Clinical trial NCT03296787
Conditions: Renal Impairment Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2017-11-21; Completion date: 2019-08-09
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect of varying degrees of renal function on the PK of TAK-954 following single-dose IV administration and to investigate the impact of hemodialysis on the PK of single IV doses of TAK-954.

Detailed description:
The drug being tested in this study is called TAK-954. This study will evaluate the effect of varying degrees of renal function on the PK of TAK-954 following single-dose IV administration and to investigate the impact of hemodialysis on the PK of single IV doses of TAK-954.

The study will enroll approximately up to 40 participants. Participants will be enrolled in one of the 5 treatment groups based on their renal impairment which will be determined based on Cockcroft and Gault (CG) equation as follows:

* Group A TAK-954 0.2 mg: Healthy Participants
* Group B TAK-954 0.2 mg: Mild Renal Impairment
* Group C TAK-954 0.2 mg: Moderate Renal Impairment
* Group D TAK-954 0.2 mg: Severe Renal Impairment or End-stage Renal Disease (ESRD) Without Hemodialysis
* Group E TAK-954 0.2 mg: End-stage Renal Disease (ESRD) With Hemodialysis

All participants in groups A to D will receive a single dose of TAK-954 and two single doses in Group E.

Enrollment in Group B (Mild) and Group E (ESRD requiring dialysis) will be based on assessment of safety and available PK data from Group C and Group D respectively.

This multi-center trial will be conducted in Czech Republic and Hungary. The overall time to participate in this study is approximately 8 weeks. Participants in Groups A to D will remain confined to clinic for 3 days. For both treatments, participants in Group E requiring dialysis will remain confined to clinic for 3 days. All participants will make a final visit to the clinic 10-14 days after receiving their last dose for a follow-up assessment.

Arms: arm 1: Participants with normal renal function receive TAK-954 0.2 milligram (mg), infusion, intravenously in fasted state, once on Day 1 of a 6-day period. arm 2: Participants receive TAK-954 0.2 mg, infusion, intravenously in fasted state, once on Day 1 of a 6-day period. arm 3: Participants receive TAK-954 0.2 mg, infusion, intravenously in fasted state, once on Day 1 of a 6-day period. arm 4: Participants without hemodialysis or End-stage Renal Disease (ESRD) receive TAK-954 0.2 mg, infusion, intravenously in fasted state, once on Day 1 of a 6-day period. arm 5: Participants with hemodialysis receive TAK-954 0.2 mg, infusion, intravenously in fasted state, once on Day 1 of a 4-day period followed by a minimum 13-day washout period, further followed by TAK-954 0.2 mg, infusion, intravenously in fasted state, once on Day 1 of a 4-day period.
Interventions: intervention 1: TAK-954
Intervention descriptions: intervention 1: TAK-954 intravenous infusion.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal Impairment and 
Dialysis Treatment on the Pharmacokinetics of a Single Intravenous Dose of TAK-954
NCT Number: NCT03296787
Protocol Approve Date: 09 October 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (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.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal Impairment 
and Dialysis Treatment on the Pharmacokinetics of a Single Intravenous Dose of TAK-954
Sponsor:
Takeda Development Centre Europe Ltd.
Trial Number:
TAK-954-1007
Compound:
TAK-954
Date:
09 October 2017
Version/Amendment 
Number:
01
Amendment History: 
Date
Amendment Number Amendment Type (for regional 
European purposes only)
Region
26 June 2017
Initial version
Not applicable
Global
09 October 2017
01
Substantial
Global
Property
non-commercial use only and subject to the applicable Terms of Use


