Conditions: Healthy Volunteers
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the effect of single dose intravenous rifampin 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 to evaluate the effect of single dose intravenous rifampin on the single-dose PK of oral TAK-906 in healthy adult participants.

The study will enroll approximately 12 participants. Participants will be randomly assigned to one of the two treatment sequences AB or BA:

* Sequence AB: TAK-906 25 mg, followed by a washout period of at least 7 days, then Rifampin 600 mg and TAK-906 25 mg
* Sequence BA: Rifampin 600 mg and TAK-906 25 mg, followed by a washout period of at least 7 days, then TAK-906 25 mg

This single center trial will be conducted in the United States. The overall time to participate in this study is 49 Days. All participants will make final visit 14 days after receiving their last dose of study drug for follow up assessment.

Arms:
arm 1: TAK-906 25 milligram (mg) (Treatment A), capsule, orally, once on Day 1 of Study Period 1, followed by a washout period of at least 7 days, further followed by rifampin 600 mg, infusion, once, intravenously over 30 minutes along with TAK-906 25 mg (Treatment B), capsule, orally, once immediately after the end of infusion on Day 1 of Study Period 2. arm 2: Rifampin 600 mg, infusion, once, intravenously over 30 minutes along with TAK-906 25 mg (Treatment B), capsule, orally, once immediately after the end of infusion on Day 1 of Study Period 1 followed by a washout period of at least 7 days, further followed by TAK-906 25 mg (Treatment A), capsule, orally, once on Day 1 of Study Period 2.

Interventions: intervention 1: TAK-906 intervention 2: Rifampin
Intervention descriptions: intervention 1: TAK-906 capsule. intervention 2: Rifampin infusion.

Protocol document:
Prot_001.pdf: 



Title: A Phase 1, Open-Label, Randomized, Two-Way Crossover Study to Evaluate the Effect of 
Single-Dose Intravenous Rifampin as a Prototypic Inhibitor of OATP1B1 and OATP1B3 on the 
Single-Dose Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
NCT Number: NCT04121078
Protocol Approve Date: 24 September 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.
Takeda submitted a protocol clarification letter for the final protocol, dated 24-September-2019, explaining the 
discrepancies within the protocol. The clarification letter is appended to the back of the protocol.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-Label, Randomized, Two-Way Crossover Study to Evaluate the Effect of 
Single-Dose Intravenous Rifampin as a Prototypic Inhibitor of OATP1B1 and OATP1B3 on 
the Single-Dose Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
Study Identifier:
TAK-906-1009
Compound:
TAK-906
Date:
24 September 2019
Version/Amendment 
Number:
Final
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1009
Page 2 of 72
Protocol Final
24 September 2019
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rifampin..................................................................................................................18
4.3
Rationale for the Proposed Study.............................................................................18
4.4
Benefit/Risk Profile .................................................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................20
5.1
Hypothesis...............................................................................................................20
5.2
Study Objectives......................................................................................................20
5.2.1
Study Primary Objective ....................................................................................20
5.2.2
Study Secondary Objective ................................................................................20
5.2.3
Study Exploratory Objective ..............................................................................20
5.3
Endpoints.................................................................................................................20
5.3.1
Primary Endpoints .............................................................................................20
5.3.2
Secondary Endpoints..........................................................................................20
5.3.3
Exploratory Endpoints .......................................................................................21
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................22
6.1
Study Design ...........................................................................................................22
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................23
6.2.1
Rationale of Study Design..................................................................................23
6.2.2
Rationale for Dose .............................................................................................23
6.2.3
Rationale for Endpoints......................................................................................23
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............24
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................24
6.4
Study Beginning and End/Completion .....................................................................24
6.4.1
Definition of Beginning of the Study..................................................................24
6.4.2
Definition of End of the Study ...........................................................................24
6.4.3
Definition of Study Completion .........................................................................24
6.4.4
Definition of Study Discontinuation...................................................................24
6.4.5
Criteria for Premature Termination or Suspension of the Study..........................24
6.4.6
Criteria for Premature Termination or Suspension of a Site................................25
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Study ID TAK-906-1009
Page 3 of 72
Protocol Final
24 September 2019
6.4.7
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)..............................................................................25
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............26
7.1
Inclusion Criteria .....................................................................................................26
7.2
Exclusion Criteria ....................................................................................................26
7.3
Excluded Medications, Supplements, Dietary Products............................................28
7.3.1
Tobacco or Nicotine-Containing Products Usage ...............................................28
7.4
Diet, Fluid, Activity.................................................................................................29
7.4.1
Diet and Fluid ....................................................................................................29
7.4.2
Activity..............................................................................................................29
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................29
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................30
7.7
Subject Replacement................................................................................................30
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................31
8.1
Clinical Study Drugs................................................................................................31
8.1.1
TAK-906 Capsule ..............................................................................................31
8.1.2
Rifampin IV.......................................................................................................31
8.1.3
Study Drug Administration ................................................................................31
8.1.4
Clinical Study Drug Labeling.............................................................................31
8.1.5
Clinical Study Drug Inventory and Storage ........................................................31
8.1.6
Clinical Study Drug Blinding.............................................................................32
8.1.7
Randomization Code Creation and Storage ........................................................32
8.1.8
Clinical Study Blind Maintenance/Unblinding Procedure...................................32
8.1.9
Accountability and Destruction of Celerion-Supplied Drugs ..............................32
9.0
STUDY PROCEDURES...............................................................................................33
9.1
Administrative Procedures.......................................................................................33
9.1.1
Informed Consent Procedure..............................................................................33
9.1.2
Inclusion and Exclusion .....................................................................................33
9.1.3
Medical History/Demography ............................................................................33
9.1.4
Concomitant Medications...................................................................................33
9.2
Clinical Procedures and Assessments.......................................................................33
9.2.1
Physical Examination.........................................................................................34
9.2.2
Height and Weight .............................................................................................34
9.2.3
BMI ...................................................................................................................34
9.2.4
Vital Signs .........................................................................................................34
9.2.5
12-Lead ECG.....................................................................................................34
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Study ID TAK-906-1009
Page 4 of 72
Protocol Final
24 September 2019
9.2.6
Study Drug Administration ................................................................................34
9.2.7
AE Monitoring...................................................................................................35
9.2.8
Laboratory Procedures and Assessments ............................................................35
9.3
PK Sample Collection..............................................................................................37
9.3.1
PK Measurements..............................................................................................37
9.3.2
...................................................................................38
9.3.3
Blood Volume....................................................................................................39
9.3.4
Confinement ......................................................................................................39
10.0
ADVERSE EVENTS ....................................................................................................40
10.1
Definitions and Elements of AEs .............................................................................40
10.1.1 SAEs..................................................................................................................42
10.1.2 Special Interest AEs...........................................................................................43
10.2
AE Procedures.........................................................................................................44
10.2.1 Assigning Severity/Intensity of AEs...................................................................44
10.2.2 Assigning Causality of AEs................................................................................44
10.2.3 Start Date...........................................................................................................45
10.2.4 End Date............................................................................................................45
10.2.5 Pattern of Adverse Event (Frequency)................................................................45
10.2.6 Action Taken With Study Treatment..................................................................45
10.2.7 Outcome ............................................................................................................45
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................46
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....48
11.0
STATISTICAL METHODS..........................................................................................49
11.1
Statistical and Analytical Plans ................................................................................49
11.1.1 Analysis Sets......................................................................................................49
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................49
11.1.3 PK Analysis .......................................................................................................49
11.1.4 Coproporphyrin Assessment ..............................................................................50
11.1.5 Safety Analysis ..................................................................................................50
11.2
Interim Analysis and Criteria for Early Termination ................................................51
11.3
Determination of Sample Size..................................................................................51
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................52
12.1
Study-Site Monitoring Visits ...................................................................................52
12.2
Protocol Deviations..................................................................................................52
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................52
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Study ID TAK-906-1009
Page 5 of 72
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24 September 2019
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................53
13.1
IRB and/or IEC Approval ........................................................................................53
13.2
Subject Information, Informed Consent, and Subject Authorization .........................54
13.3
Subject Confidentiality ............................................................................................55
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................55
13.4.1 Publication and Disclosure.................................................................................55
13.4.2 Clinical Study Registration.................................................................................56
13.4.3 Clinical Study Results Disclosure.......................................................................56
13.5
Insurance and Compensation for Injury....................................................................56
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................57
14.1
Administrative Information......................................................................................57
14.1.1 Study Contact Information .................................................................................57
14.1.2 INVESTIGATOR AGREEMENT......................................................................58
14.1.3 Study-Related Responsibilities...........................................................................59
14.1.4 List of Abbreviations .........................................................................................59
15.0
DATA HANDLING AND RECORDKEEPING............................................................61
15.1
CRFs (Electronic and/or Paper)................................................................................61
15.2
Record Retention .....................................................................................................61
16.0
REFERENCES..............................................................................................................63
17.0
APPENDICES...............................................................................................................65
LIST OF IN-TEXT TABLES
Table 6.a
Randomization Sequences..................................................................................22
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................28
Table 9.a
Primary Specimen Collections ...........................................................................37
Table 9.b
Exploratory Specimen Collections .....................................................................38
Table 9.c
Approximate Blood Volume ..............................................................................39
Table 10.a
Takeda Medically Significant AE List................................................................43
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................65
Appendix B
Elements of the Subject Informed Consent.........................................................67
Appendix C
Investigator Consent to the Use of Personal Information ....................................70
Appendix D
Pregnancy and Contraception.............................................................................71
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1009
Page 6 of 72
Protocol Final
24 September 2019
1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge, Massachusetts USA 02139
Telephone: +1 (617) 679-7000
Compound:
TAK-906
Study Identifier: TAK-906-1009
Phase: 1
Protocol Title: A Phase 1, Open-Label, Randomized, Two-Way Crossover Study to Evaluate the Effect of 
Single-Dose Intravenous Rifampin as a Prototypic Inhibitor of OATP1B1 and OATP1B3 on the Single-Dose 
Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
Study Design:
This is a phase 1, open-label, randomized, two-way crossover study to evaluate the effect of single-dose intravenous 
(IV) rifampin on the single-dose pharmacokinetics (PK) of oral TAK-906 in healthy adult subjects.
The study will include a screening visit, two treatment periods, and a follow-up visit. Treatment will consist of a single 
oral dose of 25 mg TAK-906 capsule (Treatment A), and a single oral dose of 25 mg TAK-906 capsule together with 
a single IV dose of 600 mg rifampin (Treatment B). Eligible subjects will be randomly assigned to 1 of 2 treatment 
sequences (ie, AB, BA). Randomization sequences are presented below:
Table 1a Randomization Sequences
Sequence
Number of Subjects
Study Period 1
Study Period 2
AB
6
TAK-906 oral
Rifampin IV+ TAK-906 oral
BA
6
Rifampin IV + TAK-906 oral
TAK-906 oral
Treatment A = 25 mg TAK-906 capsule 
Treatment B = 25 mg TAK-906 capsule together with a single IV dose of 600 mg rifampin 
Each dose of TAK-906 will be separated by a washout period of at least 7 days from the time of Study Period 1 
TAK-906 dose administration.
On Day 1 of Treatment A after an overnight fast of at least 10 hours, a single oral dose of TAK-906 capsule will be 
administered. 
On Day 1 of Treatment B after an overnight fast of at least 10 hours, IV rifampin will be administered over a 
30-minute period, and TAK-906 capsule will be given immediately at the end of the infusion.
In each treatment arm, subjects will be confined from the day prior to dosing (Day -1, Check-in), at the time indicated 
by the Clinical Research Unit (CRU), until after the 48-hour blood draw (Day 3). 
Blood samples for assessment of TAK-906 concentrations will be measured from predose to 48 hours after each dose 
of TAK-906.
Safety will be assessed by monitoring for adverse events (AE), vital signs, electrocardiograms (ECGs), clinical 
laboratory results, and physical examinations throughout each study period.
There will be a washout period of at least 7 days between the TAK-906 dosing in each study period. 
All subjects who received at least one dose of study drug (including subjects who terminate the study early) will return 
to the CRU 14 ± 2 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. 
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TAK-906
Study ID TAK-906-1009
Page 7 of 72
Protocol Final
24 September 2019
Study Primary Objective:
!
To evaluate the effect of single-dose IV rifampin on the single-dose PK of orally administered TAK-906.
Secondary Objective:
!
To evaluate the safety and tolerability of a single oral dose of TAK-906 in the presence and absence of 
rifampin.
Exploratory Objective:
Study Subject Population: Healthy male and female subjects aged 19 to 55 years inclusive. Body Mass Index (BMI) 
18.0-30.0 kg/m2.
Planned Number of Subjects:
12 
Planned Number of Sites:
1 
Dose:
25 mg TAK-906 capsule (1 x 25 mg TAK-906 
capsule; Treatment A)
25 mg TAK-906 capsule (1 x 25 mg TAK-906 
capsule) and a single IV dose of 600 mg rifampin 
(Treatment B)
Route of Administration:
Treatment A: oral (TAK-906)
Treatment B: oral (TAK-906), IV infusion (rifampin)
Duration of Treatment:
On Day 1 of Treatment A, subjects will receive a 
single oral dose of TAK-906.
On Day 1 of Treatment B, subjects will receive a
30-minute IV infusion of rifampin followed by a 
single oral dose of TAK-906
Planned Study Duration:
Approximately 49 days including Screening Period and 
Follow-up Visit.
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, 19-55 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.
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 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 informed consent form (ICF) throughout the duration 
of the study and through to the follow-up visit (ie, 14 ± 2 days after the last TAK-906 dosing) (refer to Appendix 
D).
7.
If male, must agree not to donate sperm from signing of the ICF until follow-up visit (ie, 14 ± 2 days after the last 
TAK-906 dosing). 
8.
Understands the study procedures in the ICF, and be willing and able to comply with the protocol.
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TAK-906
Study ID TAK-906-1009
Page 8 of 72
Protocol Final
24 September 2019
Criteria for Exclusion:
Subjects must not be enrolled in the study if they meet any of the following criteria:
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) 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, to rifampin, or to related 
compounds or contraindicated compounds such as antivirals [1].
7.
Female subjects of childbearing potential.
8.
Female subjects with a positive pregnancy test or lactating at screening or first check-in. 
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).
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, herbal remedies, or vitamin supplements 
within 14 days prior to the first dosing and throughout the study. After first dosing, acetaminophen (up to 2 g 
per 24 hours) may be administered at the discretion of the investigator or designee; Sponsor must be 
consulted prior to administering acetaminophen to a subject.

