that any possible PK interactions are detected. 
6.3.3
Rationale for Endpoints
The primary PK endpoints will include Cmax, AUCinf and AUClast, as these parameters describe the 
exposure and bioavailability of TAK-906 and are the most relevant PK parameters for the purpose 
of evaluating an interaction. 
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the blood collection for plasma concentrations for TAK-906 is the critical 
procedure and samples are required to be collected, as appropriate, as close to the scheduled times 
defined in this protocol as possible.
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drugs to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 6.5.5.
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TAK-906
Study ID TAK-906-1006
Page 21 of 68
Protocol Final
04 Feb 2019
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the
ICF) of the first subject.
6.5.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0).
6.5.3
Definition of Study Completion
The end of the study is defined as the completion of the evaluations in the follow-up visit for the 
last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up.
6.5.4
Definition of Study Discontinuation
In consultation with the Sponsor, Celerion reserves the right to terminate the study in the interest 
of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.5.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.5.6
Criteria for Premature Termination or Suspension of a Site
NA
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TAK-906
Study ID TAK-906-1006
Page 22 of 68
Protocol Final
04 Feb 2019
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 9.1.2.2. 
After the first dose, acetaminophen (up to 2 g per 24 hour period) may be administered at the 
discretion of the Investigator or designee. Thyroid hormone replacement medication may be 
permitted if the subject has been on the same stable dose for the immediate 3 months prior to first 
study drug administration.
If deviations occur, the investigator or designee in consultation with the Sponsor if needed will 
decide on a case-by-case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing 
(Days -28 to predose [Day 1])
Post First Dosing (Day 1) to Follow-Up 
Alcohol
Prohibited from 48 hours prior to first 
dosing
Prohibited from 48 hours prior to first dosing in 
each period and throughout until end of PK 
collection in Treatment Period 2.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first 
dosing a
Prohibited from 24 hours prior to first dosing in 
each period and throughout the period of PK 
sample collection in each Study Period a.
Nicotine 
Prohibited from 3 months prior to first 
dosing
Prohibited from 3 months prior to first dosing in 
each period until end of PK collection in Study 
Period 2
Medications 
See Sections 7.1 and 9.1.2.2
See Sections 7.1 and 9.1.2.2
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first 
dosing
Prohibited until end of PK collection in Treatment 
Period 2.
Other Fruit Juice
Prohibited from 72 hours prior to first 
dosing
Prohibited from 72 hours prior to first dosing in 
each period and throughout the period of PK 
sample collection in each Study Period.
Vegetables from the mustard green 
family (eg, kale, broccoli, 
watercress, collard greens, kohlrabi, 
Brussels sprouts, mustard), and 
charbroiled meats
Prohibited from 7 days prior to first 
dosing
Prohibited until end of PK collection in Study 
Period 2.
a small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated coffee or other decaffeinated 
beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be considered a deviation to this 
restriction. 
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TAK-906
Study ID TAK-906-1006
Page 23 of 68
Protocol Final
04 Feb 2019
7.2
Diet, Fluid, Activity 
7.2.1
Diet and Fluid
Water (except water provided with each oral dosing) will be restricted 1 hour prior to and 1 hour 
after each oral study drug administration, but will be allowed ad libitum at all other times, when 
dosing occurs at the CRU. Other fluids may be given as part of meals and snacks but will be 
restricted at all other times throughout the confinement period.
On Day 1 of Study Period 1 and Day 4 of Study Period 2, subjects will fast overnight for at least 
10 hours prior to TAK-906 administration and will continue to fast for at least 4 hours postdose. 
On Days 1 to 3 and Day 5 of Study Period 2, subjects will fast for at least 1 hour prior to dosing and 
will continue to fast for at least 2 hours postdose. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all food 
and drink except water between meals and snacks.
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time in each treatment 
period.
7.2.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when they 
are supine or semi-reclined for study procedures. However, should AEs occur at any time, subjects 
may be placed in an appropriate position or will be permitted to lie down on their right side.
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the study.
7.3
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason.
In addition, subjects may be withdrawn from the study by the Investigator or designee for the 
following reasons:

AEs.

Difficulties in blood collection.

Positive pregnancy test.