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Study No. TAK-954-1007
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Protocol Incorporating Amendment No. 01
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY........................................................................................................6
1.1
Protocol Amendment 01 Summary of Changes ........................................................11
2.0
TRIAL SCHEMATIC ...................................................................................................13
3.0
SCHEDULE OF TRIAL PROCEDURES......................................................................15
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Rationale for the Proposed Trial...............................................................................20
4.3
Benefit/Risk Profile .................................................................................................20
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective ..............................................................................................21
5.1.2
Secondary Objective ..........................................................................................21
5.1.3
Exploratory Objectives.......................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoint...............................................................................................21
5.2.2
Safety Endpoints................................................................................................22
5.2.3
Exploratory Endpoints .......................................................................................22
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................23
6.1
Trial Design.............................................................................................................23
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................25
6.2.1
Rationale of Trial Design and Dose....................................................................25
6.2.2
Rationale for Endpoints......................................................................................26
6.3
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................26
6.3.1
Critical Procedures Based on Trial Objectives: Timing of Procedures ................27
6.4
Trial Beginning and End/Completion.......................................................................28
6.4.1
Definition of Beginning of the Trial ...................................................................28
6.4.2
Definition of End of the Trial.............................................................................28
6.4.3
Definition of Trial Discontinuation ....................................................................28
6.4.4
Criteria for Premature Termination or Suspension of the Trial............................28
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................32
7.3
Excluded Medications, Supplements, and Dietary Products .....................................35
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
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7.4
Diet, Fluid, and Activity ..........................................................................................36
7.4.1
Diet and Fluid ....................................................................................................36
7.4.2
Activity..............................................................................................................36
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................36
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................37
7.7
Subject Replacement................................................................................................37
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................38
8.1
Clinical Trial Drug...................................................................................................38
8.1.1
Clinical Trial Drug Labeling ..............................................................................38
8.1.2
Clinical Trial Drug Inventory and Storage..........................................................38
8.1.3
Clinical Trial Drug Blinding ..............................................................................38
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs...............................38
8.1.5
Ancillary Supplies..............................................................................................38
9.0
TRIAL PROCEDURES.................................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent Procedure..............................................................................39
9.1.2
Assignment of Screening Numbers ....................................................................39
9.1.3
Inclusion and Exclusion Criteria.........................................................................39
9.1.4
Medical History/Demographics..........................................................................39
9.1.5
Prior and Concomitant Medication Review ........................................................39
9.1.6
Full Physical Examinations ................................................................................39
9.1.7
Brief Physical Examinations ..............................................................................40
9.1.8
Vital Sign Measurements ...................................................................................40
9.1.9
Height and Weight .............................................................................................40
9.1.10 BMI ...................................................................................................................40
9.1.11 12-Lead ECG.....................................................................................................40
9.1.12 AE Monitoring...................................................................................................41
9.1.13 Pregnancy ..........................................................................................................41
9.2
Laboratory Procedures and Assessments..................................................................41
9.3
PK and PGx Samples...............................................................................................43
9.3.1
PK Evaluations ..................................................................................................44
9.3.2
PGx Measurements ............................................................................................45
9.4
Trial Drug Administration........................................................................................47
9.5
Confinement ............................................................................................................48
10.0
ADVERSE EVENTS ....................................................................................................49
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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10.1
Definitions and Elements of AEs .............................................................................49
10.1.1 SAEs..................................................................................................................51
10.2
AE Procedures.........................................................................................................52
10.2.1 Assigning Severity/Intensity of AEs...................................................................52
10.2.2 Assigning Causality of AEs................................................................................52
10.2.3 Assigning Relationship to Trial Procedures........................................................52
10.2.4 Start Date...........................................................................................................53
10.2.5 Stop Date...........................................................................................................53
10.2.6 Frequency ..........................................................................................................53
10.2.7 Action Concerning Trial Drug............................................................................53
10.2.8 Outcome ............................................................................................................53
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................54
10.2.10
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities .........................................................................................................56
11.0
STATISTICAL METHODS..........................................................................................57
11.1
Statistical and Analytical Plans ................................................................................57
11.1.1 Analysis Sets......................................................................................................57
11.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................57
11.1.3 PK Analysis .......................................................................................................57
11.1.4 Safety Analysis ..................................................................................................58
11.2
Interim Analysis and Criteria for Early Termination ................................................59
11.3
Determination of Sample Size..................................................................................59
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................60
12.1
Trial-Site Monitoring Visits.....................................................................................60
12.2
Protocol Deviations..................................................................................................60
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................60
13.0
ETHICAL ASPECTS OF THE TRIAL .........................................................................61
13.1
IRB and/or IEC Approval ........................................................................................61
13.2
Subject Information, Informed Consent, and Subject Authorization .........................62
13.3
Subject Confidentiality ............................................................................................63
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................63
13.4.1 Publication and Disclosure.................................................................................63
13.4.2 Clinical Trial Registration..................................................................................64
13.4.3 Clinical Trial Results Disclosure ........................................................................64
13.5
Insurance and Compensation for Injury....................................................................64
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................65
14.1
Administrative Information......................................................................................65
14.1.1 Trial Contact Information...................................................................................65
15.0
INVESTIGATOR AGREEMENT.................................................................................66
15.1.1 Trial-Related Responsibilities ............................................................................66
15.1.2 List of Abbreviations .........................................................................................67
16.0
DATA HANDLING AND RECORDKEEPING............................................................69
16.1
eCRFs......................................................................................................................69
16.2
Record Retention .....................................................................................................69
17.0
REFERENCES..............................................................................................................71
18.0
APPENDICES...............................................................................................................72
LIST OF IN-TEXT TABLES
Table 6.a
Renal Function Categories Based on the CG Equation .......................................23
Table 6.b
Subject Groups per Treatment/Period.................................................................24
Table 7.a
Inclusion Criteria ...............................................................................................31
Table 7.b
Exclusion Criteria ..............................................................................................33
Table 7.c
Excluded Medications, Supplements, and Dietary Products (a) ..........................35
Table 9.a
Primary Specimen Collections ...........................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................52
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................72
Appendix B
Elements of the Subject Informed Consent.........................................................74
Appendix C
Investigator Consent to Use of Personal Information..........................................77
Appendix D
Pregnancy and Contraception.............................................................................78
Appendix E
Detailed Descriptions of Amendments to Text ...................................................80
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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1.0
TRIAL SUMMARY
Name of Sponsor:
Takeda Development Centre Europe Ltd.
Compound:
TAK-954
Trial Number: TAK-954-1007
Phase: 1
Protocol Title: A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal Impairment and Dialysis 
Treatment on the Pharmacokinetics of a Single Intravenous Dose of TAK-954
Trial Design:
This is a phase 1, open-label, parallel group trial in subjects with normal renal function as well as subjects with mild, 
moderate, and severe renal impairment (RI) and end stage renal disease (ESRD) as defined in the table below.
Group
Description of Subjects
Estimated Creatinine 
Clearance (CLcr) 
Range (mL/min)
Treatment Regimen
A
Normal renal function (healthy)
≥90
Treatment 1: 0.2 mg TAK-954
Treatment 2: Probe cocktail
B
Mild RI
60-<90
Treatment 1: 0.2 mg TAK-954
C
Moderate RI
30-<60
Treatment 1: 0.2 mg TAK-954
Treatment 2: Probe cocktail
D
Severe or ESRD not requiring dialysis
<30
Treatment 1: 0.2mg TAK-954
E
ESRD requiring dialysis
<15
Period 1:
0.2 mg TAK-954 (1 hour after 
dialysis)
Period 2: 
0.2 mg TAK-954 (2 hours before 
dialysis)
At the Screening Visit, for baseline categorization purposes, subjects will be stratified into groups by the degree of RI 
calculated using the Cockcroft and Gault (CG) equation below:
CLcr (mL /min ) = 140 −age (years) • total body weight (kg) • (0.85 for females)
72 • serum creatinine (mg/dL)
Subjects will receive a single dose of 0.2 mg TAK-954 administered as a 60-minute intravenous (IV) infusion. For 
standardization purpose, trial drugs will be administered following an 8-hour fast. For Groups A (healthy), C 
(moderate RI), and E (ESRD with dialysis), the trial will include a Screening Visit, 2 treatment periods, and a 
Follow-up Visit. For Groups B (mild RI) and D (severe RI or ESRD not requiring dialysis), the trial will include a 
Screening Visit, 1 treatment period, and a Follow-up Visit.
Enrollment will be staggered, beginning with moderate RI (Group C) and severe RI or ESRD not requiring dialysis 
(Group D) subjects. The enrollment of healthy subjects (Group A) will begin after approximately 25% of the subjects 
from moderate and/or subjects with severe RI or ESRD not requiring dialysis have been enrolled. The enrollment of 
mild RI subjects (Group B) and subjects with ESRD requiring dialysis (Group E) will depend on available safety and 
pharmacokinetic (PK) data from subjects with moderate RI (Group C) and severe RI or ESRD not requiring dialysis 
(Group D). Takeda personnel and the investigators will review safety and PK data from the subjects with moderate RI 
and severe RI or ESRD not requiring dialysis and confirm or modify the TAK-954 dose and decide whether or not to 
enroll subjects with mild RI and/or subjects requiring dialysis. Additional healthy subjects may be enrolled if 
necessary.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Healthy (Group A) and moderate RI (Group C) subjects:
Healthy and moderate RI subjects will receive a single dose of TAK-954 0.2 mg (Treatment 1). Blood samples for the 
assessment of TAK-954 and its metabolites will be collected before the start of the TAK-954 infusion and through 
120 hours after the start of the infusion. TAK-954 and its metabolites will be assayed in urine. Plasma protein binding 
of TAK-954 will also be assessed. For Treatment 2, healthy subjects (a maximum of 8 subjects) and moderate RI 
subjects 
 