Any drugs known to significantly affect the absorption, distribution, metabolism, or elimination of study 
drugs (TAK-906 or rifampin), including any drug that affects the function of OATP1B1 or 1B3, 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 (PD) interaction with study drugs.
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:
Primary Endpoints
The following plasma PK parameters for TAK-906 on Day 1 in Study Period 1 and Study Period 2:

Cmax: maximum observed concentration

AUC∞: area under the concentration-time curve from time 0 to infinity calculated using the observed value of 
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TAK-906
Study ID TAK-906-1009
Page 9 of 72
Protocol Final
24 September 2019
the last quantifiable concentration
!
AUClast: area under the concentration-time curve from time 0 to time of the last quantifiable concentration
Secondary Endpoints
The safety profile for TAK-906 alone and TAK-906 + rifampin: 
!
TEAE assessments
!
Vital signs
!
12-lead ECG
!
Clinical laboratory testing (hematology, serum chemistry, and urinalysis)
Exploratory Endpoints
Statistical Considerations:
For evaluation of potential effect of rifampin on TAK-906 PK, mixed effects model analysis will be performed on the 
natural log (ln)-transformed AUC∞, AUClast, and Cmax to assess the potential effect of rifampin on TAK-906 PK. The 
mixed effects models will include sequence, treatment, and period as fixed effects, and subject nested within sequence 
as a random effect. Each mixed effects model will include calculation of least-squares means (LSM) as well as the 
difference between treatment LSM.
Ratios of LSM will be calculated using the exponentiation of the difference between treatments LSM from the 
analyses on the ln-transformed AUC∞, AUClast, and Cmax. 
Consistent with the two one-sided test [2], 90% confidence intervals (CIs) for the ratios will be derived by 
exponentiation of the CIs obtained for the difference between treatment LSM resulting from the analyses on the 
ln-transformed AUC∞, AUClast, and Cmax. 
The comparison of interest is as follows:
!
Treatment B compared with Treatment A 
 