Positive drug and alcohol test.
A subject may be withdrawn by the Investigator (or designee) or the Sponsor if enrollment into the 
study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.
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TAK-906
Study ID TAK-906-1006
Page 24 of 68
Protocol Final
04 Feb 2019
7.4
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 7.3. 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 
follow-up or early termination as described in Section 3.0. 
7.5
Subject Replacement
Subjects who discontinue for non-safety reasons may be replaced at the discretion of the 
Investigator in consultation with the Sponsor. Subjects who discontinue for safety reasons will not 
be replaced.
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TAK-906
Study ID TAK-906-1006
Page 25 of 68
Protocol Final
04 Feb 2019
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
8.1.1
TAK-906 Capsule
A single 25 mg dose of TAK-906 maleate capsule will be administered on Day 1 of Study Period 1 
and on Day 4 of Study Period 2 of the study.
Oral dose of TAK-906 drug product is a nonsterile, capsule dosage form, supplied in a hard gelatin 
capsule of TAK-906 maleate. TAK-906 maleate is the active pharmaceutical ingredient. No other 
active ingredients are included in the drug product. 
8.1.2
Esomeprazole Capsule 
Once-daily (QD) 40 mg dose of esomeprazole capsules (Nexium® capsule, or generic equivalent) 
will be administered on Days 1 through 5 of Study Period 2.
Oral dose of esomeprazole drug product is a nonsterile, capsule dosage form, supplied in a hard 
gelatin capsule of esomeprazole. Esomeprazole is the active pharmaceutical ingredient. No other 
active ingredients are included in the drug product. 
8.1.3
Clinical Study Drug Labeling
TAK-906 capsule containers will be affixed with a clinical label in accordance with local 
regulatory requirements.
Esomeprazole capsule will be provided with the commercially available package and labeling in 
accordance with local regulatory requirements.
8.1.4
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-906 products to allow completion of this 
study. 
Celerion will provide sufficient quantities of esomeprazole capsules to allow completion of the 
study. The same lot number will be used throughout the study.
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied. All study drugs will be prepared and labeled by licensed pharmacy staff according 
to the procedures outlined in the pharmacy manual. 
8.1.5
Clinical Study Drug Blinding
This is an open-label study.
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8.1.6
Randomization Code Creation and Storage 
NA
8.1.7
Clinical Trial Blind Maintenance/Unblinding Procedure
NA
8.1.8
Accountability and Destruction of Sponsor-Supplied Drugs
At the conclusion of the study, any unused TAK-906 and esomeprazole study drug will be retained 
by Celerion, returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. If no 
supplies remain, this fact will be documented in the pharmacy product accountability records.
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9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and date an 
ICF summarizing the discussion prior to screening, and will be assured that they may withdraw 
from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of the first dosing, different from the screening number.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
This is a fixed-sequence (1-way crossover) study. All subjects will receive the same treatments as 
detailed in Section 6.1.
9.1.2
Inclusion and Exclusion 
9.1.2.1
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study: 
1. Healthy, adult, male or female, 18-55 years of age, inclusive, at screening.
2. Continuous non-smoker who has not used nicotine-containing products for at least 3 months 
prior to the first dosing and throughout the study, based on screening urine cotinine test.
3. Body mass index (BMI) ≥18.0 and ˂30.0 kg/m2 at screening. 
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the principal Investigator or designee.
5. For a male or female of non-childbearing potential, use acceptable birth control methods as 
indicated in Appendix D.
6. A male subject who is nonsterilized and sexually active with a female partner of childbearing 
potential must agree to use a barrier method of contraception from signing of the ICF 
throughout the duration of the study and through to the follow up (ie, 10-14 days after the last 
dose of TAK-906) (refer to Appendix D).
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7. If male, must agree not to donate sperm from the first dosing until follow-up visit (10-14 days 
after the last dosing).
8. Understands the study procedures in the ICF, and be willing and able to comply with the 
protocol.
9.1.2.2
Exclusion Criteria
The subject must be excluded from participating in the study if the subject: 
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant endocrine, gastrointestinal (including motility 
disorder and intestinal obstruction), cardiovascular, hematological, hepatic, immunological, 
renal, respiration, genitourinary, or major neurological (including stroke and chronic seizures) 
any other clinically significant abnormalities or disease in the opinion of the Investigator or 
designee.
3. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the study.
4. History of cancer (malignancy).
5. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing. 
6. History or presence of hypersensitivity or idiosyncratic reaction to TAK-906 or related 
compounds, or to esomeprazole or PPIs (see NEXIUM® USPI).
7. Female subjects of childbearing potential.
8. Female subjects with a positive pregnancy test or who is lactating.
9. Positive urine drug or alcohol results at screening or first check-in.
10. Positive urine cotinine at screening.
11. Positive results at screening for HIV, HBsAg, or HCV.
12. QTcF interval is >450 msec or ECG findings are deemed abnormal with clinical significance 
by the Investigator or designee at screening.
13. Estimated creatinine clearance <90 mL/min at screening. 
14. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications (including PPIs, 
antacids, and H2-antagonist), herbal remedies, or vitamin supplements within 14 days prior 
to the first dosing and throughout the study. Thyroid hormone replacement medication may 
be permitted if the subject has been on the same stable dose for the immediate 3 months 
prior to first study drug administration. After first dosing, acetaminophen (up to 2 g per 
24 hours) may be administered at the discretion of the Investigator or designee.
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
Any drugs known to significantly affect the absorption, distribution, metabolism, or 
elimination of study drugs (TAK-906 or esomeprazole) within 28 days prior to the first 
dosing and throughout the study. Appropriate sources (eg, Flockhart TableTM) will be 
consulted to confirm lack of PK/pharmacodynamic interaction with study drug.
15. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to the first dosing and throughout the study.
16. Donation of blood or significant blood loss (eg, approximately 500 mL) within 56 days prior to 
the first dosing.
17. Plasma donation within 7 days prior to the first dosing.
18. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. 
The 30-day window or 5 half-lives will be derived from the date of the last blood collection or 
dosing, whichever is later, in the previous study to Day 1 of Study Period 1 of the current 
study.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.1 and in Section 9.1.2.2. All 
medications taken by subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to subject safety.
For this study, the collection of blood for plasma TAK-906 concentrations is the critical parameter 
and samples need to be collected as close to the exact time point as possible. All other procedures 
should be completed as close to the prescribed/scheduled time as possible, but can be performed 
prior or after the prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Full Physical Exam
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee.
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9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
BMI
BMI will be calculated based on the height and weight measured at screening.
9.2.4
Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Blood pressure and heart rate measurements will be performed with subjects in a supine position, 
except when they are supine or semi-recumbent because of study procedures and/or AEs 
(eg, nausea, dizziness) or if deemed necessary by the Investigator or designee. Subjects should 
have rested in a supine position for at least 5 minutes before the measurements.
Blood pressure and heart rate will be measured within 24 hours prior to Day 1 dosing of each 
treatment period for the predose time point. When scheduled postdose, vital signs will be 
performed within approximately 15 minutes of the scheduled time point.
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
investigator or designee.
ECGs will be performed with subjects in a supine position and subjects should have rested in a 
supine position for at least 5 minutes before recording the ECG. All ECG tracings will be reviewed 
by the investigator or designee.
ECGs will be measured within 24 hours prior to Day 1 dosing of each period for the predose time 
point. When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point.
9.2.6
Study Drug Administration
TAK-906 oral capsule and esomeprazole oral capsule will be provided as described in Section 8.1.
Subjects will be instructed not to crush, split, or chew the TAK-906 or esomeprazole capsules. 
Capsules should be swallowed as whole.
Treatments A and B are described as: 
Study Period 1 (Treatment A):
25 mg TAK-906 (1 x 25 mg TAK-906 capsule)
Study Period 2 (Treatment B):
40 mg esomeprazole (1 x 40 mg Nexium® capsule, or 
generic equivalent) QD for 5 days (Days 1 through 5 of 
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Study Period 2) with 25 mg TAK-906 (1 x 25 mg TAK-906 
capsule) administered 1 hour following esomeprazole dose 
on Day 4 of Study Period 2.
The oral doses of TAK-906 will be administered following an overnight fast with approximately 
240 mL of water. The oral doses of esomeprazole on Days 1 to 3 and 5 of Study Period 2 will be 
administered following a fast of at least 2 hours. 
The exact clock time of oral dosing will be recorded. 
9.2.7
AE Monitoring
Subjects will be monitored throughout the study for AEs to the study formulations and/or 
procedures as described in Section 10.0.
9.2.8
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator or designee.
9.2.9
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample being 
taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Total protein 
Albumin
Blood Urea Nitrogen
Sodium
Bilirubin (total and direct)
Potassium
Alkaline phosphatase
Chloride
Aspartate aminotransferase (AST)
Glucose 
Alanine aminotransferase (ALT)
Creatinine *
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
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Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
Other 
HIV test
Urine drug screen
Opiates (includes morphine, heroin (diacetylmorphine), 
codeine, 6-acetylmorphine, dihydrocodeine, 
hydrocodone, thebaine, and, hydromorphone)
Amphetamines
Barbiturates
Benzodiazepines
Cocaine
Cannabinoids
HBsAg
HCV (if antibody positive, confirm RNA negative)
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
Urine cotinine test
Urine alcohol screen
9.3
PK Samples
Primary specimen collection parameters are provided in Table 9.a. 
For all subjects, blood samples for the determination of plasma TAK-906 will be collected at 
scheduled time points as delineated in the Schedule of Study Procedures (Section 3.0) in 4 mL 
blood collection tubes containing the appropriate anticoagulant, respectively. The actual time of 
sample collection will be recorded on the source document in the case report form (CRF).  
 