For Treatment 1, subjects will be confined from Day -1 until the completion of the last PK sample collection on the 
morning of Day 3, or at the discretion of the investigator. For Treatment 2, subjects will be confined from Day -1 until 
completion of the last PK sample collection on the morning of Day 2. After completion of the trial (or following 
subject withdrawal), all subjects will return for a follow-up visit, 10 to 14 days after their last dose of trial drug.
Mild RI (Group B) and severe RI or ESRD not requiring dialysis (Group D):
Subjects with mild RI (if enrolled) and severe RI or ESRD not requiring dialysis will receive a single dose of TAK-954 
0.2 mg (Treatment 1). Blood samples for the assessment of TAK-954 and its metabolites will be collected before the 
start of the TAK-954 infusion and through 120 hours after the start of the infusion. TAK-954 and its metabolites will 
be assayed in urine. Plasma protein binding of TAK-954 will also be assessed. 
For Treatment 1, subjects will be confined from Day -1 until the completion of the last PK sample collection on the 
morning of Day 3, or at the discretion of the investigator. After completion of the trial (or following subject 
withdrawal), all subjects will return for a follow-up visit, 10 to 14 days after their last dose of trial drug.
Subjects with ESRD requiring dialysis (Group E):
For subjects requiring dialysis, the trial will consist of 2 treatment periods. In Period 1, subjects will receive TAK-954 
1 hour after the end of hemodialysis. In Period 2, subjects will receive TAK-954 2 hours before the start of a standard 
4-hour of hemodialysis. In both periods, blood samples for the assessment of TAK-954 and its metabolites will be 
collected before the start of the infusion and through 72 hours after the start of the infusion. Urine will be collected for 
24 hours for the determination of TAK-954 and its metabolites, provided the subject is not anuric. Plasma protein 
binding of TAK-954 will also be assessed. All PK blood samples must be collected before the start of subjects’ next 
hemodialysis session. 
For Period 2, samples from the dialysis fluid (dialysate) and blood will be obtained simultaneously immediately after 
start of dialysis, during dialysis, and end of dialysis from arterial and venous lines to the dialyzer. The 2 treatment 
periods will be separated by a minimum of 13 days from Day 1 in Period 1 and Day 1 of Period 2.
The total volume of dialysate used in the dialysis should be recorded. Blood flow, dialysate flow during the dialysis, 
the make and model of the dialyzer, and type of dialysis membrane (high-flux, low-flux) should be recorded. 
Subjects will be confined from Day -1 until after the last PK sample collection on the morning of Day 3 for both 
Periods 1 and 2, or at the discretion of the investigator. After completion of the trial (or following subject withdrawal), 
all subjects will return for a follow-up visit, 10 to 14 days after their last dose of trial drug.
Primary Objective:
The primary objectives of the trial are to evaluate the effect of varying degrees of renal function on the PK of 
TAK-954 following single-dose IV administration and to investigate the impact of hemodialysis on the PK of single 
IV doses of TAK-954.
Secondary Objectives:
!
To evaluate the safety and tolerability of TAK-954 following single-dose IV administration in subjects with 
varying degrees of renal function.
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Subject Population: 
Group A: Healthy male and female (non-childbearing potential) subjects with normal renal function.
Group B: Male and female (non-childbearing potential) subjects with mild RI.
Group C: Male and female (non-childbearing potential) subjects with moderate RI.
Group D: Male and female (non-childbearing potential) subjects with severe RI or ESRD not requiring dialysis.
Group E: Male and female (non-childbearing potential) subjects with ESRD requiring dialysis.
Number of Subjects:
Up to approximately 40 subjects (with 8 planned per 
Group) will be enrolled in this trial.
Number of Sites:
Multiple sites
Dose Levels: 
TAK-954 0.2 mg.
 
Routes of Administration: 
TAK-954: IV
 
Duration of Treatment:
TAK-954: One single dose for Groups A to D. Two 
single doses for Group E.
Period of Evaluation:
Up to approximately 8 weeks.
Main Criteria for Inclusion:
All subjects:
Male and female subjects (non-childbearing potential) who are aged 18 to 75 years, inclusive, with a BMI between 18 
to 35 kg/m2.
Group A:
As much as possible, the healthy subjects with normal renal function (CLcr ≥90 mL/min) should be comparable to 
subjects with RI with respect to median age and weight (approximately 50% of healthy subjects on each side of the 
median age and weight of currently enrolled renally-impaired subjects grouped together), sex, and race. This will be 
decided by the investigators in discussion with Takeda.
Groups B to E:
Subjects who have stable RI, defined as no clinically significant change in disease status, as documented by the 
subject’s most recent CLcr assessment; serum creatinine must not vary more than approximately 30% from Screening 
to Day -1 to confirm stable disease. Subjects should also be in good health commensurate with their renal status.
Subjects should be on a stable drug regimen defined as not starting a new drug or changing dosage within 7 days or 
5 half-lives (whichever is longer) before dosing with TAK-954.
!
Group B: Subjects with mild RI (CLcr 60 to <90 mL/min).
!
Group C: Subjects with moderate RI (CLcr 30 to <60 mL/min).
!
Group D: Subjects with severe RI or ESRD but not requiring dialysis (CLcr <30 mL/min).
!
Group E: Subjects with ESRD requiring dialysis (<15 mL/min requiring hemodialysis at least 3 times/week, and 
having been on the same dialysis treatment regimen for at least 1 month before trial entry). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-954
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Protocol Incorporating Amendment No. 01
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Main Criteria for Exclusion:
All Subjects:
Subjects who:
!
Are renal allograft recipients within 1 year of screening.
!
Have a history of gastrointestinal (GI) motility disorder or intestinal obstruction.
!
Have urinary incontinence without catheterization.
Group A: Subjects who, in the discretion of the investigator, have a history of clinically significant endocrine, GI, 
cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological 
(including stroke and chronic seizures) abnormalities or diseases will be excluded from the trial.
Groups B to E:
Subjects who:
!
Receive dialysis other than intermittent dialysis (except Group E).
!
Have renal disease secondary to hepatic disease (hepatorenal syndrome).
!
At the discretion of the investigators, have any significant hepatic, cardiac, or pulmonary disease or subjects who 
are clinically nephrotic.
Endpoints and Criteria for Evaluation:
Primary endpoints:
Plasma PK parameters for TAK-954 will include maximum observed plasma concentration (Cmax), area under the 
plasma concentration-time curve from time 0 to 72 hours (AUC72), area under the plasma concentration-time curve 
from time 0 to time of the last quantifiable concentration. (AUClast), and area under the plasma concentration-time 
curve from time 0 to infinity, calculated using the observed value of the last quantifiable concentration (AUC∞).
Urine PK parameters for TAK-954 will include the amount of drug excreted in urine (Ae), fraction of drug excreted in 
urine (fe), and renal clearance (CLR).
Dialysate PK parameters will include dialysis clearance (CLD).
Safety endpoints:
Safety and tolerability will be assessed through physical examinations, electrocardiograms (ECGs), vital signs, and 
clinical laboratory results as well as collection of spontaneous adverse events.
Statistical Considerations:
To evaluate the effect of RI on the PK of TAK-954 and any measured metabolites, an analysis of variance (ANOVA) 
with renal function group as a fixed effect will be performed on t1/2 and the natural logarithms of AUCt, AUC72, AUC∞, 
and Cmax for TAK-954 and any measured metabolites. Within the ANOVA framework, comparisons of each RI group 
versus the normal renal function group will be made using appropriate contrast statements.
The relationship between renal function and the PK of TAK-954 and any measured metabolites (Cmax and AUCs) will 
be evaluated through graphics and regression modeling with CLR included in the regression model as a continuous 
variable.
Descriptive statistics (mean, standard deviation, standard error, % coefficient of variation [%CV], minimum, median, 
and maximum) will be used to summarize concentrations 
 PK parameters 
according to the renal function group (healthy subjects and moderate subjects).
 