Additional statistical analyses may be performed if deemed appropriate. A more detailed description of the planned 
analyses will be presented in the Statistical Analysis Plan (SAP).
Sample Size Justification:
With a sample size of 12 subjects, there is an 80% probability for the 90% CIs to be within 65% and 135% of the point 
estimate of the geometric mean ratio for Cmax and for AUC of TAK-906 with and without rifampin. Thus, if the 
observed ratios of geometric means of TAK-906 with and without rifampin is 2 for Cmax and AUC, then the 
corresponding 90% CIs based on data from 12 subjects will be approximately (1.6, 2.5). This calculation assumes that 
log(Cmax) and log(AUC) of TAK-906 are normally distributed with intra-subject coefficients of variation that do not 
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TAK-906
Study ID TAK-906-1009
Page 10 of 72
Protocol Final
24 September 2019
exceed 31%. 
Subjects who drop out for non-safety reasons may be replaced at the discretion of the investigator in consultation with 
the Sponsor. Subjects who drop out for safety reasons will not be replaced.
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TAK-906
Study ID TAK-906-1009
Page 11 of 72
Protocol Final
24 September 2019
2.0
STUDY SCHEMATIC
Screening
Treatment Study Periods 1 and 2 a
Follow-up Visit
Day -28 to Day -2 
Day -1
Day 1
Days 2 and 3
14 ± 2 days after last 
TAK-906 dosing 
Check-in
Dosing at Hour 0 b
PK sampling and safety monitoring up to 48 
hours postdose
< - - - - - - - - - - - -  confinement  - - - - - - - - - - - - >
a Prior to dosing on Day 1 of Period 1, subjects will be randomized in a ratio of 1:1 to one of two treatment sequences. Subjects will 
receive each treatment on one occasion. Each TAK-906 dosing will be separated by at least 7 days from the time of Study Period 1 
dose administration.
b TAK-906 administration is defined as Hour 0.
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TAK-906
Study ID TAK-906-1009
Page 12 of 72
Protocol Final
24 September 2019
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES 
Procedures/Assessments
Screening
Study Days for Treatment A (a)
Study Days
Day -28 to -2
-1
1
2
3
Hours
Check-in
Predose
0
0.5
1
1.5
2
3
4
6
8
12
16 (l)
24
36
48
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
X
------------------------------------Continuous Monitoring-----------------------------
Clinical Procedures/Assessments
Full physical examination (m)
X
X (b)
Height
X
Weight
X
BMI
X
12-Lead Safety ECG
X
X (b) (c)
X(c)
X(c)
X(c)
X(c)
X(c)
Semi-recumbent vital signs (heart rate, 
systolic blood pressure and diastolic 
blood pressure) 
X
X(b) (d) 
X(d)
X(d)
X(d)
X(d)
X(d)
Vital signs (respiratory rate, oral [at the 
floor of the mouth]/tympanic 
temperature) 
X
X
Dosing of TAK-906 at the clinical 
research unit (e)
X
AE monitoring
---------------------------------Continuous Monitoring--------------------------------
Laboratory Procedures/Assessments
Hematology
X
X 
X(i)
Urinalysis
X
X 
X(i)
Chemistry
X
X 
X(i)
Serum pregnancy test (♀ only)
X
X
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TAK-906
Study ID TAK-906-1009
Page 13 of 72
Protocol Final
24 September 2019
CONFIDENTIAL
Procedures/Assessments
Screening
Study Days for Treatment A (a)
Study Days
Day -28 to -2
-1
1
2
3
Hours
Check-in
Predose
0
0.5
1
1.5
2
3
4
6
8
12
16 (l)
24
36
48
Serum FSH (PMP ♀only)
X
Urine drug screen
X
X
Urine cotinine screen
X
Urine alcohol test (f)
X
X
Hepatitis screen 
X
Human immunodeficiency virus screen 
X
Pharmacokinetics Evaluations
Other
Confinement 
X--------------------------------------------------------------------------------------------X
Meals fasting (k)
X-----------------------------------------X
CCI
CCI
CCI
Property of Takeda: For non-commercial use 
use 
X-----
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TAK-906
Study ID TAK-906-1009
Page 14 of 72
Protocol Final
24 September 2019
CONFIDENTIAL
Procedures/Assessments
Study Days for Treatment B (a)
Follow-up 
Visit
Study Days
-1
1
2
3
14 ± 2 days 
after last dose 
of TAK-906
Hours
Check-in
Predose
-0.5
0
0.5
1
1.5
2
3
4
6
8
12
16 (l)
24
36
48
Administrative Procedures
Inclusion/exclusion criteria
X
Prior and concomitant 
medication review
------------------------------------------Continuous Monitoring-----------------------------------
Clinical Procedures/Assessments
Full physical examination (m)
X (b)
X
12-Lead Safety ECG
X (b) (c)
X(c)
X(c)
X(c)
X(c)
X(c)
X
Semi-recumbent vital signs 
(heart rate, systolic blood 
pressure and diastolic blood 
pressure)
X (b) (d)
X(d)
X(d)
X(d)
X(d)
X(d)
X
Vital signs (respiratory rate, oral 
[at the floor of the 
mouth]/tympanic temperature) 
X
Dosing of rifampin at the clinical 
research unit (e)
X
Dosing of TAK-906 at the 
clinical research unit (e)
X
AE monitoring
---------------------------------------------Continuous Monitoring--------------------------------------------
Laboratory Procedures/Assessments
Hematology
X 
X(i)
X
Urinalysis
X 
X(i)
X
Chemistry
X 
X(i)
X
Serum pregnancy test (♀only)
X
X
Urine drug screen
X
Urine alcohol test (f)
X
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TAK-906
Study ID TAK-906-1009
Page 15 of 72
Protocol Final
24 September 2019
CONFIDENTIAL
Procedures/Assessments
Study Days for Treatment B (a)
Follow-up 
Visit
Study Days
-1
1
2
3
14 ± 2 days 
after last dose 
of TAK-906
Hours
Check-in
Predose
-0.5
0
0.5
1
1.5
2
3
4
6
8
12
16 (l)
24
36
48
Pharmacokinetics Evaluations
Other
Confinement 
X----------------------------------------------------------------------------------X
Meals fasting (k)
X----------------------------------X
(a)
There will be a washout period of at least 7 days between the TAK-906 dosing in each study period.
(b) Day 1 predose of Period 1 and Period 2 assessment may be done within approximately 24 hours prior to study drug administration.
(c)
Triplicate measurements to be conducted at predose, and at 1, 2, 4, 8 and 48 hours postdose (times relative to TAK-906 dose [Hour 0]). 
(d) Measured at predose, and at 1, 2, 4, 8 and 48 hours postdose (times relative to TAK-906 dose [Hour 0]). Subjects should have rested in a semi-recumbent position for at least 5 
minutes before the measurements 
(e)
Dosing will occur at the CRU based on the treatment the subjects are randomized to receive within a study period. Treatment A: 25 mg TAK-906 capsule; Treatment B: 25 mg 
TAK-906 capsule given immediately after a single 30-minute IV dose of 600 mg rifampin.
(f)
An alcohol breath test may be performed at the discretion of the investigator.
(g)
 
(h)
 
(i)
To be performed on Day 3 of each period or prior to early termination from the study.
(j)
To be collected in Period 1 only.
(k) Both doses of TAK-906 and rifampin (Day 1 of Period 1 and Day 1 of 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 post TAK-906 dose. 
(l)
The 16-hour postdose on Day 1 will be either on Day 1 or Day 2, depending on the time of dosing on Day 1.
CCI
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TAK-906
Study ID TAK-906-1009
Page 16 of 72
Protocol Final
24 September 2019
CONFIDENTIAL
(m) Symptom-driven physical examination may be performed at other times, at the investigators or designee’s discretion.
Abbreviations: ♀ = female, AE = Adverse events, 
, CRU = Clinical research unit, 
 
, ECG = Electrocardiogram, FSH = Follicle stimulating hormone, 
, PMP = Postmenopausal.
CCI
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CCI
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TAK-906
Study ID TAK-906-1009
Page 17 of 72
Protocol Final
24 September 2019
4.0
INTRODUCTION
4.1
Background
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 exacerbation [3]. These symptoms may 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 [4]. In cases of chronic 
gastroparesis, diabetic (29%), postsurgical (13%), and idiopathic (36%) etiologies comprise the 
majority of cases in the tertiary referral setting [5]. 
TAK-906 is a peripherally selective (eg limited penetration of the blood brain barrier [BBB]) 
dopamine D2/D3 receptor antagonist. It has demonstrated suitable PK and pharmacodynamic (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 of other D2/D3 antagonists. 
Because of its low BBB penetration and a weak human ether-a-go-go-related gene channel affinity 
indicative of a low potential cardiac risk, TAK-906 is anticipated to have an improved safety 
profile, compared to other D2/D3 antagonists (eg, metoclopramide and domperidone).
TAK-906 is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide 
(OATP) 1B1 and OATP1B3. Further uptake and kinetic studies using OATP1B1/1B3-expressing 
cells and human hepatocytes as a reference of pravastatin suggested that almost all the in vivo 
TAK-906 uptake into human hepatocytes is by a saturable process of transporters, not by a passive 
process and TAK-906 is taken up into the human hepatocytes predominantly by OATP1B1. 
Refer to the TAK-906 Investigator’s Brochure for complete information on the investigational 
product [6].
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-906-1009
Page 18 of 72
Protocol Final
24 September 2019
4.2
Rifampin
Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin inhibits 
deoxyribonucleic acid-dependent ribonucleic acid (RNA) polymerase activity in susceptible 
Mycobacterium tuberculosis organisms. Rifampin can be administered by oral route or by an IV 
infusion of 30-minutes to 3 hours. The IV doses are the same as oral doses [1]. 
After intravenous administration of a 300 or 600 mg dose of rifampin infused over 30 minutes to 
healthy male volunteers (n=12), mean peak plasma concentrations were 9.0 ± 3.0 and 17.5 ± 5.0
mcg/mL, respectively. After IV administration of 300 or 600 mg doses, rifampin plasma 
concentrations in these volunteers remained detectable for 8 and 12 hours, respectively
Plasma concentrations after the 600 mg dose, which were disproportionately higher (up to 30% 
greater than expected) than those found after the 300 mg dose, indicated that the elimination of 
larger doses was not as rapid. 
Rifampin is widely distributed throughout the body. It is present in effective concentrations in 
many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. 
Most of the unbound fraction is not ionized and therefore diffuses freely into tissues. Rifampin is 
rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and 
deacetylation to the primary metabolite, 25-desacetyl-rifampin. This metabolite is 
microbiologically active. Less than 30% of the dose is excreted in the urine as rifampin or 
metabolites. 
Rifampin, when acutely dosed, is an inhibitor of OATP 1B1/1B3 and P-gp transporters. Following 
multiple dosing, rifampin is a potent inducer of drug metabolism by inducing a variety of hepatic 
and intestinal CYP enzymes, especially CYP3A4, and hepatic P-gp. 
Rifampin is classified as Food and Drug Administration (FDA) pregnancy category C. 
Refer to the most recent package insert in US for complete information on rifampin [1].
4.3
Rationale for the Proposed Study
TAK-906 is a substrate of P-gp and OATP1B1 and OATP1B3. Further uptake and kinetic studies 
using OATP1B1/1B3-expressing cells and human hepatocytes as a reference of pravastatin 
suggested that almost all the in vivo TAK-906 uptake into human hepatocytes is by a saturable
process of transporters, not by a passive process and TAK-906 is taken up into the human 
hepatocytes predominantly by OATP1B1. 
Rifampin, widely known as a potent inducer of many drug metabolizing enzymes including 
CYP450 and UDP-glucuronosyltransferases [7, 8], is a potent inhibitor of OATP1B1 and 
OATP1B3 [9] when dosed acutely. Recently, Reitman et al. have demonstrated that oral rifampin, 
given acutely, is also an inhibitor of P-gp at the gut but not the systemic level [10]. In order to 
discriminate between the effect of rifampin on P-gp and on OATP1B, rifampin will be 
administered as an IV formulation.
This study is designed to investigate the effect of a potent inhibitor of OATP1B1 and OATP1B3 
(rifampin) on the oral single-dose PK of TAK-906 in healthy adult subjects. Rifampin has been 
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TAK-906
Study ID TAK-906-1009
Page 19 of 72
Protocol Final
24 September 2019
chosen as it is recommended by the FDA and EMA as a suitable potent OATP1B1 and OATP1B3 
inhibitor for use in drug-drug interaction (DDI) studies [11, 12].
4.4
Benefit/Risk Profile
The doses of TAK-906 and rifampin selected for this study are not anticipated to induce any 
potential risk or benefit to subjects participating in this study and are administered as outlined in 
the IB and product label, respectively.
The safety monitoring practices employed by this protocol (ie, AE monitoring, 12-lead ECG, vital 
signs, clinical laboratory tests, and physical examinations) are considered adequate to protect 
subjects’ safety.
There will be no direct health benefit for study subjects 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-906-1009
Page 20 of 72
Protocol Final
24 September 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 single-dose IV rifampin on the single-dose PK of orally administered 
TAK-906.
5.2.2
Study Secondary Objective
!
To evaluate the safety and tolerability of a single oral dose of TAK-906 in the presence and 
absence of rifampin. 
5.2.3
Study Exploratory Objective
!
5.3
Endpoints
5.3.1
Primary Endpoints
The following plasma PK parameters for TAK-906 on Day 1 in Study Period 1 and Study 
Period 2:
!
Cmax: maximum observed concentration
!
AUC∞: area under the concentration-time curve from time 0 to infinity calculated using the 
observed value of the last quantifiable concentration
!
AUClast: area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration
5.3.2
Secondary Endpoints
The safety profile for TAK-906 alone and TAK-906 + rifampin: 
!
TEAE assessments
!
Vital signs
!
12-lead ECG
!
Clinical laboratory testing (hematology, serum chemistry, and urinalysis)
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-906-1009
Page 21 of 72
Protocol Final
24 September 2019
5.3.3
Exploratory Endpoints
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y and subject to the applicable Terms of 