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately.
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Property of Takeda: For non-commercial use only and subject to the applic
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Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Plasma
PK analysis
Mandatory
9.3.1
PK Measurements 
9.3.2
PK Measurements 
9.3.2.1
Plasma PK Measurements
The PK parameters of TAK-906 will be derived using noncompartmental analysis methods and
will be determined from the concentration-time data for all evaluable subjects. Actual sampling
times, rather than scheduled sampling times, will be used in all PK computations involving
sampling times. A more detailed description will be given in the clinical pharmacology analysis 
plan.
PK parameters for plasma TAK-906 and 
 concentrations will be calculated as 
follows, as appropriate, following oral administration:
AUClast:
The area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUCinf:
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration.
Cmax:
Maximum observed concentration.
Other PK parameters may be calculated if deemed necessary for the interpretation of the data. All 
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
However, samples obtained within 10% of the nominal time from dosing will not be captured as a 
protocol deviation, as long as the exact time of the sample collection is noted on CRF.
The decision as to which plasma samples collected will be assayed for evaluation of PK will be 
determined by the sponsor. If indicated, these samples may also be assayed and/or pooled for assay 
in an exploratory manner for metabolites.
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9.3.3
 
9.3.4
Confinement
In Study Period 1, subjects will be housed on Day -1, at the time indicated by the CRU until after 
the 48-hour blood draw and/or study procedures on Day 3. In Study Period 2, Subjects will be 
housed on Day 3 at the time indicated by the CRU until after the 48-hour blood draw and/or study 
procedures on Day 6.
Subjects will return for dosing and/or study procedures as indicated in the Schedule of Study 
Procedures (Section 3.0). A subject may be required to remain at the CRU for longer at the 
discretion of the Investigator or designee.
As per site preference, subjects may be confined throughout the washout period.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
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of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
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. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the 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 assessed by the Investigator and/or the Sponsor, 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
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
NA
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The PI or designee will review each AE and assess its relationship to drug treatment (refer to 
Section 10.2.2). All AEs, including signs, symptoms, or clinically significant treatment-emergent 
laboratory abnormalities will be graded on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 toxicity grading scale. 
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Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on the following general guideline [9]:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*.
Grade 3
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL**.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
A Semi-colon indicates ‘or’ within the description of the grade.
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 
5 options for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option. 
ADL=Activities of Daily Living 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
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10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
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10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up visit on Day 10-14 after the last dose of TAK-906. For subjects who discontinue prior to 
the administration of study medication, AEs will be followed until the subject discontinues study 
participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All 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 AEs will be documented in the AE page of the CRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
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A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs 
NA
10.2.8.5 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 CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a 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 10.2.8.3. 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. Follow-up laboratory tests as described in Section 9.2.8 must also be 
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performed. In addition, an LFT Increases CRF must be completed and transmitted with the Takeda 
SAE form (as per Section 10.2.9). 
10.2.9 Safety Reporting to Investigators, 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 within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a SAP. The SAP will be prepared by Celerion and agreed upon with the 
Sponsor. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoints definition and/or its analysis will also be reflected in a 
protocol amendment. Additional statistical analyses other than those described in this section may 
be performed if deemed appropriate.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
All subjects who received at least one dose of the study drug will be included in the safety 
evaluations.
11.1.1.2 PK Set
Samples from all subjects will be assayed even if the subjects do not complete the study. All 
subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) will 
be included in the statistical analyses.
11.1.1.3 PD Set
NA
11.1.2 Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3 PK Analysis
Descriptive statistics will be provided for the plasma TAK-906 concentrations using appropriate 
summary statistics to be fully specified in the SAP.
PK parameters for plasma TAK-906 concentrations will be calculated as described in 
Section 9.3.2.1.
For evaluation of potential effect of esomeprazole on TAK-906 PK, an ANOVA will be performed 
on the ln-transformed Cmax, AUClast, and AUCinf. The ANOVA model will include treatment as 
CCI
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fixed effect and subject as a random effect. Each ANOVA will include calculation of least-squares 
means (LSM) as well as the difference between treatment LSM. The geometric mean of the 
relative bioavailability of the TAK-906 with esomeprazole regimen relative to the TAK-906 
regimen alone and the associated 90% CIs will be determined by exponentiation of the appropriate 
estimates for the difference between regimens in the log-transformed parameters
11.1.4 PD Analysis 
NA
11.1.5 Safety Analysis
All safety data will be populated in the individual CRFs. 
Dosing dates and times will be listed by subject.
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics.
11.1.5.1 AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by treatment for the number and percentage of 
subjects reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing 
including verbatim term, coded term, treatment, severity, and relationship to treatment will be 
provided.
11.1.5.2 Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by treatment and point of time of collection and a 
shift table describing out of normal range shifts will be provided.
11.1.5.3 Vital Signs and ECG Parameters
Vital signs and ECG assessments will be summarized by treatment and point of time of collection.
11.1.5.4 Physical Examination 
Physical examination findings will be presented in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
The total of twelve (12) subjects will be enrolled in this study. This sample size will provide at 
least 80% power to conclude the Cmax of TAK-906 will not decrease more than 50% in the 
presence of esomeprazole, assuming that the intra-subject %CV for Cmax of TAK-906 will not 
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exceed 45% and a true ratio of 0.8. Lower intra-subject variability was observed for AUC in 
previous studies; therefore, the power is expected to be greater for AUC.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (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 the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of CRFs 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.
12.2
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.
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. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
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13.0
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 International Council for Harminsation (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 A. The principles of Helsinki are addressed through 