The estimated difference between 
moderate RI (Group C) and healthy subjects with normal renal function (Group A) will be obtained and a 90% 
confidence interval. This estimate and difference will then be exponentiated to provide an estimated ratio and 90% 
confidence interval for moderate RI relative to normal renal function for each analyte 
. 
Additional statistical analyses will be performed, if deemed appropriate. A more detailed analysis will be presented in 
the SAP.
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TAK-954
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Safety:
Safety data will be presented by renal function groups. Treatment-emergent adverse events will be summarized by 
causal relationship to the trial drug and by intensity for each renal function group. Clinical laboratory variables, ECGs, 
and vital signs parameters (uncorrected and corrected QT intervals, PR, and QRS and heart rate) will be summarized 
with descriptive statistics for baseline, postdose, and change from baseline to postdose values by renal function 
groups.
Sample Size Justification:
The planned sample size of 8 subjects in each renal function group is in line with regulatory guidance for these types of
studies (“Food and Drug Administration Guidance for Industry Pharmacokinetics in Patients with Impaired Renal 
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” and “European Medicines Agency 
Guideline on the Evaluation of the PK of Medicinal Products in Patients with Impaired Renal Function”).
Subjects who drop out may be replaced at the discretion of the investigators in consultation with the sponsor. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 11 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CO
1.1
Protocol Amendment 01 Summary of Changes
Rationale for Amendment 01
The primary reason for this amendment is in response to comments from the Czech 
Competent Authority, State Institute for Drug Control, namely to adjust the design of the 
cocktail probe part of the study, clarify number of subjects, update and clarify the 
modifications permitted within protocol parameters.
The amendment opportunity was taken to make additional non-substantial changes, 
including further clarifications and additional routine safety precautions.
Minor grammatical, editorial, and formatting changes are included for clarification 
purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix 
E.
Changes in Amendment 01
1. Clarification of the number of subjects included in the study. 
2. Clarification to altering the trial design.
3.
4. The addition of an exclusion criteria for subjects with QTcF >450 msec.
5. Added section for pregnancy.
6. Added pregnancy test on Day -1.
7. Revision of postmenopausal criteria for women.
8. Removal of “legal representative” language.
9. Addition of an exclusion criteria for subjects with legal incapacity or limited legal 
capacity.
10. Pregnancy and contraception wording changed. 
11. Removal of waste dialysis fluid concentration sample collection and associated 
pharmacokinetic parameters.
12. Added clarification that subjects who are anuric, urine laboratory tests may be 
conducted with a blood sample. 
13. Add further safety monitoring and measure with regards to potential risk of anemia (in 
particular in renal impaired subjects) due to blood withdrawals. 
14. Blood collection timepoint for protein binding edited.
15. Removed the PK parameter of tmax.
Property of Takeda: For non-commercial use
ly and subject to the applicable Terms of Use
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TAK-954
Study No. TAK-954-1007
Page 12 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CO
16. Added an exclusion criteria for subjects with hemoglobin levels ≤110 g/L at Screening 
for the Czech Republic site only.
17. Additional vital sign measurements added.
18. Added information on cocktail drug administration.
19. Added exclusion criteria based on bilirubin levels.
20. Added exclusion criteria for restricted concomitant medications.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 13 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CONFIDENTIAL
2.0
TRIAL SCHEMATIC
Day 
5
Day 
4
Day 
3
Day         
2
Treatment 1
Groups A and C
Day 
6
Day 
2
Treatment 2
Groups A and C
TAK-954 
Single 
Dose
TAK-954 PK
Day 
1
Minimum of 13 days from Treatment 1 
Day 1 to Treatment 2 Day 1
Cocktail 
Probe 
Single 
Dose
Day 
1
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-954
Study No. TAK-954-1007
Page 14 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CONFIDENTIAL
PK=pharmacokinetic.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 15 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CONFIDENTIAL
3.0
SCHEDULE OF TRIAL PROCEDURES
Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Treatment 1 (Groups A, B, C and D)
Period 1 (Group E)
Treatment 2 (Groups A and C)
Period 2 (Group E)
Day
-28 to -2
-1
1
2
3
4
5
6
-1
1
2
3
4
10-14 days 
after last dose
Administrative 
Procedures
Informed consent 
X
Inclusion/exclusion criteria
X
X
Medical 
history/demographics
X
Prior and concomitant 
medication review
X----------------------------------------------------------------------------------------------------------------------------------------X
Clinic 
Procedures/Assessments
Full physical examination
X
X (a)
X
Brief physical examination
X (a)
Semirecumbent vital signs 
(heart rate [HR], systolic 
blood pressure [SBP] and 
diastolic blood pressure 
[DBP])
X
X (b)
X
X
X
X
X
X 
(b)
X
X
X
X
Vital signs (respiratory rate, 
oral [at the floor of the 
mouth]/tympanic 
temperature)
X
X (b)
X 
(b)
X
Height
X
Weight
X
X
X
Body mass index (BMI)
X
Standard 12-lead 
electrocardiogram (ECG)
X
X (b)
X
(b)
X
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TAK-954
Study No. TAK-954-1007
Page 16 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CONFIDENTIAL
Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Treatment 1 (Groups A, B, C and D)
Period 1 (Group E)
Treatment 2 (Groups A and C)
Period 2 (Group E)
Day
-28 to -2
-1
1
2
3
4
5
6
-1
1
2
3
4
10-14 days 
after last dose
Adverse event (AE) 
monitoring
X-----------------------------------------------------------------------------------------------------------------------------------------------------X
Laboratory 
Procedures/Assessments
Serum chemistry
X
X
X
X
Hematology
X
X
X
X
Urinalysis
X
X
X
X
Serum follicle-stimulating 
hormone (FSH)
X
Urine drug screen
X
X (a)
X
Urine alcohol test/alcohol 
breath test (c)
X
X (a)
X
HIV test
X
Hepatitis panel
X
Urine pregnancy test (hCG)
X
X
Pharmacokinetics (PK) 
Evaluations
Plasma samples for 
TAK-954 PK (d)
X----------------------------------------X
X-----------------------------X
Urine sample for TAK-954 
PK (e)
X
X
X
X
Dialysis fluid sample for 
TAK-954 PK (f)
X
Simultaneous blood 
collection (for plasma 
analysis) from arterial and 
venous lines to the dialyzer 
(f)
X
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TAK-954
Study No. TAK-954-1007
Page 17 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CONFIDENTIAL
Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Treatment 1 (Groups A, B, C and D)
Period 1 (Group E)
Treatment 2 (Groups A and C)
Period 2 (Group E)
Day
-28 to -2
-1
1
2
3
4
5
6
-1
1
2
3
4
10-14 days 
after last dose
Plasma sample for 
TAK-954 protein binding 
(g)
X
X
Plasma samples for CYP 
substrate PK (i)
X
X
Urine samples for CYP 
substrate PK (j)
X
X
Pharmacogenomic (PGx) 
Evaluations
Blood sample for DNA PGx 
X
Blood sample for RNA PGx 
X
Drug Administration
TAK-954 dosing 
X
X 
(h)
Other
Confinement
X
X
X
X
X
X
X
X (h)
Meals (k)
X
X
Footnotes are on the following page.
Property of Takeda: For non-co
cial use only and subject to the applicable Terms of Use
ab
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2 (Gro
Period 2 (
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TAK-954
Study No. TAK-954-1007
Page 18 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
CONFIDENTIAL
(a) Within 24 hours of dosing (starting of infusion) on Day 1.
(b) On TAK-954 dosing days, vital signs assessments (blood pressure and HR) at predose (within 30 minutes of the start of the infusion), 0.5 (during the infusion), 
1 (just after the end of the infusion), 2, 4, 12 hours after the start of infusion. ECG, respiratory rate and temperature assessments to be performed only at pre-infusion 