TAK-906
Study ID TAK-906-1009
Page 22 of 72
Protocol Final
24 September 2019
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a phase 1, open-label, randomized, two-way crossover study to evaluate the effect of 
single-dose IV rifampin on the single-dose PK of oral TAK-906 in healthy adult subjects.
Subjects will be screened from Day -28 to -2, to determine eligibility before randomization and 
eligible subjects will return to the clinic at Check-in (Day -1, Period 1). 
The study will include a screening visit, two treatment periods, and a follow-up visit. Treatment 
will consist of a single oral dose of 25 mg TAK-906 capsule (Treatment A), and a single oral dose 
of 25 mg TAK-906 capsule together with a single IV dose of 600 mg rifampin (Treatment B). 
Eligible subjects will be randomly assigned to 1 of 2 treatment sequences (ie, AB, BA). 
Randomization sequences are presented below:
Table 6.a
Randomization Sequences
Sequence
Number of Subjects
Study Period 1
Study Period 2
AB
6
TAK-906 oral
Rifampin IV+ TAK-906 oral
BA
6
Rifampin IV + TAK-906 oral
TAK-906 oral
Treatment A = 25 mg TAK-906 capsule 
Treatment B = 25 mg TAK-906 capsule together with a single IV dose of 600 mg rifampin 
Each dose of TAK-906 will be separated by a washout period of at least 7 days from the time of Study Period 1 
TAK-906 dose administration.
On Day 1 of Treatment A after an overnight fast of at least 10 hours, a single oral dose of TAK-906 
capsule will be administered. 
On Day 1 of Treatment B after an overnight fast of at least 10 hours, IV rifampin will be 
administered over a 30-minute period, and TAK-906 capsule will be given immediately at the end 
of the infusion.
In each treatment arm, subjects will be confined from the day prior to dosing (Day -1, Check-in), at 
the time indicated by the CRU, until after the 48-hour blood draw (Day 3). 
Blood samples for assessment of TAK-906 concentrations will be measured from predose to 
48 hours after each dose of TAK-906. 
Safety will be assessed by monitoring for AEs, vital signs, ECGs, clinical laboratory results, and 
physical examinations throughout each study period.
There will be a washout period of at least 7 days between the TAK-906 dosing in each study 
period. 
All subjects who received at least one dose of study drug (including subjects who terminate the 
study early) will return to the CRU 14 ± 2 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.
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TAK-906
Study ID TAK-906-1009
Page 23 of 72
Protocol Final
24 September 2019
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design 
This study is designed in accordance with FDA Guidance documents for DDI studies to assess if 
TAK-906 is an OATP substrate. 
The study design is open-label and treatments are administered in a crossover fashion, as the 
primary objective is to compare the PK of a single dose of TAK-906 administered alone and when 
administered with rifampin. Because this is an objective measurement, there is no risk of potential 
bias of the study results; hence, neither study blinding nor inclusion of a placebo group is required. 
In healthy subjects, the biological half-life of rifampin in serum averages about 3 hours after a 
600 mg dose and the half-life following a single oral dose of TAK-906 (5 mg - 300 mg) averaged 
approximately 4 hours when administered in the fasted state, therefore a washout period of at least 
7 days between TAK-906 doses in Study Periods 1 and 2 is sufficient to prevent any carryover 
effects.
6.2.2
Rationale for Dose 
A single oral dose of TAK-906 25 mg has been chosen as it is expected to be a clinically 
efficacious dose. In addition, this dose is well below the maximum single dose (300 mg) that has 
been investigated to date and was shown to be well tolerated in healthy subjects, to allow for any 
increases in exposure that may be observed with transporter inhibition.
The recommended single IV dose of 600 mg rifampin was selected to ensure maximal selectivity 
for inhibiting the hepatic transporters, OATP1B1 and OATP1B3, and to avoid effects on gut 
transporters (eg, P-gp) as well as to not result in enzyme and transporter induction [13, 14].
6.2.3
Rationale for Endpoints
6.2.3.1
Pharmacokinetic Endpoints
The primary PK endpoints will include Cmax, AUC∀, 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. 
6.2.3.2
Safety Endpoints
TEAEs, vital signs, ECG findings, and laboratory test results are commonly used safety endpoints.
6.2.3.3
Exploratory Endpoints
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TAK-906
Study ID TAK-906-1009
Page 24 of 72
Protocol Final
24 September 2019
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the collection of blood 
 is 
the critical parameter and is required to be collected as close to the scheduled times defined in this 
protocol 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.
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
No design or dosing modifications are allowed. Modifications to study procedures are permitted as 
required for management/treatment of AE’s.
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of screening (ie, signing of the ICF) of 
the first subject.
6.4.2
Definition of End of the Study
The end of study for each sequence is defined as the date of the last scheduled study procedure (ie, 
the follow-up visit on Day 14 ± 2 days for all subjects including those who received at least one 
dose of study drug and withdrawn early as outlined in the Schedule of Study Procedures 
(Section 3.0).
6.4.3
Definition of Study Completion
The end of the study is scheduled after 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 subjects is 
lost to follow-up.
6.4.4
Definition of Study Discontinuation
In consultation with the Sponsor, Celerion reserves the right to terminate the study in the interests 
of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time and not allow 
additional enrollment, but to continue the study safety monitoring procedures for subjects that 
have already dosed for abnormalities as required.
6.4.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.
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-906-1009
Page 25 of 72
Protocol Final
24 September 2019

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit 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.
6.4.6
Criteria for Premature Termination or Suspension of a Site
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.4.7
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) 
In the event that the Sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by the 
Sponsor; the procedure will be followed by applicable study sites during the course of termination 
or study suspension.
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TAK-906
Study ID TAK-906-1009
Page 26 of 72
Protocol Final
24 September 2019
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
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, 19-55 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. 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 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 visit (ie, 14 ± 2 days after the 
last TAK-906 dosing) (refer to Appendix D).
7. If male, must agree not to donate sperm from signing of the ICF until follow-up visit (ie, 14 ± 2
days after the last TAK-906 dosing).
8. Understands the study procedures in the ICF, and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
Subjects must not be enrolled in the study if they meet any of the following criteria:
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) 
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, to rifampin, or to 
related compounds or contraindicated compounds such as antivirals [1].
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7. Female subjects of childbearing potential.
8. Female subjects with a positive pregnancy test or lactating at screening or first check-in.
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, herbal remedies, or 
vitamin supplements within 14 days prior to the first dosing and throughout the study. 
After first dosing, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the investigator or designee; Sponsor must be consulted prior to administering 
acetaminophen to a subject.