the protocol and through appendices containing requirements for informed consent and 
investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, 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, ICF) reviewed; and state the 
approval date. The Sponsor will ship drug/notify site once the Sponsor has confirmed the adequacy 
of site regulatory documentation and, when applicable, the Sponsor has received permission from 
competent authority to begin the study. Until the site receives drug/notification no protocol 
activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by 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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13.2
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 ICF, 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 ICF 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 ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, 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 ICF, 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 ICF, 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 ICF 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 ICF 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 ICF, 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 ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
Subjects who consented and provided a blood sample for DNA analysis can withdraw their 
consent and request disposal of a stored sample at any time prior to analysis. Notify Sponsor of 
consent withdrawal.
13.3
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 13.2).
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 CRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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13.4.2 Clinical Trial Registration 
In order to ensure that information on clinical studies reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical studys it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting study 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Refer to the study site agreement regarding the Sponsor’s policy on subject compensation and 
treatment for injury. If the investigator has questions regarding this policy, he or she should contact 
the Sponsor or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Serious adverse event and pregnancy reporting
PPD
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14.1.2 Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the Sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
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14.1.4 List of Abbreviations
AE
Adverse event
ADL
Activities of Daily Living 
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC%extrap
Percent of AUC∞extrapolated 
AUClast
Area under the concentration-time curve, from time 0 to the last observed non-zero 
concentration
AUCinf
Area under the concentration-time curve, from time 0 extrapolated to infinity
BBB
Blood brain barrier
BMI
Body mass index
bpm
Beats per minute
CFR
Code of Federal Regulations
CI
Confidence interval
cm
Centimeter
Cmax
Maximum observed concentration 
CRF
Case report form
CRU
Clinical Research Unit
CTCAE
Common Terminology Criteria for Adverse Events
CV
Intra-subject variability
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
g
Gram(s)
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
Kel
Apparent first-order terminal elimination rate constant
kg
Kilogram
LFT
Liver function test(s)
ln
Natural log
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INR
International normalized ratio
LSM
Least-squares
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
n
Sample size
NA
Not applicable
NMDA
N-methyl-D-aspartate
oz
Ounce
OATP
Organic anion-transporting polypeptide
PK
Pharmacokinetic(s)
PO
Oral administration
PPI
Proton pump inhibitor
PT
Prothrombin time
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspected unexpected serious adverse reactions
t½
Apparent first-order terminal elimination half-life
TEAE
Treatment-emergent adverse event
Tmax
Time to reach maximum observed concentration [Cmax]
ULN
Upper limit of normal
US
United States
USA
United States of America
WHO
World Health Organization
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan.
15.1
CRFs (Electronic and/or Paper)
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor or its 
designee will train appropriate site staff in the use of the CRF. These forms are used to transmit the 
information collected in the performance of this study to the Sponsor and regulatory authorities. 
CRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the investigator with use of change and modification records of the 
CRFs. The principal investigator must review the data change for completeness and accuracy, and 
must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating 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), 
copy of CRFs, including the audit trail, and detailed records of drug disposition to enable 
evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on 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, 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 
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Study ID TAK-906-1006
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drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and Sponsor. 
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.0
REFERENCES
1. Parkman HP, Hasler WL, Fisher RS, American Gastroenterological A. American 
Gastroenterological Association technical review on the diagnosis and treatment of 
gastroparesis. Gastroenterology 2004;127(5):1592-622.
2. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L, American College of G. Clinical 
guideline: management of gastroparesis. Am J Gastroenterol 2013;108(1):18-37; quiz 8.
3. Hyett B, Martinez FJ, Gill BM, Mehra S, Lembo A, Kelly CP, et al. Delayed radionucleotide 
gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. 
Gastroenterology 2009;137(2):445-52.
4. Takeda Pharmaceuticals, Inc. Global Investigator Brochure. Edition 2.0, July 2018.
5. NEXIUM® delayed-release 20 and 40 mg capsules, AstraZeneca Pharms, label, 07 June 2018 
Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021153s053,022101s017,02195
7s020lbl.pdf
6. NEXIUM® FDA review of NDA 21-153/21-154 for AstraZeneca Pharmaceuticals 
Esomeprazole Magnesium Delayed-Release Capsules, March 12, 1999. Available at: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.
7. Andersson T1, Röhss K, Bredberg E, Hassan-Alin M. Pharmacokinetics and 
pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol 
Ther. 2001 Oct;15(10):1563-9.
8. Wilder-Smith CH1, Röhss K, Nilsson-Pieschl C, Junghard O, Nyman L. Esomeprazole 40 mg 
provides improved intragastric acid control as compared with lansoprazole 30 mg and 
rabeprazole 20 mg in healthy volunteers.Digestion. 2003;68(4):184-8. Epub 2003 Dec 19. 
9. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 toxicity grading scale. 27Nov2017.
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 Terms of Use


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17.0
APPENDICES
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Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study -related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study -related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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 
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contact and receive written approval from the Sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
12. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Study ID TAK-906-1006
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject, as 
applicable:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of DNA analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study 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 
published.
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25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing of informed consent throughout the duration of the study and through to the 
follow-up visit (ie, 10-14 days after the last dose of TAK-906). 
26. A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical study registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and through to the 
follow-up visit, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. Females of 
childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception below.
Female Subjects and Their Male Partners
*A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral oophorectomy, hysteroscopic sterilization, and bilateral 
tubal ligation or bilateral salpingectomy. A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range (FSH >40 IU/L) may be used to confirm a post-menopausal state in 
younger women (eg, those <45 year old) or women who are not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
1. Unacceptable methods of contraception are:

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
2. Subjects will be provided with information on highly effective/effective 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.
3. During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed for all women only and all subjects (male and female) will receive 
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Study ID TAK-906-1006
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continued guidance with respect to the avoidance of pregnancy and sperm donation as part of 
the study procedures. Such guidance should include a reminder of the following:
a) contraceptive requirements of the study.
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Is there a chance for a female partner who could become pregnant?
Pregnancy
Women of childbearing potential will not be included in this study.
Any pregnancies in the partner of a male subject during the study and until the follow up visit, 
should be recorded following authorization from the subject’s partner. 
If 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 was participating in a clinical 
study at the time his female partner became pregnant and provide details of the study drug the 
subject received (blinded or unblinded, as applicable).
All pregnancies in female partners of male subjects will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted.
Property of Takeda: For non-commercial use only and subject to the applic
 Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Single-Sequence, Open-Label, 2-Period, Crossover Study to Evaluate the Effect of the 
Proton Pump Inhibitor Esomeprazole on the Single-Dose Pharmacokinetics of Oral TAK-906 
in Healthy Adult Subjects
NCT Number: NCT03849690
SAP Approve Date: 22 April 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-906-1006
CELERION STUDY NUMBER: CA27239
A Single-Sequence, Open-Label, 2-Period, Crossover Study to Evaluate the Effect of the
Proton Pump Inhibitor Esomeprazole on the Single-Dose Pharmacokinetics of Oral
TAK-906 in Healthy Adult Subjects
PHASE 1
Version: Final
Date: 22 April 2019
Prepared by:
Based on:
Protocol Dated: 04 February 2019
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
to Evalu
o Eva
se Phar
e Pha
ubjects
ubject
on: Fina
n: Fin
: 22
22 Ap
A
d on:
d on:
Pr
P
a: For non-commerci
rty


TAK-906-1006
Celerion Study Number CA27239
Page 2 of 20
Statistical Analysis Plan Final
22 April 2019
1.1
Approval Signatures
Study Title:
A Single-Sequence, Open-Label, 2-Period, Crossover Study to Evaluate the 
Effect of the Proton Pump Inhibitor Esomeprazole on the Single-Dose 
Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
the
he
bject to the applicab