(TAK-954 and 
and end of infusion (TAK-954 only).
(c) Additional alcohol breath or urine alcohol tests may be done at the discretion of the investigators.
(d) Time points for PK blood samples for TAK-954: 
Groups A to D: 
!
Treatment 1: Predose (within 30 minutes of infusion), and 0.33, 0.5, 0.67, 1 (just after the end of infusion), 1.5, 2, 3, 4, 6, 12, 24, 36, 48, 72, 96, and 
120 hours after start of infusion. 
Group E: 
!
Period 1 and 2: Predose (within 30 minutes of infusion), and 0.33, 0.5, 0.67, 1 (just after the end of infusion), 1.5, 2, 3, 4, 6, 12, 24, 36, 48, and 72 hours 
after start of infusion.
(e) Time points for PK urine samples for TAK-954:
Groups A to D: 
!
Treatment 1: Predose (within 30 minutes before start of infusion), 0-6, 6-12, and 12-24 hours after the start of infusion. 
Group E (provided they are not functionally anuric): 
!
Period 1 and 2: Predose (within 30 minutes before start of infusion), 0-6, 6-12, and 12-24 hours after the start of infusion.
(f) Time points for PK dialysis fluid samples and simultaneous blood collection (for plasma analysis) from arterial lines and venous lines to the dialyzer for 
TAK-954 (Group E):
!
Period 2: Immediately after start of dialysis (15 minutes), 3 samples during dialysis (1, 2, 3 hours), and 1 sample at the end of dialysis (4 hours). 
(g) Time points for blood for protein binding:
Groups A to D:
!
Treatment 1: 1 and 12 hours after the start of infusion the TAK-954 infusion. 
Group E
!
Period 1: 1 and 12 hours after the start of the TAK-954 infusion. 
!
Period 2: Before dialysis and end of dialysis.
(h) Group E only.
(i) 
!
Treatment 2: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose.
(j) 
!
Treatment 2: Predose, 0-6, 6-12, and 12-24 hours postdose.
(k) Lunch and dinner will be provided.
Property of Takeda
n-commercial use only and subject to the applicable Terms of Use
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TAK-954
Study No. TAK-954-1007
Page 19 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
4.0
INTRODUCTION
4.1
Background
TAK-954 is a small molecule, serotonin type 4 (5-HT4) receptor agonist that is being investigated 
for potential use in the treatment of gastrointestinal (GI) motility disorders. Takeda is developing 
TAK-954 for the treatment of reduced GI motility, particularly in settings where an intravenous 
(IV) formulation is advantageous, such as critically ill subjects within intensive care units (ICU) 
that are at a high risk of developing intolerance of enteral feeding support. Impaired renal function 
is a potential complication associated with critical illness and patients in the ICU. Exclusion of 
patients with severe renal impairment (RI; based on a creatinine clearance [CLcr] of ≤30 mL/min) 
from phase 2 studies with TAK-954 is currently recommended until further information becomes 
available on the product.
TAK-954 has been investigated in healthy subjects at single oral doses from 0.1 to 20 mg 
(maximum tolerated dose [MTD] 10 mg), multiple oral doses from 0.2 to 10 mg once daily (QD) 
for 10 days (MTD 5 mg), and multiple IV doses from 0.1 to 0.5 mg QD for 5 days. A single IV 
dose of 0.5 mg TAK-954 has also been investigated in critically ill patients with enteral feeding 
intolerance (EFI) and compared with metoclopramide. After multiple IV infusion dosing in 
healthy subjects (0.1 and 0.5 mg over 1 hour), TAK-954 concentrations declined in a biphasic 
manner, with mean terminal elimination half-life (t1/2) values ranging from 18.0 to 18.9 hours on 
Day 5. TAK-954 steady state was achieved by Day 3, with minimal accumulation of TAK-954 
after multiple IV dosing of 0.5 mg. The increase in exposure from the 0.1 mg to 0.5 mg IV dose 
was approximately dose proportional, and the mean amount of TAK-954 excreted unchanged in 
urine on Day 5 ranged from 28% to 32%. In subjects who were critically ill and received 0.5 mg by 
IV infusion, the PK exposure was lower relative to that observed in healthy subjects. The average 
percentage of plasma protein binding was 56% in human plasmas.
Two active metabolites were identified preclinically, but TAK-954 was not extensively 
metabolized to either of these metabolites following oral dosing (mean maximum observed plasma 
concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 48 hours 
metabolite to parent ratios ranged from 0.0008 to 0.004). Renal excretion of these metabolites was 
also low with concentrations in urine generally being below the limit of detection.
Evidence of GI prokinetic activity in healthy subjects (increased bowel movement frequency, 
looser stool consistency, and decreased time to first bowel movement) was observed at all dose 
levels after receiving single and multiple doses (oral and IV). In 7 subjects who were critically ill, 
scintigraphy data qualitatively suggested TAK-954 decreased gastric emptying time following a 
liquid meal.
After IV doses in healthy subjects, TAK-954 was generally well tolerated at doses ranging from 
0.1 to 0.5 mg QD for 5 consecutive days. No serious adverse events were reported. The most 
common adverse events (AEs) (ie, headache and postural dizziness) were not clinically significant 
and resolved spontaneously. Among the AEs reported, 3 subjects experienced modest and 
transient cardiovascular AEs upon standing following the first dose (ie, postural tachycardia and 
postural dizziness) that resolved spontaneously, and were not observed upon challenge. Following 
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TAK-954
Study No. TAK-954-1007
Page 20 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
single infusions of TAK-954 of 0.5mg in subjects who were critically ill with enteral feeding 
intolerance (EFI), no subjects had an AE that led to trial discontinuation or interruption of 
treatment. Vital sign changes from baseline noted over the course of treatment were minimal and 
typical of critically ill subjects. No clinically relevant changes in ECGs in either treatment group 
were observed.
Please refer to the TAK-954 Investigator’s Brochure for complete information on the 
investigational product.
4.2
Rationale for the Proposed Trial
Impaired renal function is a likely complication associated with critical illness and patients in the 
ICU setting. The purpose of this trial is to investigate the effect of RI on the PK of TAK-954 
following a single 0.2 mg IV dose of TAK-954, to assess whether posology adjustment is required 
for patients with decreased renal function, and, if so, to ultimately develop dosing 
recommendations based on renal function. At this stage of the development of TAK-954, the 
exposure-response relationship for efficacy and safety has not been fully characterized and the 
target exposure or target concentration range, within which no clinically relevant difference in 
efficacy and safety is expected, is not currently defined.
4.3
Benefit/Risk Profile
There is no expected clinical benefit to the trial participants. Potential risks are based on clinical 
findings, the mechanism of action, and nonclinical findings. 
Also, there is minimal risk associated with trial procedures including scheduled, periodic 
phlebotomy (limited to <500 mL) and noninvasive procedures including vital sign assessments 
and ECGs. The principal mitigation for these risks includes appropriate selection of the trial 
populations, the clinical research unit (CRU) setting, which permits close monitoring and rapid 
institution of appropriate care as needed, appropriate specified monitoring procedures, and 
utilization of experienced staff trained in trial procedures. Overall, the risk:benefit profile is 
considered appropriate for this trial. 
RI can potentially affect the PK disposition of drugs subject to nonrenal clearance. CYP enzymes 
are thought to potentially mediate this process, but the extent to which kidney disease alters the 
function of these proteins in humans is unknown. During the study, the several other medications 
(caffeine and midazolam) will be given to assess the potential for renal insufficiency to affect 
nonrenal clearance mechanisms. The side effects of these medications predominately affect the GI, 
cardiovascular, and central nervous system organ systems, although side effects outside of these 
organ systems have also been reported. 
 