Any drugs known to significantly affect the absorption, distribution, metabolism, or 
elimination of study drugs (TAK-906 or rifampin) including any drug that affects the 
function of OATP1B1 or 1B3, 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/PD interaction with study drugs.
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.
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Study ID TAK-906-1009
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7.3
Excluded Medications, Supplements, Dietary Products
Use of excluded agents (prescription or nonprescription) 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])
After First Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing.
Prohibited until end of PK 
collection in Period 2.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing in 
each period a
Prohibited until end of PK 
collection in each period a.
Medications b
See Sections 7.2 and 7.3
See Sections 7.2 and 7.3  
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited until end of PK 
collection in Period 2.
Other Fruit Juice
Prohibited from 72 hours prior to first dosing
Prohibited until end of PK 
collection in Period 2.
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 Period 2.
a small amounts of caffeine derived from normal foodstuffs e.g., 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.
b Occasional use of acetaminophen, up to 2 g per 24 hours, as approved by the investigator or designee is allowed 
following approval by the Sponsor.
If deviations occur, the investigator will decide on a case-by-case basis whether the subject may 
continue participation in the study based on the time the drugs were administered and their 
pharmacology.
7.3.1
Tobacco or Nicotine-Containing Products Usage
Subjects will not have used nicotine-containing products for at least 3 months prior to the first 
dosing and will not use throughout the study.
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Study ID TAK-906-1009
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7.4
Diet, Fluid, Activity 
7.4.1
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 each Study Period, 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 of TAK-906. Water may be 
consumed without restrictions beginning 1 hour after dosing. Lunch will be provided 
approximately 4 hours after dosing of TAK-906. Dinner will be provided approximately 9 to 10 
hours after dosing of TAK-906. An evening snack will be permitted at the appropriate time. The 
meals and snacks served will be similar across study days, periods, and subjects.
If a blood draw or any study procedure coincides with a meal, the blood draw/study procedures 
will take precedence to the meal.
7.4.2
Activity
Subjects will be seated for oral administration of TAK-906 capsule and will be in a 
semi-recumbent position for IV administration of rifampin. When rifampin and TAK-906 are 
dosed together subjects will be seated upright just after IV administration of rifampin for the 
TAK-906 dosing.
Subjects will remain ambulatory or seated upright for the first 4 hours post TAK-906 dose, except 
when they are required to be in a different position for other 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 discharge from the clinic 
on Day 3 of Period 2.
7.5
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. 

A positive pregnancy test for females. 

Positive drug or alcohol results. 

Difficulties in blood collection.
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Study ID TAK-906-1009
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
Interruption of IV infusion.
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.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit and the Follow-up Visit. 
7.7
Subject Replacement
Discontinued subjects may be replaced at the discretion of the Sponsor and the investigator. 
Subjects who drop out for safety reasons will not be replaced.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drugs 
8.1.1
TAK-906 Capsule
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
Rifampin IV
IV rifampin drug product is a solution for infusion; containing rifampin 600 mg, sodium 
formaldehyde sulfoxylate 10 mg, and sodium hydroxide to adjust pH. Rifampin is the active 
pharmaceutical ingredient. 
No other active ingredients are included in the drug product.
8.1.3
Study Drug Administration
Treatments will consist of a single oral dose of 25 mg TAK-906 capsule (Treatment A), and a 
single oral dose of 25 mg TAK-906 capsule administered immediately after completion of a single 
IV dose of 600 mg rifampin (Treatment B).
TAK-906 will be administered orally following an overnight fast with approximately 240 mL of 
water. Subjects will be instructed not to crush, split or chew the oral study drug.
The IV rifampin will be administered in a 30-minute infusion, prior to administration of TAK-906.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period, as per the randomization scheme.
The exact clock time of oral dosing will be recorded; the start and end of infusion for the IV dose 
will be recorded. Each TAK-906 administration is defined as Hour 0.
8.1.4
Clinical Study Drug Labeling
TAK-906 capsule containers will be affixed with a clinical label in accordance with local 
regulatory requirements.
Rifampin will be provided with the commercially available package and labeling in accordance 
with local regulatory requirements.
8.1.5
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-906 and the CRU will provide sufficient 
quantities of rifampin (the same lot number will be used throughout the study) to allow completion 
of this study.
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The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report.
Investigational drugs must be kept in an appropriate, limited-access, secure place until it is used, 
destroyed or returned to the Sponsor or designee for destruction. Investigational drugs must be 
stored under the conditions specified on the label, and remain in the original container until 
dispensed. 
A temperature log of the drug storage area must be maintained every working day.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied. All study products will be prepared and labeled by licensed pharmacy staff 
according to the procedures outlined in the pharmacy manual.
8.1.6
Clinical Study Drug Blinding
This is an open-label study.
8.1.7
Randomization Code Creation and Storage 
Eligible subjects will be randomly assigned to 1 of 2 treatment sequences ie, AB or BA according 
to a randomization schedule generated by Celerion where Treatment A is 25 mg TAK-906 capsule 
and Treatment B is 25 mg TAK-906 capsule given immediately after a single 30-minute IV dose of 
600 mg rifampin.
8.1.8
Clinical Study Blind Maintenance/Unblinding Procedure
NA.
8.1.9
Accountability and Destruction of Celerion-Supplied Drugs
At the conclusion of the study, any unused TAK-906 study drug will be retained by Celerion, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. At the conclusion of 
the study, any unused rifampin will be destroyed. If no supplies remain, this fact will be 
documented in the pharmacy product accountability records.
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Study ID TAK-906-1009
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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 randomization identification number at the time of the first dosing, different from the 
screening number, and will receive the corresponding product at the corresponding site of 
administration.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subjects No. 1).
9.1.1.2
Study Drug Assignment
This is a 2-way, crossover study. Subjects will receive each treatment in 2 periods as detailed in 
Section 6.1.
9.1.2
Inclusion and Exclusion 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0.
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 7.2 and in Section 7.3. 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 
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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 concentrations for TAK-906 is the critical 
parameter and is required to be collected as close to the scheduled times defined in this protocol 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.
9.2.1
Physical Examination
Physical examinations 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.
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 semi-recumbent 
position (at least 5 minutes), except when they are required to be in a different position because of 
other study procedures and/or AEs (eg, nausea, dizziness) or if deemed necessary by the 
investigator or designee. 
9.2.5
12-Lead ECG
Triplicate 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 semi-recumbent position. All ECG tracings will be 
reviewed by the investigator or designee.
9.2.6
Study Drug Administration
Single dose of oral TAK-906 or single dose of oral TAK-906 coadministered with IV rifampin will 
be provided as described in Section 8.1.3.
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Study drugs will be administered on Day 1 of each period per the randomization.
The pharmacy at the CRU will provide all doses for each subject, as per the randomization 
(Section 8.1.7).
9.2.7
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study drugs 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.
9.2.8.1
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:
Blood Urea Nitrogen
Sodium
Bilirubin (total and direct)
Potassium
Alkaline phosphatase
Glucose
Aspartate aminotransferase (AST)
Chloride
Alanine aminotransferase (ALT)
Total protein
Albumin
Creatinine*
* At Screening, creatinine clearance will be calculated using Cockcroft-Gault formula.
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Study ID TAK-906-1009
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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
Urine alcohol screen
Urine cotinine screen
Serum pregnancy test (human chorionic gonadotropin 
[hCG]) (a)
FSH if menopause is suspected (b)
(a) Serum hCG pregnancy test will be done on all female subjects at Screening, Check-in (Day -1) and at Follow-up 
Visit Day /Early Termination.
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, defined as no 
menses for 12 months without an alternative medical cause; a high 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) and not surgically sterile. The FSH result must be 
>40 IU/L for the subject to be permitted not to use highly effective contraception.
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Study ID TAK-906-1009
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9.3
PK Sample Collection
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.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
Plasma sample for PK analysis
Mandatory
If a subject experiences an 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 investigator.
9.3.1
PK Measurements 
The PK parameters of TAK-906 will be determined from the concentration-time profiles for all 
evaluable subjects using a noncompartmental analysis method. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times. A more 
detailed description will be given in the clinical pharmacology analysis plan.
The following PK parameters will be calculated from plasma concentrations of TAK-906 
 