TAK-906-1006
Celerion Study Number CA27239
Page 3 of 20
Statistical Analysis Plan {Final}
22 April 2019
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objective..................................................................................................7
4.3
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Secondary Endpoint...................................................................................................9
5.3
Exploratory Endpoints ...............................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.2
Analysis Sets ...........................................................................................................13
7.3
Study Information....................................................................................................13
7.4
Disposition of Subjects ............................................................................................13
7.5
Demographic and Other Baseline Characteristics.....................................................13
7.6
Medical History and Concurrent Medical Conditions...............................................14
7.7
Medication History and Concomitant Medications...................................................14
7.8
Study Drug Exposure and Compliance.....................................................................14
7.9
Efficacy Analysis.....................................................................................................14
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................14
7.10.1 Pharmacokinetic Analysis ..................................................................................14
7.10.2 Pharmacodynamic Analysis ...............................................................................16
7.11
Other Outcomes.......................................................................................................16
7.12
Safety Analysis........................................................................................................16
7.12.1 Adverse Events ..................................................................................................16
7.12.2 Clinical Laboratory Evaluations .........................................................................17
7.12.3 Vital Signs .........................................................................................................18
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Statistical Analysis Plan {Final}
22 April 2019
7.12.4 12-Lead ECGs ...................................................................................................18
7.12.5 Physical Exams..................................................................................................18
7.12.6 Overdose............................................................................................................18
7.13
Interim Analysis ......................................................................................................18
7.14
Preliminary Analysis................................................................................................18
7.15
Changes in the Statistical Analysis Plan...................................................................19
8.0
REFERENCES..............................................................................................................20
LIST OF IN-TEXT TABLES
Table 4.a
Study Drugs Planned Dose Levels........................................................................8
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................15
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................8
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Statistical Analysis Plan {Final}
22 April 2019
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance 
AUC
AUCinf
area under the curve
area under the plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the 
last quantifiable concentration.
BLQ
BMI
below the limit of quantitation
body mass index
CI
CL/F
Cmax
confidence interval
apparent total plasma clearance
maximum observed plasma concentration
CPAP
CRF
Clinical Pharmacology Analysis Plan
case report form
CRU
clinical research unit
CS
CSR
CV
ECG
clinically significant
clinical study report
coefficient of variation
electrocardiogram
Geom CV
geometric coefficient of variation 
Geom Mean
geometric mean
GMR
geometric mean ratio
ICF
ICH
informed consent form
International Conference on Harmonization
ln
LSM
natural log
least-square means
Mean
MedDRA
arithmetic mean
Medical Dictionary for Regulatory Activities
PI
PK
Principal Investigator
pharmacokinetics
PO
orally administered 
PPI
proton pump inhibitor 
QD
once daily
SAE
serious adverse event
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Celerion Study Number CA27239
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Statistical Analysis Plan {Final}
22 April 2019
SD
SEM
SOC
t½
standard deviation
standard error of the mean
system organ class
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
Tmax
tables, figures, and listings
time to first occurrence of Cmax
Vz/F
apparent volume of distribution during the terminal elimination phase
WHO
World Health Organization
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Celerion Study Number CA27239
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Statistical Analysis Plan {Final}
22 April 2019
4.0
OBJECTIVES
4.1
Primary Objectives
To evaluate the effect of the proton pump inhibitor (PPI), esomeprazole, on the single-dose 
pharmacokinetics (PK) of orally administered (PO) TAK-906. 
4.2
Secondary Objective
To evaluate the safety and tolerability of a single PO dose of TAK-906 in the presence and 
absence of the PPI, esomeprazole. 
4.3
Study Design
This is a single-sequence, open-label, 2-period crossover study in 12 healthy adult subjects. The 
study is designed to investigate the effect of a PPI, esomeprazole, on the PK of TAK-906. The 
study will include a screening visit, a study Period 1 (Days 1 to 3), followed by at least a 4-day 
washout from the time of TAK-906 dose, a study Period 2 (Days 1 to 6), and a follow-up visit. 
Screening of subjects will occur within 28 days prior to the first dosing
In study Period 1, subjects will be confined from the day prior to dosing (Day -1), at the time 
indicated by the clinical research unit (CRU), until after the 48-hour blood draw (Day 3). In 
study Period 2, subjects will come to the CRU on the mornings of Day 1 to Day 2, at the time 
indicated by the CRU, for dosing and/or study procedures as appropriate. Subjects will be 
confined from morning of Day 3, at the time indicated by the CRU, until after the 48-hour blood 
draw on Day 6. At any time, a subject may be required to remain at the CRU for longer at the 
discretion of the Principal Investigator (PI).
On Day 1 of study Period 1, subjects will receive a single oral dose of TAK-906. On Days 1 
through 5 of Study Period 2, subjects will receive esomeprazole (Nexium®) dose once daily 
(QD). On Day 4 of study Period 2, a single oral dose of TAK-906 will be administered 1 hour 
following the esomeprazole dose. Serial blood samples will be collected predose and for 48 
hours after each TAK-906 dose to determine the PK of TAK-906.
All subjects who received at least one dose of study drug (including subjects who terminate the 
study early) will return to the CRU approximately 10-14 days after the last dose of TAK-906 for 
follow-up procedures, and to determine if any adverse event (AE) has occurred since the last 
study visit.
The planned dose levels of TAK-906 and esomeprazole to be used are outlined in Table 4.a. 
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Statistical Analysis Plan {Final}
22 April 2019
Table 4.a
Study Drugs Planned Dose Levels
Dose
Route of Administration
Study Period 1 (Treatment A)
TAK-906
25 mg
Oral capsule
Study Period 2 (Treatment B)
TAK-906
Esomeprazole
25 mg
40 mg
Oral capsule 
Oral capsule
A schematic of the study design is included as Figure 4.a. 
Figure 4.a
Schematic of Study Design
Screening
Study Period 1 (a)
Within Day -28 to -2 for 
screening; first dosing in 
Study Period 1
Day -1
Day 1
Days 2 – 3 
Check-in
TAK-906 dosing 
Plasma sampling for TAK-906 PK and safety monitoring for at least 48 
hours postdose
< - - - - - - - - - - - - Confinement (b) (c) - - - - - - - - - - - - >
(a) There will be a washout of at least 4 days between dosing in Study Period 1 and first dosing in Study Period 2.
(b) A subject may be required to remain at the CRU for longer at the discretion of the PI or designee.
(c) Subjects will start the confinement on Day -1 of Study Period 1 and be released from CRU after Day 3 study
assessments are complete.
Study Period 2 (a)
Study exit
Follow-up (b)
Days 1-2
Day 3
Day 4
Day 5
Day 6
Day 6 of 
Treatment 
Study 
Period 2
10-14 days 
after last 
dosing
Check-in
Esomeprazole 
dosing
Esomeprazole 
dosing
Esomeprazole dosing
TAK-906 dosing
Esomeprazole 
dosing
Plasma sampling for TAK-906 PK and safety 
monitoring for at least 48 hours postdose
Outpatient 
visit
< - - - - - - - - - - - - Confinement (c) (d) - - - - - - - - - - - - >
(a) There will be a washout of at least 4 days between dosing in Study Period 1 and first dosing in Study Period 2.
(b) All subjects who received at least one dose of study drug (including subjects who terminate the study early) will 
return to the CRU approximately 10-14 days after the last dose of TAK-906 for follow-up procedures, and to 
determine if any AE has occurred since the last study visit
(c) A subject may be required to remain at the CRU for longer at the discretion of the PI or designee.
(d) In Study Period 2, subjects will return to the CRU on the morning of Days 1 and 2 for dosing and/or study 
procedures as appropriate. Subjects will be confined from morning of Day 3 of Study Period 2, at the time indicated 
by the CRU, until after 48-hour blood draw on Day 6.
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Statistical Analysis Plan {Final}
22 April 2019
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The following plasma PK parameters will be calculated for TAK-906 on Day 1 in study Period 1 
and on Day 4 in study Period 2: 
!
Cmax: Maximum observed concentration
!
AUClast: Area under the concentration-time curve from time 0 to time of the last
quantifiable concentration
!
AUCinf: Area under the concentration-time curve from time 0 to infinity
5.2
Secondary Endpoint
The following safety variables will be used to characterize the safety and tolerability of 
TAK-906:
!
Treatment –emergent adverse event (TEAE) assessment
!
Vital signs
!
12-lead electrocardiograms (ECG)
!
Clinical laboratory testing (hematology, serum chemistry, and urine analysis)
5.3
Exploratory Endpoints
CCI
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TAK-906-1006
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Statistical Analysis Plan {Final}
22 April 2019
6.0
DETERMINATION OF SAMPLE SIZE
A total of twelve (12) subjects will be enrolled in this study. This sample size will provide at
least 80% power to conclude the Cmax of TAK-906 will not decrease more than 50% in the
presence of esomeprazole, assuming that the intra-subject coefficient of variation (CV%) for 
Cmax of TAK-906 will not exceed 45% and a true ratio of 0.8. Lower intra-subject variability 
was observed for AUC in previous studies; therefore, the power is expected to be greater for 
AUC.
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Statistical Analysis Plan {Final}
22 April 2019
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using Phoenix® WinNonLin® Version 7.0, or higher. All 
statistical analyses will be conducted using SAS® Version 9.3, or higher. All data recorded on the 
CRF will be listed by subject. All tables, figures and listings (TFLs) shells and numbering list 
specified in the Clinical Pharmacology Analysis Plan (CPAP) will be included.
The concentration data will be used as reported by the respective bioanalytical groups without 
rounding for all analyses. All PK parameters tables should include three significant figures, 
except Tmax, and t1/2 which will be presented with 2 decimal places. %CV should have 1 
decimal place.
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. BLQ values will be treated as zero for the 
calculation of summary statistics, the generation of concentration plots, and the calculation of PK 
parameters, unless they are obvious outliers (e.g. BLQ value between 2 measurable values), in 
which case they will be treated as missing. In log-linear plots these values would not be 
presented. In the tables presenting summary statistics of concentration-time series, the total 
number of values (n) and the number of values that are above the level of quantification 
(n_ABLQ) will be presented. The following footnote will also be added to appropriate 
concentration versus time figures: All values reported as BLQ have been replaced with zero.
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
recorded data. Geometric mean ratios (GMRs) and 90% CIs around the ratio will be reported 
using 2 decimal places. 
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical evaluation if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that subject’s Cmax value in that period 

A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist)

A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist)
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Statistical Analysis Plan {Final}
22 April 2019
See Clinical Pharmacology Analysis Plan (CPAP) for details on the PK parameter calculations 
and data presentation including specifics on the following:

Insufficient data to determine a reliable t½ value and other terminal elimination rate constant 
dependent parameters

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables

Concentration data file used for PK analysis

PK parameter WinNonLin® output file used to generate the tables, figures, and listings 
(TFLs)