he combination of these drugs is expected to be safe and tolerable when administered 
in the healthy and moderate RI subjects [1].
Property
f Takeda: For non-commercial use only and subject to the applicable Terms of Use
d 
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TAK-954
Study No. TAK-954-1007
Page 21 of 95
Protocol Incorporating Amendment No. 01
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Objectives
The main objective of the trial is to evaluate the effect of varying degrees of renal function on the 
single dose PK of IV TAK-954. PK data will be used to test the hypothesis that TAK-954 PK 
exposure will increase with decreasing renal function. It is predicted that mean TAK-954 exposure 
(area under the plasma concentration-time curve [AUC]) in subjects with moderate and severe RI 
will increase roughly 50% and 58%, respectively, compared with that predicted in healthy 
subjects.
A sub-set of this study will be to explore the potential for renal insufficiency to affect non-renal 
clearance mechanisms using different CYP probes including caffeine and midazolam. 
5.1.1
Primary Objective
The primary objectives of the trial are to evaluate the effect of varying degrees of renal function on 
the PK of TAK-954 following single-dose IV administration and to investigate the impact of 
hemodialysis on the PK of single IV doses of TAK-954.
5.1.2
Secondary Objective
The secondary objective of the trial is to evaluate the safety and tolerability of TAK-954 following 
single-dose IV administration in subjects with varying degrees of renal function.
5.1.3
Exploratory Objectives
Exploratory objectives of this trial are to: 
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoints of the trial will include the following:
Plasma PK parameters will be collected predose and up to 120 hours postdose:
!
Cmax.
!
Area under the plasma concentration-time curve from time 0 to 72 hours (AUC72).
!
Area under the plasma concentration-time curve from time 0 to the last measurable time point, 
(AUClast).
Property of Takeda:
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on the
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TAK-954
Study No. TAK-954-1007
Page 22 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
!
Area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration (AUC∞).
Urine PK parameters will be collected predose and up to 24 hours postdose:
!
Amount of drug excreted in urine (Ae).
!
Fraction of drug excreted in urine (fe).
!
Renal clearance (CLR).
Dialysate PK parameters will be collected predose and up to 4 hours postdose:
!
Dialysate clearance (CLD).
5.2.2
Safety Endpoints
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and 
laboratory assessments, and collection of spontaneous AEs.
5.2.3
Exploratory Endpoints
Prope
 subject to the applicable Terms of Use
e:
nat
natioions, 
ns
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TAK-954
Study No. TAK-954-1007
Page 23 of 95
Protocol Incorporating Amendment No. 01
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a phase 1, open-label, parallel group trial in subjects with normal renal function as well as 
subjects with mild, moderate, and severe RI and end-stage renal disease (ESRD). There will be 
approximately 40 subjects (8 subjects per group) if all groups are enrolled.
At the Screening Visit, for baseline categorization purposes, subjects will be stratified into groups 
by the degree of RI (as defined in Table 6.a) calculated using the Cockcroft and Gault (CG) 
equation:
CLcr (mL /min ) = 140 −age (years) • total body weight (kg) • (0.85 for females)
72 • serum creatinine (mg/dL)
Table 6.a
Renal Function Categories Based on the CG Equation
Group
Description of 
Subjects
Estimated CLcr
Range 
(mL/min)
Treatment Regimen
A
Normal renal function 
(healthy)
≥90
Treatment 1: 0.2 mg TAK-954
Treatment 2: 
B
Mild RI
60-<90
Treatment 1: 0.2 mg TAK-954
C
Moderate RI
30-<60
Treatment 1: 0.2 mg TAK-954
Treatment 2: 
D
Severe or ESRD not 
requiring dialysis
<30
Treatment 1: 0.2 mg TAK-954
E
ESRD requiring 
dialysis
<15
Period 1: 0.2 mg TAK-954 (1 hour 
after dialysis)
Period 2: 0.2 mg TAK-954 (2 
hours before dialysis)
Eligible subjects will be enrolled into the trial and will receive a single dose of 0.2 mg TAK-954 
administered as a 60-minute IV infusion. For standardization purpose, trial drugs will be 
administered following an 8-hour fast. 
For healthy subjects, moderate RI subjects, and subjects receiving dialysis, the trial will include a 
Screening Visit, 2 treatment periods, and a Follow-up Visit. For mild RI and severe RI or ESRD 
subjects, the trial will include a Screening Visit, 1 treatment period, and a Follow-up Visit. Subject 
groups per treatment/period will be as follows in Table 6.b:
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TAK-954
Study No. TAK-954-1007
Page 24 of 95
Protocol Incorporating Amendment No. 01
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Table 6.b
Subject Groups per Treatment/Period
Treatment 1 (Groups A, B, C and D)
Period 1 (Group E)
Treatment 2 (Groups A and C)
Period 2 (Group E)
Subject groups
A, B (optional), C, and D 
A and C
Subject groups
E (depending on safety data)
E
Enrollment will be staggered, beginning with subjects with moderate RI (Group C) and severe RI 
or ESRD not requiring dialysis (Group D). The enrollment of healthy subjects (Group A) will 
begin after approximately 25% of the subjects from Groups C and/or D have been enrolled. The 
enrollment of subjects from Groups B and E will depend on available safety and PK data from 
subjects in Groups C and D. Takeda personnel and the investigators will review Groups C and D 
safety and PK data and confirm or modify the TAK-954 dose and decide whether or not to enroll 
subjects with mild RI (Group B) and/or subjects with ESRD requiring dialysis (Group E). 
Additional healthy subjects (Group A) may be enrolled if necessary.
Healthy (Group A) and moderate RI (Group C) subjects:
Healthy and moderate RI subjects will receive a single dose of TAK-954 0.2 mg (Treatment 1). 
Blood samples for the assessment of TAK-954 and its metabolites will be collected before the start 
of the TAK-954 infusion and through 120 hours after the start of the infusion. TAK-954 and its 
metabolites will be assayed in urine. Plasma protein binding of TAK-954 will also be assessed. For 
Treatment 2, healthy subjects (a maximum of 8 subjects) and moderate RI subjects 
 