as appropriate, unless otherwise specified:
AUClast:
The area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration.
AUC∞:
Area under the concentration-time curve from time 0 to infinity, calculated 
using the observed value of the last quantifiable concentration.
AUCextrap%:
The area under the curve from the last quantifiable concentration to infinity 
calculated using the observed value of the last quantifiable concentration, 
expressed as a percentage of AUC∞.
Cmax:
Maximum observed concentration.
CCI
CCI
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-906-1009
Page 38 of 72
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24 September 2019
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points with 
detectable concentrations.
The actual date and time of sample collection will be recorded on the source document and CRF. 
Samples collected 10% from the nominal time will not be considered a protocol deviation as long 
as the exact date and time of PK sampling collection is recorded in the CRF. 
The decision as to which plasma samples collected will be assayed for evaluation of PK will be 
determined by the Sponsor.
 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Study ID TAK-906-1009
Page 39 of 72
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9.3.3
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.c.
Table 9.c
Approximate Blood Volume
Sample Type
Sample Volume 
(mL)
Number of Samples
Total Volume 
(mL)
Screening and 
Day -1 
Days 1-3 + 
FU
Clinical laboratory tests (Screening)
12.5
1
NA
12.5
Clinical laboratory tests (Non screening)
12.5
2
3
62.5
Total Approximate Blood Sampling Volume
305*
NA=not applicable. 
*Total blood volume collections for the study may increase if additional assessments are needed for AE/SAE 
occurrence, or at the investigator’s discretion.
9.3.4
Confinement
In each treatment period, 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. Subjects will return for study 
procedures as indicated in the Schedule of Study Procedures (Section 3.0).
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
investigator or designee.
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Property of Takeda: For non-commercial use only 
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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 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 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
There are no AEs of Special Interest for this study. 
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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.
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 [15]:
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, i.e., 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.
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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.
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 
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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.
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 14 ± 2 days after last TAK-906 dosing in Period 2. 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.
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
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:
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 
There are no AEs of Special Interest for this study.
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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 
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
All statistical analysis of the study will be performed using the statistical software, SAS 
version 9.3 or higher Details concerning the standards for precision, decimals, descriptive 
statistics will be in the SAP.
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a SAP. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 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 PK Set
The PK set will consist of all subjects who received study drug and have at least 1 measurable 
plasma concentration.
11.1.1.2 Safety Set
The safety analysis set will consist of all subjects who are enrolled and received at least 1 dose of 
study drug.
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
TAK-906 concentrations will be listed and summarized descriptively by PK sampling time. 
Summary will be done by treatment. Individual subject and arithmetic mean profiles of the 
concentration time data will be plotted by treatment on linear and semi-log scales. For summary 
statistics and arithmetic mean plots by sampling time, the nominal PK sampling times will be used, 
and for individual subject plots by PK sampling time, the actual PK sampling times will be used. 
TAK-906 PK parameters for each subject will be listed and summarized by treatment using 
descriptive statistics.
If applicable, descriptive statistics will be provided for the plasma
concentrations using
appropriate summary statistics to be fully specified in the SAP. PK parameters for plasma
concentrations may be calculated as described in Section 9.3.1 as available.
For evaluation of potential effect of rifampin on TAK-906 PK, mixed effects models will be 
performed on the ln-transformed AUC∞, AUClast, and Cmax to assess the potential effect of 
rifampin on TAK-906 PK. The mixed effects models will include sequence, treatment, and period 
CCI
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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as fixed effects, and subject nested within sequence as a random effect. Each mixed effects model 
will include calculation of LSM as well as the difference between treatment LSM. 
Ratios of LSM will be calculated using the exponentiation of the difference between treatments 
LSM from the analyses on the ln-transformed AUC∞, AUClast, and Cmax. 
Consistent with the two one-sided test [2], 90% CIs for the ratios will be derived by exponentiation 
of the CIs obtained for the difference between treatment LSM resulting from the analyses on the 
ln-transformed AUC∞, AUClast, and Cmax. 
The comparison of interest is as follows:
!
Treatment B compared with Treatment A 
Additional statistical analyses may be performed if deemed appropriate. A more detailed 
description of the planned analyses will be presented in the SAP.
Summary statistics for the parameters of
will be tabulated. Results, if any, may be 
summarized in a report separate from the main clinical study report.
11.1.5 Safety Analysis
All safety data will be populated in the individual CRFs and listed by subject.
11.1.5.1 AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion. Data will be summarized using preferred term and primary 
system organ class.
The number and percentage of subjects with TEAEs, defined as any AEs, regardless of 
relationship to study drug and SAEs, which occur on or after dosing in subjects, will be 
summarized by MedDRA® system organ class, and preferred term, by severity, and by relationship 
to study drug. Separate summaries will also be generated for AEs by treatment-relationship and 
severity. Data listings will be provided for all AEs (including PTEs for enrolled subjects), AEs 
leading to study drug discontinuation, AEs leading to study visit discontinuation, SAEs, and AEs 
resulting in death.
11.1.5.2 Clinical Laboratory Evaluation
Baseline, postbaseline, and change from Baseline in clinical laboratory tests will be summarized. 
Individual results for clinical laboratory tests will be listed. A shift table describing out of normal 
range shifts will be provided.
11.1.5.3 Vital Signs
Baseline, postbaseline, and change from Baseline in vital signs will be summarized. Individual 
results for vital signs will be listed.
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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11.1.5.4 ECGs
Baseline, postbaseline, and change from Baseline in ECG results will be summarized. Individual 
results for ECG measures will be listed.
11.1.5.5 Other Safety Parameters
Physical examination findings will be presented in the data listings.
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization (WHO) drug dictionary and will 
be listed by subject.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned. There is no predetermined criteria for early termination.
11.3
Determination of Sample Size
With a sample size of 12 subjects, there is an 80% probability for the 90% CIs to be within 65%
and 135% of the point estimate of the geometric mean ratio for Cmax and for AUC of TAK-906 
with and without rifampin. Thus, if the observed ratios of geometric means of TAK-906 with and 
without rifampin is 2 for Cmax and AUC, then the corresponding 90% CIs based on data from 
12 subjects will be approximately (1.6, 2.5). This calculation assumes that log(Cmax) and 
log(AUC) of TAK-906 are normally distributed with intra-subject coefficients of variation that do 
not exceed 31%. 
Subjects who drop out for non-safety reasons may be replaced at the discretion of the investigator 
in consultation with the Sponsor. Subjects who drop out for safety reasons will not be replaced.
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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 (CRO) 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 Harmonisation (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 informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the 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 informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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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 informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
subjects and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. 
The subject 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 determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject at the time of consent and prior to the subject 
entering into the study. The subject should be instructed to sign using their legal names, not 
nicknames, using blue or black ballpoint ink. The investigator must also sign and date the informed 
consent form and subject authorization (if applicable) at the time of consent and prior to subject 
entering into the study; however, the Sponsor may allow a designee of the investigator to sign to 
the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
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Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify Sponsor 
of consent withdrawal.
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 Study 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 Study 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 studies 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 America’s 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 Study 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
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
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(R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator’s 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.
14.1.4 List of Abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUClast
The area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUC∞
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration.
 
BBB
Blood brain barrier 
BMI
Body mass index
CFR
Code of Federal Regulations
CI
Confidence interval
Cmax
Maximum observed concentration 
CRF
Case report form
CRU
Clinical Research Unit
DDI
Drug-drug interaction
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
FU
Follow-up
g 
Gram
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
CC
ICCI
CCI
CCI
CCI
Property of Takeda: For non-comme
um obse
m ob
Case
Ca
C
U
g
GCP
GC
H
omm
n-co
subject to the applicable Terms of Use
om time 0
om time
from tim
rom tim
 concentr
oncen
nd 
and
ly an
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Regulatio
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ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
kg
Kilogram
L
Liters
LFT
Liver function test
ln
Natural log
LSM
Least-squares means
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg 
Milligram
min 
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec 
Millisecond
NA
Not applicable
OATP
Organic anion transporting polypeptide
P-gp
P-glycoprotein
PD
Pharmacodynamic
PK
Pharmacokinetic(s)
PTE
Pretreatment event
RCF
Relative centrifugal force
RNA
ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSARs
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
USA
United States of America
WBC
White blood cell
WHO
World Health Organization
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
polypeptid
lypept
s)
vent
ent
entrifugal
trifug
cleic acid
eic aci
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us adv
Statistica
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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. 
AEs, medical history, and concurrent conditions will be coded using MedDRA®. Drugs will be 
coded using the WHO Drug Dictionary.
15.1
CRFs (Electronic and/or Paper)
Completed CRFs are required for each subject who signs an informed consent.
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. The 
final signed CRFs are provided to the Sponsor on a compact disc.
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), 
electronic 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 
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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 
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. Rifadin IV®, Summary of Product Characteristics, Sanofi-Aventis U.S. LLC. July2019. 
Available at: https://www.medicines.org.uk/emc/product/1416/smpc.b
2. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach 
for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987;15: 
657-80.
3. 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.
4. 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.
5. 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.
6. Takeda Pharmaceuticals, Inc. Global Investigator Brochure. Edition 2.0, July 2018.
7. Niemi M, Backman JT, Neuvonen M, and Neuvonen PJ. Effects of gemfibrozil, itraconazole, 
and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: 
potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 
2003;(46):347–51.
8. Schuetz EG, Schinkel AH, Relling MV, Schuetz JD. P-glycoprotein: a major determinant of 
rifampicin-inducible expression of cytochrome P4503A in mice and human. Proc Natl Acad 
Sci USA 1996;(93):4001–5.
9. Gui C, Miao Y, Thompson L, Wahlgren B, Mock M, Stieger B, et al. Effect of pregnane X 
receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol. 
2008;584(1):57–65.
10. Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, Stone JA, Ding Y, 
Witter R, Gibson C, Roupe K, Evers R, Wagner JA, Stoch A. Rifampin's acute inhibitory and 
chronic inductive drug interactions: experimental and model-based approaches to drug-drug 
interaction trial design. Clin Pharmacol Ther 2011;89(2):234-42.
11. Food and Drug Administration, Clinical Drug Interaction Studies - Study Design, Data 
Analysis, and Clinical Implications, Guidance for Industry. October 2017. Available at: 
https://www.fda.gov/media/108130/download.
12. European Medicines Agency, Guideline on the investigation of drug interactions. 
01 January 2013. Available at https://www.ema.europa.eu/en/investigation-drug-interactions.
13. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the 
pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther
2007;81(2):194-204.
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14. Frymoyer A, Shugarts S, Browne M, WuL Frassetto AHB, Benet LZ. Effect of Single-Dose 
Rifampin on the Pharmacokinetics of Warfarin in Healthy Volunteers. Clin Pharmacol Ther 
2010;88(4)540–47.
15. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
Version 5.0 toxicity grading scale. 27Nov2017.
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17.0
APPENDICES
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 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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2 years following notification by the Sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(Investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study 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. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 
18 weeks after the dose of study drug. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. If a subject is found to be pregnant 
during study, study drug will be discontinued and the investigator will offer the subject the 
choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 18 weeks after 
the dose of study drug. If the partner or wife of the subject is found to be pregnant during the 
study, the investigator will offer the subject the choice to receive unblinded treatment 
information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix 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 trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects 
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. 
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 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:
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906
Study ID TAK-906-1009
Page 72 of 72
Protocol Final
24 September 2019
CONFIDENTIAL
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 applicable Terms of Use