Analysis of variance (ANOVA) results presented in in-text and end-of-text tables

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures

Individual concentration-time figures presented in Appendix 16.2.6
For demographic data where appropriate, variables will be summarized descriptively. For the 
categorical variables, the count and proportions of each possible value will be tabulated, where 
applicable. The denominator for the proportion will be based on the number of subjects who 
provided non missing responses to the categorical variable. For continuous variables, the number 
of subjects with non-missing values, mean, SD, minimum, median, and maximum values will be 
tabulated.
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Day 1 for the study is defined as the date on which a subject is administered their first dose of the 
study drug(s) in Period 1. Other study days are defined relative to Day 1 with Day -1 being the 
day prior to Day 1 of Period 1. Study day prior to the first dose in Period 1 will be calculated as: 
date of assessment-date of first dose in Period 1; study day on or after the date of first dose will 
be calculated as: date of assessment-date of first dose in Period 1 +1.
Day 1 for each period is defined as the date on which a subject is administered their first dose of 
the study drug(s) in each period. Other study days are defined relative to Day 1 with Day -1 
being the day prior to Day 1 of each period. Study day prior to the first dose of each treatment 
will be calculated as: date of assessment-date of first dose in each period; study day on or after 
the date of first dose will be calculated as: date of assessment-date of first dose in each period
+1.
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Statistical Analysis Plan {Final}
22 April 2019
7.2
Analysis Sets
Safety Set:
All subjects who received at least one dose of the study drug will be included in the safety
evaluations. Subjects in this analysis set will be used for demographic, baseline characteristics 
and safety summaries.
PK Set:
Samples from all subjects will be assayed even if the subjects do not complete the study. All
subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg,
exposure to treatment, availability of measurements and absence of major protocol violations) 
will be included in the statistical analyses. In terms of criteria for evaluable subjects, please see 
CPAP.
7.3
Study Information
Study information including date first subject signed informed consent form, date for the first 
dose, date for the last dose, date of last subject’s last visit/contact, date of last subject’s last 
procedure for collection of data for primary endpoint, the version of Medical Dictionary for 
Regulatory Activities (MedDRA®), the version of World Health Organization (WHO) 
Dictionary, and SAS version used for creating the datasets will be listed. 
7.4
Disposition of Subjects
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized. Study completion status, including 
reason for discontinuation, will also be listed by subject. 
7.5
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively. Summary statistics 
(number of subjects [n], mean, SD, minimum, median, and maximum) will be generated for 
continuous variables (age [calculated from the date of signed Informed Consent Form [ICF], 
weight, height and body mass index [BMI]) and the number and percentage of subjects within 
each category will be presented for categorical variables (sex, race, and ethnicity). For height the 
screening measurement will be reported but for weight and BMI the baseline value, which is the 
last observation prior to dosing, will be reported. The demographics listing will also include 
protocol version and date, ICF version and date, the date of each signed the ICF. 
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Statistical Analysis Plan {Final}
22 April 2019
7.6
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing the 
ICF. Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing the ICF. Each subject’s medical history and concurrent medical conditions will 
be listed. Any medical condition started after taking the study drug will be classified as an 
adverse event. The medical history listing will include whether the event was medical or 
surgical, the body system or organ class involved, start date (if known) and end date or whether 
the condition was ongoing, and a description of the condition or event. There will be no 
statistical analysis of medical history.
7.7
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and
efficacy/safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant 
medication includes any medication other than study drug taken at any time between time of 
signing the ICF through the end of the study (including follow-up visit). All medication history 
and concomitant medications recorded during the study will be coded with the WHO Dictionary 
Version 01-Sep-2018 and listed. The listing will include the medication name, dosage, route of 
administration, start date and time (if known), end date and time, or whether it continued after 
study completion, and indication for use. 
7.8
Study Drug Exposure and Compliance
Not applicable.
7.9
Efficacy Analysis
Not applicable.
7.10
Pharmacokinetic/Pharmacodynamic Analysis
7.10.1 Pharmacokinetic Analysis
Blood samples (one 4 mL sample per scheduled time) for PK analysis of TAK-906 will be 
collected as specified in Table 7:1 following administration of TAK-906 alone (sampling Day 1 
– Period 1) or coadministered with esomeprazole (sampling Day 4 – Period 2).
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Statistical Analysis Plan {Final}
22 April 2019
Table 7.a
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Sampling Day
Scheduled Time (hours)
TAK-906
Plasma
1
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose (a) 
(b).
TAK-906
Plasma
4
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours postdose (a) 
(b) (c).
(a) If a subject experiences a serious adverse event (SAE), a blood sample for PK analysis should also be obtained at 
the unscheduled visit. PK samples will be collected at Early Termination at the discretion of the PI.
(b) The 16-hour postdose on Day 1 of study Period 1 and Day 4 of study Period 2 will be either on Day 1 or Day 2 
of Period 1 and Day 4 or Day 5 of Study Period 2, depending on the time of dosing on Day 1 of study Period 1 and 
Day 4 of study Period 2, respectively.
(c) The collection times for analysis of TAK-906 PK parameters will be relative to TAK-906 dose on Day 4 for 
Period 2.
The actual date and time of sample collection will be recorded on the source document in the 
case report form (CRF). 
 