 
 
he 2 treatments will be 
separated by a minimum of 13 days from Day 1 for Treatment 1 and Day 1 of Treatment 2.
For Treatment 1, subjects will be confined from Day -1 until the completion of the last PK sample 
collection on the morning of Day 3, or at the discretion of the investigator. For Treatment 2, 
subjects will be confined from Day -1 until completion of the last PK sample collection on the 
morning of Day 2. After completion of the trial (or following subject withdrawal), all subjects will 
return for a follow-up visit, 10 to 14 days after their last dose of trial drug.
Mild RI (Group B) and severe RI or ESRD not requiring dialysis (Group D):
Subjects with mild RI (if enrolled) and severe RI or ESRD not requiring dialysis will receive a 
single dose of TAK-954 0.2 mg (Treatment 1). Blood samples for the assessment of TAK-954 and 
its metabolites will be collected before the start of the TAK-954 infusion and through 120 hours 
after the start of the infusion. TAK-954 and its metabolites will be assayed in urine. Plasma protein 
binding of TAK-954 will also be assessed. 
For Treatment 1, subjects will be confined from Day -1 until the completion of the last PK sample 
collection on the morning of Day 3, or at the discretion of the investigator. After completion of the 
trial (or following subject withdrawal), all subjects will return for a follow-up visit, 10 to 14 days 
after their last dose of trial drug.
Property of Takeda: For non-comm
e only and subject to the applicable Terms of Use
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Subjects with ESRD requiring dialysis (Group E):
For subjects requiring dialysis, the trial will consist of 2 treatment periods. In Period 1, subjects 
will receive TAK-954 1 hour after the end of hemodialysis. In Period 2, subjects will receive 
TAK-954 2 hours before the start of a standard 4-hour of hemodialysis. In both periods, blood 
samples for the assessment of TAK-954 and its metabolites will be collected before the start of the 
infusion and through 72 hours after the start of the infusion. Urine will be collected for 24 hours for 
the determination of TAK-954 and its metabolites, provided the subject is not anuric. Plasma 
protein binding of TAK-954 will also be assessed. All PK blood samples must be collected before 
the start of subjects’ next hemodialysis session. 
For Period 2, samples from the dialysis fluid (dialysate) and blood will be obtained simultaneously 
immediately after start of dialysis, during dialysis, and end of dialysis from arterial and venous 
lines to the dialyzer. The 2 treatment periods will be separated by a minimum of 13 days from 
Day 1 in Period 1 and Day 1 of Period 2.
The total volume of dialysate used in the dialysis should be recorded. Blood flow, dialysate flow 
during the dialysis, the make and model of the dialyzer, and type of dialysis membrane (high-flux, 
low-flux) should be recorded. 
Subjects will be confined from Day -1 until after the last PK sample collection on the morning of 
Day 3 for both Periods 1 and 2, or at the discretion of the investigator. After completion of the trial
(or following subject withdrawal), all subjects will return for a follow-up visit, 10 to 14 days after 
their last dose of trial drug.
For all groups, safety will be assessed by monitoring for adverse events, vital signs, ECGs, safety 
labs and physical examinations throughout the trial. 
6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale of Trial Design and Dose
Following IV dosing to healthy subjects, up to 32% of the dose of TAK-954 was eliminated as 
unchanged drug in the urine and hence, renal elimination appears to be an important clearance 
pathway. Therefore, reductions in renal function have the potential to increase TAK-954 and 
metabolite exposure. This trial will include subjects with normal renal function as well as subjects 
with mild, moderate, and severe RI and ESRD, since impaired renal function is a potential 
complication associated with critical illness and the intended patient population. 
RI can potentially effect the PK disposition of drugs subject to nonrenal clearance. CYP enzymes 
are thought to potentially mediate this process, but the extent to which kidney disease alters the 
function of these proteins in humans is unknown. 
 
An IV dose of 0.2 mg TAK-954 has been selected as a dose which is predicted to be within the 
clinically relevant range, but is lower than the maximum multiple IV dose (0.5 mg QD) that has 
been investigated so far, to allow for any increases in exposure that may be observed with 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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reductions in renal elimination. Based on dose linear interpolation of 0.5 mg IV single dose 
exposure, the AUC∞following a single 0.2 mg IV dose is estimated to be ~ 20 ng•h/mL. The 
average steady state AUC∞value following multiple QD doses was 46 ng•h/mL for the maximum 
tested IV dose (0.5 mg). TAK-954 will be administered as a single dose. A single dose is 
appropriate given that TAK-954 is administered IV and has been shown to have linear and 
time-independent PK. In single-dose studies, the same dose can, in most cases, be administered to 
all subjects in the study, regardless of renal function, since the peak concentration is generally not 
greatly affected by renal function.
 
The combination of these drugs is expected to be safe and tolerable when administered 
in the healthy and moderate RI subjects [1].
6.2.2
Rationale for Endpoints
6.2.2.1
PK
The primary endpoint for this trial consists of standard PK variables (Cmax, AUClast, AUC72, and 
AUC∞, in plasma; Ae, fe, CLR in urine; and CLD in dialysate (as determined by extraction from 
blood) to determine the PK of TAK-954 in renally-impaired subjects with matching healthy 
subjects.
In addition to dialysate clearance (CLD), other parameters may be calculated as appropriate and as 
described in the clinical pharmacology analysis plan (CPAP).
6.2.2.2
Exploratory Endpoints
6.2.2.3
Safety Endpoints
For safety evaluation, variables that are generally examined in phase 1 studies (AEs, physical 
examinations, clinical safety laboratory tests [clinical chemistry, hematology, urinalysis 
(urinalysis not performed for hemodialysis subjects)], standard 12-lead ECGs, and vital signs 
[supine and standing (except during dialysis)], blood pressure and pulse rate, body temperature) 
were selected. 
6.3
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 1 assessment of TAK-954 in humans and the PK and safety profiles of the 
compound are still being elucidated. This protocol is written with some flexibility to accommodate 
the inherent dynamic nature of phase 1 clinical trials. Modifications outlined below may be 
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required to achieve the scientific goals of the trial objectives and/or to ensure appropriate safety 
monitoring of the trial subjects. 

Decrease in the dose of the trial drug administered.

A planned PK data review may be eliminated if agreed to by sponsor and investigators. 

Addition of a PK data review (eg, the decision to start enrolment of Group B (mild RI) after 
Group C (moderate RI) data is available, or the decision to start enrolment of Group E 
(subjects with ESRD requiring dialysis) after Group D (severe RI or ESRD not requiring 
dialysis) data is available).

The number of subjects in Group D (severe RI or ESRD not requiring dialysis) and Group E 
(subjects with ESRD requiring dialysis) may be less than 8 subjects.
Based on emerging PK data, the actual PK sampling times may change but the number of samples 
will remain the same. If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or additional PD markers.
Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This may include 
repeat samples or modified PK/PD time points based on emerging data from previous 
subjects/cohorts in the study as per protocol. The total blood volume withdrawn from any single 
subject will not exceed the maximum allowable volume. 
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests) currently outlined in the protocol may be modified during the trial based on data 
as it is analyzed per protocol from previous subjects/cohorts in the study. These changes will not 
increase the number of trial procedures for a given subject during his/her participation in the entire 
trial. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatinine kinase to serum chemistry panel that was 
already drawn). 
It is understood that the current trial may employ some or none of the alterations described above. 
Any of these per protocol alterations (part of trial design to meet its objectives) must be detailed by 
the Sponsor in a letter to the Trial File and forwarded to the investigators for retention. The letter 
may be forwarded to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
at the discretion of the investigators. Any other changes, if considered substantial, will be 
documented in a protocol amendment which will require approval before they are implemented.
6.3.1
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this trial, the collections of the blood samples for PK are the critical procedures. 

At any postdose time point, the blood samples for PK needs to be collected as close to the exact 
nominal time point as possible.

All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
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–
ECG and vital signs measurements should be performed before the nominal time of the PK 
if scheduled together.

The order of priority can be changed during the trial with joint agreement of the investigators 
and the sponsor.

Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.4.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or Follow-up 
Visit/interaction associated with a planned visit (this can be a phone contact), discontinues from 
the trial, or is lost to follow-up (ie, the investigator is unable to contact the subject), 
6.4.3
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a non–safety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a non–safety-related reason. 