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SAP_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-Label, Randomized, Two-Way Crossover Study to Evaluate the Effect of 
Single-Dose Intravenous Rifampin as a Prototypic Inhibitor of OATP1B1 and OATP1B3 on the 
Single-Dose Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
NCT Number: NCT04121078
SAP Approve Date: 02 December 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-906-1009
CELERION STUDY NUMBER: CA28400
A Phase 1, Open-Label, Randomized, Two-Way Crossover Study to Evaluate the Effect of 
Single-Dose Intravenous Rifampin as a Prototypic Inhibitor of OATP1B1 and OATP1B3 
on the Single-Dose Pharmacokinetics of Oral TAK-906 in Healthy Adult Subjects
PHASE 1
Version: Amendment 1
Date: 02 December 2019
Prepared by:
Based on:
Protocol Dated: 24 September 2019
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
tudy to E
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or of OA
or of O
906 in H
06 in 
Amendm
mend
02 Decem
 Dec
Protoco
otoc
or non-commerci
erty of T


TAK-906-1009
Celerion Study Number CA28400
Page 2 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
1.1
Approval Signatures
Study Title:
A Phase 1, Open-Label, Randomized, Two-Way Crossover Study to 
Evaluate the Effect of Single-Dose Intravenous Rifampin as a Prototypic 
Inhibitor of OATP1B1 and OATP1B3 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
ypic
pic
y
acokinet
okin
d subject to the applicab


TAK-906-1009
Celerion Study Number CA28400
Page 3 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
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
Study Primary Objective............................................................................................7
4.2
Study Secondary Objective ........................................................................................7
4.3
Study Exploratory Objective......................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
Exploratory Endpoints ...............................................................................................9
5.4
Additional Endpoints...............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
7.1
General Principles....................................................................................................10
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.2
Analysis Sets ...........................................................................................................12
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...............................................13
7.7
Medication History and Concomitant Medications...................................................13
7.8
Study Drug Exposure and Compliance.....................................................................14
7.9
Efficacy Analysis.....................................................................................................14
7.10
Pharmacokinetic Analysis........................................................................................14
7.10.1 TAK-906 
Pharmacokinetic Analysis ...................................................14
7.10.2
................15
7.11
Other Outcomes.......................................................................................................16
7.12
Safety Analysis........................................................................................................16
7.12.1 Adverse Events ..................................................................................................16
CCI
CCI
Property of Takeda: For non
ti
on-commercial use only and subject to the applicable Terms of Use
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7.


TAK-906-1009
Celerion Study Number CA28400
Page 4 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
7.12.2 Clinical Laboratory Evaluations .........................................................................17
7.12.3 Vital Signs .........................................................................................................18
7.12.4 12-Lead ECGs ...................................................................................................18
7.12.5 Physical Exams..................................................................................................18
7.12.6 Overdose............................................................................................................18
7.13
Interim Analysis ......................................................................................................19
7.14
Preliminary Analysis................................................................................................19
7.15
Changes in the Statistical Analysis Plan...................................................................19
8.0
REFERENCES..............................................................................................................20
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906-1009
Celerion Study Number CA28400
Page 5 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance 
AUC
AUC∞/ AUCinf  
area under the curve
area under the plasma concentration-time curve from time 0 to infinity
AUClast / 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
Cmax / Cmax
confidence interval
maximum observed concentration
CPAP
CRF
Clinical Pharmacology Analysis Plan
case report form
CRU
clinical research unit
CS
CSR
CV
DDI
DMP
ECG
clinically significant
clinical study report
coefficient of variation
drug-drug interaction
data management plan
electrocardiogram
Geom CV
geometric coefficient of variation 
Geom Mean
geometric mean
GMR
geometric mean ratio
ICF
informed consent form
IV
ln
LOQ
LSM
intravenous
natural log
limit of quantitation 
least-square means
Mean
MedDRA
arithmetic mean
Medical Dictionary for Regulatory Activities
CCI
CCI
CCI
CCI
Property of T
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akeda: For non-commercial use only and subjec
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TAK-906-1009
Celerion Study Number CA28400
Page 6 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
OATP
PI
PK
organic anion transporting polypeptide
Principal Investigator
pharmacokinetics
SAE
serious adverse event
SD
SEM
SOC
standard deviation
standard error of the mean
system organ class
TEAE
treatment-emergent adverse event
TFL
tables, figures, and listings
WHO
World Health Organization
CCI
CCI
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
d subjec


TAK-906-1009
Celerion Study Number CA28400
Page 7 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
4.0
OBJECTIVES
4.1
Study Primary Objective
To evaluate the effect of single dose intravenous (IV) rifampin on the single-dose 
pharmacokinetics (PK) of orally administered TAK-906.
4.2
Study Secondary Objective
To evaluate the safety and tolerability of a single oral dose of TAK-906 in the presence and 
absence of rifampin.
4.3
Study Exploratory Objective
4.4
Study Design
This is a phase 1, open-label, randomized, two-way crossover study to evaluate the effect of 
single-dose IV rifampin on the single-dose PK of oral TAK-906 in healthy adult subjects.
Subjects will be screened from Day -28 to -2, to determine eligibility before randomization and 
eligible subjects will return to the clinic at check-in (Day -1, Period 1). 
The study will include a screening visit, two treatment periods, and a follow-up visit. Treatment 
will consist of a single oral dose of 25 mg TAK-906 capsule (Treatment A), and a single oral 
dose of 25 mg TAK-906 capsule immediately after a single IV dose of 600 mg rifampin 
(Treatment B). Eligible subjects will be randomly assigned to 1 of 2 treatment sequences (i.e., 
AB, BA). Randomization sequences are presented in the table below:
Table 4:1 Randomization Sequences
Sequence
Number of Subjects
Study Period 1
Study Period 2
AB
6
TAK-906 oral
Rifampin IV+ TAK-906 oral
BA
6
Rifampin IV + TAK-906 oral
TAK-906 oral
Treatment A = 25 mg TAK-906 capsule 
Treatment B = 25 mg TAK-906 capsule given immediately after a single 30-minute IV dose of 600 mg rifampin  
Each dose of TAK-906 will be separated by a washout period of at least 7 days from the time of Study Period 1 
TAK-906 dose administration.
On Day 1 of Treatment A after an overnight fast of at least 10 hours, a single oral dose of 
TAK-906 capsule will be administered. On Day 1 of Treatment B after an overnight fast of at 
CCI
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TAK-906-1009
Celerion Study Number CA28400
Page 8 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
least 10 hours, IV rifampin will be administered over a 30-minute period, and TAK-906 capsule 
will be given immediately at the end of the infusion.
In each treatment arm, subjects will be confined from the day prior to dosing (Day -1, Check-in), 
at the time indicated by the clinical research unit (CRU), until after the 48-hour blood draw 
(Day 3). Blood samples for assessment of TAK-906 concentrations will be measured from 
predose to 48 hours after each dose of TAK-906. There will be a washout period of at least 7 
days between the TAK-906 dosing in each study period. 
Safety will be assessed by monitoring for adverse events (AEs), vital signs, electrocardiograms 
(ECGs), clinical laboratory results, and physical examinations throughout each study period. All 
subjects who received at least one dose of study drug (including subjects who terminate the study 
early) will return to the CRU 14 ± 2 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.
A schematic for the study design is included in the figure below: 
Figure 4:1 Study Design
The treatment description and planned dose levels of TAK-906 and rifampin to be evaluated are 
outlined in the table below. 
Table 4:2 Treatment Descriptions and Planned Dose Levels of TAK-906 and Rifampin
Treatment A
A single oral dose of 25 mg TAK-906 (1 x 25 mg capsule) administered at Hour 0 on Day 
1 following an overnight fast.
Treatment B
A single oral dose of 25 mg TAK-906 (1 x 25 mg capsule) immediately after a single 30-
minute IV dose of 600 mg rifampin.
Screening
Treatment Study Periods 1 and 2 a
Follow-up Visit
Day -28 to Day -2 
Day -1
Day 1
Days 2 and 3
14 ± 2 days after last 
TAK-906 dosing 
Check-in
Dosing at Hour 0 b
PK sampling and safety monitoring up to 
48 hours postdose
< - - - - - - - - - - - -  confinement  - - - - - - - - - - - - >
a Prior to dosing on Day 1 of Period 1, subjects will be randomized in a ratio of 1:1 to one of two treatment sequences. Subjects 
will receive each treatment on one occasion. Each TAK-906 dosing will be separated by at least 7 days from the time of Study
Period 1 dose administration.
b TAK-906 administration is defined as Hour 0.  
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-906-1009
Celerion Study Number CA28400
Page 9 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The following plasma PK parameters for TAK-906 on Day 1 following Treatment A and 
Treatment B:
!
Cmax: maximum observed concentration
!
AUC∞: area under the concentration-time curve from time 0 to infinity calculated using 
the observed value of the last quantifiable concentration
!
AUClast: area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration
5.2
Secondary Endpoints
The secondary endpoints are the following for Treatment A and Treatment B: 
!
Treatment-emergent adverse event (TEAE) assessments
!
Vital signs
!
12-lead ECG
!
Clinical laboratory testing (hematology, serum chemistry, and urinalysis)
5.3
Exploratory Endpoints
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TAK-906-1009
Celerion Study Number CA28400
Page 10 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
5.4
Additional Endpoints 
6.0
DETERMINATION OF SAMPLE SIZE
With a sample size of 12 subjects, there is an 80% probability for the 90% confidence intervals 
(CIs) to be within 65% and 135% of the point estimate of the geometric mean ratio (GMR) for 
Cmax and for AUC of TAK-906 with and without rifampin. Thus, if the observed GMRs of TAK-
906 with and without rifampin is 2 for Cmax and AUC, then the corresponding 90% CIs based on 
data from 12 subjects will be approximately (1.6, 2.5). This calculation assumes that log(Cmax) 
and log(AUC) of TAK-906 are normally distributed with intra-subject coefficients of variation 
that do not exceed 31%. 
Subjects who drop out for non-safety reasons may be replaced at the discretion of the 
investigator in consultation with the Sponsor. Subjects who drop out for safety reasons will not 
be replaced.
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 9.4, or higher. All data recorded on the 
case report form (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 
hich will be presented with 2 decimal places. 
The following summary statistics will be calculated for plasma concentrations and PK 
parameters: Sample size (n) is presented as an integer (no decimal places), arithmetic mean, 
median, and geometric mean (Geom Mean) values will be presented to 1 more level of precision 
than the concentration and PK parameter values. Standard deviation (SD) and standard error of 
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TAK-906-1009
Celerion Study Number CA28400
Page 11 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
the mean (SEM) will be presented to 2 more levels of precision than the individual values. 
Minimum and maximum values will be presented to the same precision as the individual values. 
Arithmetic percent coefficient of variation (CV%) and geometric percent coefficient of variation 
(Geom CV%) will be presented to 1 decimal place. 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. 
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. For TAK-906 and
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.
 