The PK parameters of TAK-906 listed in the CPAP for this study will be determined from the 
concentration-time profiles for subjects in the PK set using a noncompartmental analysis method. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. If actual sample times are missing, nominal times may be used.
Concentrations will be listed and summarized descriptively by PK sampling time. Summary will 
be done by treatment using the summary statistics listed in the CPAP. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive summary statistics. Individual subject and arithmetic mean 
profiles of the concentration-time data will be plotted by treatment on linear (with and without 
SD) and semi-log scales. For summary statistics and arithmetic mean plots by sampling time, the 
nominal PK sampling time will be used, for individual subject plots by time, the actual PK 
sampling time will be used. 
PK parameters will be summarized descriptively by treatment using the summary statistics listed 
in the CPAP. Excluded parameters will be presented and footnoted as such in the PK parameter 
table listings, and those values will be excluded from the descriptive summary statistics. 
Drug-Drug Interaction 
For evaluation of potential effect of esomeprazole on TAK-906 PK, an ANOVA will be 
performed on the natural log (ln)-transformed Cmax, AUClast, and AUCinf, which have been 
exponentiated to provide estimates on the original scale. The ANOVA model will include 
treatment as fixed effect and subject as a random effect. Each ANOVA will include calculation 
of least-squares means (LSM) as well as the difference between treatment LSM. The geometric 
mean of the relative bioavailability of the TAK-906 with esomeprazole relative to the TAK-906
alone and the associated 90% confidence intervals (CIs) will be determined by exponentiation of 
CCI
Property of Takeda: For non-commercial use only and
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TAK-906-1006
Celerion Study Number CA27239
Page 16 of 20
Statistical Analysis Plan {Final}
22 April 2019
the appropriate estimates for the difference between treatments in the log-transformed 
parameters.
PROC MIXED DATA=XXXX;
CLASS Treatment Subject;
MODEL <PK_Parameter> = Treatment / DDFM=KR;
RANDOM Subject;
ESTIMATE ‘Treatment B vs A ’ Treatment -1 1 / CL ALPHA = 0.10 E;
LSMEANS Treatment;
Run;
7.10.2 Pharmacodynamic Analysis
Not applicable.
7.11
Other Outcomes
Not applicable.
7.12
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and type of TEAEs, changes from 
baseline in the subjects’ clinical laboratory results, vital signs, and ECG’s using the safety set.. 
All clinical safety data will be listed by subject and assessment time points, including rechecks, 
unscheduled assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
7.12.1 Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate or severe), relationship to study drug (related or not 
related) and action relative to the study drug for both TAK-906 and eomeprazole. Study 
procedure taken due to AE will also be listed. All AEs occurring during this study will be coded 
using the MedDRA® Version 21.1. However, only TEAEs occurring after administration of the 
first dose of study drug and through the end of the study (approximately 14 (± 2) days after the 
last dose of investigational product administration) will be summarized. 
A TEAE is defined as an AE that is starting or worsening at the time of or after study drug 
administration. 
For each treatment, TEAEs will be coded using MedDRA® Version 21.1 and tabulated by 
System Organ Class (SOC) and Preferred Term. Summary tables will include number of subjects 
reporting the AE and as percent of safety set by treatment. The most commonly reported non-
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Statistical Analysis Plan {Final}
22 April 2019
serious TEAEs (i.e., those events reported by >5% of all subjects in each treatment group, 
excluding SAEs) will also be summarized. For the list of all AE summary table see CPAP.
In addition, TEAEs will be summarized as number of AEs and percentage of AEs for each 
treatment for the overview of TEAEs. 
Additional TEAE summary tables will be presented by severity and relationship to study drug
(TAK-906 and eomeprazole). If a subject has multiple AEs with different severity levels within 
the same term, the subject will be counted in the most severe category only. If a subject has both 
related and unrelated AEs with the same term, the subject will be counted as having related 
TEAEs.
For treatment B, the TEAEs will be summarized separately for two segments (Treatment B1 and 
Treatment B2). Treatment B1 will be esomeprazole which is started from the first esomeprazole
dosing and prior to TAK-906 dosing. Treatment B2 will be esomeprazole + TAK-906 which is 
after the dosing of TAK-906 on Day 4 of Period 2.
Should any SAEs occur they will be summarized the same way as TEAE. All AEs will be 
displayed in the data listings and TEAEs will be discussed in the text of the study report.
7.12.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1) 
of Study Period 1, Day 1 predose of Study Period 2, and on Day 6 of Study Period 2 or prior to 
early termination from the study, and at the follow-up visit. In addition, laboratory safety tests 
may be performed at various unscheduled time points, if deemed necessary by the PI.
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by assessment time points. Change 
from baseline will be summarized. Baseline is defined as the last assessment including rechecks 
taken prior to dosing in Study Period 1. 
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
baseline (above normal (H), normal (N), or below normal (L)) with those postdose time points. 
For urinalysis tests, the categories are normal (N) and abnormal (A). Out-of-range values and 
corresponding recheck results will be listed. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a clinically significant (CS) range. If the value falls within the CS 
range, it will be noted as “N” for not clinical significant. If the value fails the CS range, it will be 
flagged with a “Y” which prompts the PI to determine how the out-of-range value should be 
followed using 4 Investigator flags: "N", not clinically significant, "R", requesting a recheck, "^", 
checking at the next scheduled visit, or "Y", clinically significant. All clinically significant lab 
tests and the corresponding values will be listed by subject. All clinical laboratory data will be 
presented in by-subject data listings.
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Statistical Analysis Plan {Final}
22 April 2019
7.12.3 Vital Signs
Single measurements of heart rate and blood pressure will be obtained at screening, predose, and 
at 1, 2, 4, 8, and 48 hours postdose (times relative to TAK-906 dose) in each period or upon early 
termination, and at the follow-up visit. Respiration rate, and temperature, are collected at 
screening and Day 1 predose of Study Period 1only. Additional unscheduled vital signs 
measurements may be taken at other times, if deemed necessary by the PI.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results and change from baseline by treatment and time point of collection. Baseline is 
defined as the last assessment including rechecks taken prior to TAK-906 dosing in each period. 
Vital signs will also be displayed in a data listing by subject.
7.12.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded at screening, predose, and at 1, 2, 4, 8, and 48 hours 
postdose (times relative to TAK-906 dose) or upon early termination, and at the follow-up visit. 
Additional unscheduled ECGs may be recorded at other times if deemed necessary by the PI. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by treatment and time point of collection. Baseline is defined as 
the last assessment including rechecks taken prior to TAK-906 dosing in each period. ECG data 
will also be displayed in a data listing by subject.
7.12.5 Physical Exams
A full physical exam will be performed at screening, Day 1 predose of Study Period 1, and at the 
follow-up visit. Symptom driven physical exams may be performed at other times at the 
discretion of the PI. Physical exam findings will be presented in a data listing by subject. 
Reproductive system findings will also be listed by subject.
7.12.6 Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs. 
7.13
Interim Analysis
No interim analysis will be performed.
7.14
Preliminary Analysis
Analysis will be completed as described in the CPAP and Section 7.9.1 of the SAP, with the 
following changes: 1) QCed data will be used (not QAed); 2) nominal times will be used for the 
calculation of PK parameters (not actual sampling times); 3) tables and figures will be created 
using Phoenix® WinNonLin® Version 7.0 or higher.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906-1006
Celerion Study Number CA27239
Page 19 of 20
Statistical Analysis Plan {Final}
22 April 2019
7.15
Changes in the Statistical Analysis Plan 
There are no changes in the statistical analysis plan.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906-1006
Celerion Study Number CA27239
Page 20 of 20
Statistical Analysis Plan {Final}
22 April 2019
8.0
REFERENCES
Not applicable.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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