 
The following 
footnotes will also be added to appropriate concentration versus time figures, as appropriate: 
!
All values reported as BLQ have been replaced with zero
!
All values reported as BLQ have been set to ½ the LOQ 
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
recorded data. 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)
See CPAP for details on the PK parameter calculations and data presentation including specifics 
on the following:
!
Insufficient data to determine a reliable t½z value and other terminal disposition phase rate 
constant dependent parameters
!
PK parameters presented by analyte (if applicable), treatment, including the units, precision, 
and summary statistics that will be presented in in-text and end-of-text tables
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TAK-906-1009
Celerion Study Number CA28400
Page 12 of 20
Statistical Analysis Plan Amendment 1
02 December 2019

Concentration data presented by analyte (if applicable), 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 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 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 generated as: date of assessment-date of first dose in each period; study day on or after 
the date of first dose will be generated as: date of assessment-date of first dose in each period +1.
7.2
Analysis Sets
PK Set:
The PK set will consist of all subjects who received study drug and who have at least 1 
measurable plasma PK concentration.
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.
Safety Set:
The safety analysis set will consist of all subjects who are enrolled and received at least 1 dose of 
study drug.
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Statistical Analysis Plan Amendment 1
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7.3
Study Information
A study information table will be generated including the following items: date of first subject’s 
signed informed consent form, date of first dose, date of 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.
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 by randomized treatment sequence 
and overall. 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 by randomized 
treatment sequence and overall. Summary statistics (number of subjects [n], mean, SD, 
minimum, median, and maximum) will be generated for continuous variables (age [recorded in 
the CRF], 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). Height, weight, and BMI recorded at screening will be used in the baseline 
summaries. Demographics data will also be listed as recorded on the CRF, including the date of 
informed consent.
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 
informed consent form (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(s) will be classified as an adverse event. All medical history may be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA® ), as described in the Data 
Management Plan (DMP). If appropriate, the medical history listing will include whether the 
event was medical or surgical, the body system or organ class involved, coded term, 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 
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 
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Page 14 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
medications recorded during the study will be coded with the World Health Organization (WHO) 
Dictionary, as described in the DMP, and listed. If appropriate, the listing will include the 
medication name, coded term, 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
The date, time, and dosage of each TAK-906 and rifampin dose will be listed by subject.
7.9
Efficacy Analysis
Not applicable.
7.10
Pharmacokinetic Analysis
7.10.1 TAK-906 and 
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 (Treatment A) 
or TAK-906 + rifampin (Treatment B).
Table 7:1
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Sampling Day
Period
Scheduled Time (hours)
TAK-906
Plasma
1
1 and 2
Predose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours 
postdose.
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.
The actual date and time of sample collection will be recorded on the source document in the 
CRF. Plasma
concentrations may be measured from the same samples used for TAK-906 
plasma concentration assessments.
Concentrations of TAK-906
will be listed and summarized descriptively by analyte and 
PK sampling time. Summary will be done by treatment using the summary statistics described 
above. 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. The 
individual subject profiles of the concentration-time data will be plotted by treatment on linear 
(without SD) and semi-log scales. The arithmetic mean profiles of the concentration-time data 
will be plotted by treatment on linear (with and without SD) and semi-log scales. The median 
profiles of concentration-time data will be plotted on linear (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. 
The PK parameters of TAK-906 
for this study listed in the CPAP and above in Section 
5.0 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 
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Statistical Analysis Plan Amendment 1
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times, will be used in all computations involving sampling times. If actual sample times are 
missing, nominal times may be used. PK parameters of TAK-906
will be summarized 
descriptively by analyte and treatment using the summary statistics described above. 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 
An ANOVA will be performed on the natural log (ln)-transformed AUC∞, AUClast, and Cmax , 
using a mixed effects model, to assess the potential effect of rifampin on TAK-906 
PK
parameters. The mixed effects models will include sequence, treatment, and period as fixed 
effects, and subject nested within sequence as a random effect. Each model will include 
calculation of LSM as well as the difference between treatment LSM. Ratios of LSM will be 
calculated using the exponentiation of the difference between treatments LSM from the analyses 
on the ln-transformed AUC∞, AUClast, and Cmax. 
Consistent with the two one-sided test, 90% CIs for the ratios will be derived by exponentiation 
of the CIs obtained for the difference between treatment LSM resulting from the analyses on the 
ln-transformed AUC∞, AUClast, and Cmax. 
The comparison of interest is as follows:
!
Treatment B compared with Treatment A 
The following SAS code will be used to run the analysis: 
PROC MIXED DATA=XXXX;
CLASS Treatment Subject Period Sequence;
MODEL <PK_Parameter> = Treatment Period Sequence / DDFM=KR;
RANDOM Subject(Sequence);
ESTIMATE ‘Treatment B vs A’ Treatment -1 1 / CL ALPHA = 0.10 E;
LSMEANS Treatment;
Run;
7.10.2
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Statistical Analysis Plan Amendment 1
02 December 2019
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 12-lead 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 (CTCAE Grades 1 through 5), relationship to study drug(s) (related or 
not related) and action relative to the study drug(s) as recorded in the CRF. Study procedure 
taken due to AE will also be listed. All AEs occurring during this study will be coded using the 
MedDRA®, as described in the DMP. However, only TEAEs occurring after administration of 
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Statistical Analysis Plan Amendment 1
02 December 2019
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® 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-serious TEAEs (i.e., 
those events reported by >5% of all subjects in each treatment, 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(s). 
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. For each relationship to study drug, if a subject has 
both related and unrelated AEs with the same term, the subject will be counted as having related 
TEAEs.
Should any SAEs (including all-cause mortalities) 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 each period, Day 3 of each period 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 treatment and assessment time 
points. Change from baseline will be summarized. Baseline is defined as the last assessment 
including rechecks taken prior to the first dosing in each period (Day -1 Check-in). 
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 
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Statistical Analysis Plan Amendment 1
02 December 2019
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
laboratory tests, as indicated by the PI, and the corresponding values will be listed by subject. All 
clinical laboratory data will be presented in by-subject data listings.
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 will only be collected at 
screening and prior to first dosing in each period. 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 dosing in each period. Change 
from baseline will not be calculated for respiratory rate and temperature. Vital signs will also be 
displayed in a data listing by subject.
7.12.4 12-Lead ECGs
Triplicate 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. 
The average of the triplicates will be calculated for each parameter, reported as an integer, and 
used in the analysis. 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 average of the last triplicate assessment including rechecks taken prior 
to 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, prior to dosing in each period, 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. 
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Page 19 of 20
Statistical Analysis Plan Amendment 1
02 December 2019
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 7.10.1 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.
7.15
Changes in the Statistical Analysis Plan 
The effect of the drug-drug interaction (DDI) for
metabolite following TAK-906 + 
rifampin compared to TAK-906 alone was not outlined in the final protocol (dated 24 September 
2019). The concentrations and PK parameters
ill be presented and summarized, and 
the model-based statistical analysis on the DDI effect will be performed
 data.
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Page 20 of 20
Statistical Analysis Plan Amendment 1
02 December 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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