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons: 

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from clinical or nonclinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.4.4
Criteria for Premature Termination or Suspension of the Trial
6.4.4.1
Criteria for Premature Termination or Suspension of Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
is unable to ensure adequate performance of the trial, or as otherwise permitted by the contractual 
agreement.
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6.4.4.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Site(s)
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend the trial 
or the participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or trial suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must meet the requirements as 
indicated in Table 7.a:
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Table 7.a
Inclusion Criteria
Subjects:
All 
subjects
Group A 
(Healthy 
subjects ONLY) 
Groups B-E 
(Renally impaired 
subjects ONLY)
1.
Must understand the trial procedures and agree to 
participate by providing written informed consent.
X
2.
Must be willing and able to comply with all trial 
procedures and restrictions.
X
3.
Must be a man or woman (with no childbearing 
potential) aged 18 to 75 years, inclusive, at the 
Screening Visit. 
X
4.
Must have a BMI ≥18 and ≤35 kg/m2 at the 
Screening Visit.
X
5.
Must meet birth control requirements (a).
X
6.
Is considered to be healthy (for healthy subjects) 
or medically stable (for subjects with RI) as 
documented by the subject’s most recent CLcr
assessment (serum creatinine must not vary more 
than approximately 30% from Screening to Day -1 
to confirm stable disease) and as determined by 
the investigators, based on medical history and 
clinical evaluations including physical 
examination, clinical laboratory tests, vital sign 
measurements, and 12-lead ECG performed at the 
Screening Visit and at check-in on Day -1 
(Treatment 1). Subjects with RI should have no 
clinically significant changes in medical history or 
clinical laboratory values within 30 days before 
trial drug administration on Day 1. If clinical 
laboratory tests within 30 days before trial drug 
administration on Day 1 are unavailable, clinical 
laboratory tests on Day -1 may be compared with 
those from the Screening Visit and used by the 
investigators to determine the subject’s medical 
status.
X
7.
Must be comparable to subjects with RI with 
respect to median age and weight (approximately 
50% of healthy subjects on each side of the median 
age and weight of currently enrolled 
renally-impaired subjects grouped together), sex, 
and race. This will be decided by the investigators 
in discussion with Takeda.
X
8.
Must not have used tobacco- or 
nicotine-containing products (eg, nicotine patch) 
for at least 6 months before administration of the 
initial dose of the trial drug and will refrain from 
all tobacco use for the duration of trial 
participation.
X
Footnotes are on last table page.
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Table 7.a
Inclusion Criteria (continued)
Subjects:
All 
subjects
Group A 
(Healthy 
subjects ONLY) 
Groups B-E 
(Renally impaired 
subjects ONLY)
9.
Must abstain from the use of tobacco- or 
nicotine-containing products 48 hours before 
dosing and during confinement in the clinic.
X
10. Must have RI as defined at Screening by the CG 
equation (b).
X
11. Should be on a stable drug regimen defined as not 
starting a new drug or changing dosage within 
7 days or 5 half-lives (whichever is longer) before 
dosing with TAK-954.
X
(a) The following birth control requirements will be met if the subject: 
–
Is a male subject who is sterile or agrees to use an appropriate method of contraception, including a condom with 
or without spermicidal cream or jelly, from consent until 30 days after administration of the trial drug. No 
restrictions are required for a vasectomized male subject provided the subject is at least 1 year post–bilateral 
vasectomy procedure from consent. A male subject whose vasectomy procedure was performed less than 1 year 
before consent must follow the same restrictions as a nonvasectomized man. Appropriate documentation of 
surgical procedure should be provided.
–
Is a male subject who agrees to not donate sperm from consent until 30 days after administration of trial drug.
–
Is a female subject with no childbearing potential, defined by at least 1 of the following criteria:

Postmenopausal (defined as 12 months of amenorrhea without an alternative medical cause with serum FSH 
levels >40 mIU/mL). Appropriate documentation of FSH levels is required).

Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical 
procedure.

Had a tubal ligation with appropriate documentation of surgical procedure.

Has a congenital condition resulting in no uterus.
(b) RI criteria:

Group B: Subjects with mild RI (CLcr 60-<90 mL/min).

Group C: Subjects with moderate RI (CLcr 30-<60 mL/min).

Group D: Subjects with severe RI or ESRD but not requiring dialysis (CLcr <30 mL/min).

Group E: Subjects with ESRD requiring dialysis (<15 mL/min requiring hemodialysis at least 3 times per
week, and having been on the same dialysis treatment regimen for at least 1 month before trial entry).
7.2
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject meets any of the criteria 
in Table 7.b: 
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Table 7.b
Exclusion Criteria
Subjects who:
All 
subjects
Group A 
(Healthy 
subjects ONLY)
Groups B-E 
(Renally impaired 
subjects ONLY)
1.
Have participated in another investigational trial within 
4 weeks before the Screening visit. The 4-week window 
will be derived from the date of the last trial procedure 
and/or AE related to the trial procedure in the previous trial 
to the pretrial/Screening Visit of the current trial.
X
2.
Have legal incapacity or limited legal capacity.
X
3.
Are an employee or immediate family member (eg, spouse, 
parent, child, sibling) of the sponsor.
X
4.
Have a QTcF > 450 msec at Baseline.
X
5.
Have uncontrolled, clinically significant disease or other 
abnormality which may impact the ability of the subject to 
participate or potentially confound the trial results.
X
6.
Are a breastfeeding woman.
X
7.
Have a positive test result for hepatitis B surface antigen 
(HBsAg), hepatitis C antibody (HCV), or human 
immunodeficiency virus (HIV) antibody/antigen, at 
Screening. Note: Subjects with positive HBV or HCV 
serology may be enrolled if quantitative PCR for HBV or 
HCV viral RNA is negative.
X
8.
Have a recent history (past 2 years) substance abuse 
disorder.
X
9.
Have bilirubin levels above 1.5 times the ULN at Screening 
or Day -1.
X
10. Have a known hypersensitivity to any component of the 
formulation of TAK-954 or related compounds.
X
11. Have a known hypersensitivity to any of the components of 
the probe cocktail.
X
12. Had major surgery, donated or lost 1 unit of blood 
(approximately 500 mL) within 8 weeks of the first dose.
X
13. Are renal allograft recipients within 1 year before 
screening.
X
14. Have a history of gastrointestinal (GI) motility disorder or 
intestinal obstruction.
X
15. Have urinary incontinence without catheterization.
X
16. Consume excessive amounts, defined as greater than 
6 servings (1 serving is approximately equivalent to 120 mg 
of caffeine) of coffee, tea, cola, energy drinks, or other 
caffeinated beverages per day.
X
17. At the discretion of the investigator, have a history of 
clinically significant endocrine, GI (including motility 
disorder and intestinal obstruction), cardiovascular, 
X
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Subjects who:
All 
subjects
Group A 
(Healthy 
subjects ONLY)
Groups B-E 
(Renally impaired 
subjects ONLY)
hematological, hepatic, immunological, renal, respiratory, 
genitourinary, or major neurological (including stroke and 
chronic seizures) abnormalities or diseases.
18. Have a history of cancer (malignancy).
X
19. Ingest alcohol within 3 days before trial drug administration 
and during the confinement period.
X
20. Are unable to refrain from or anticipates the use of any 
medication, including prescription and nonprescription 
drugs or herbal remedies, beginning approximately 7 days 
before administration of the initial dose of trial drug, 
throughout the trial (including washout intervals between 
trial periods), until the Follow-up Visit. There may be 
certain medications that are permitted, see Section 7.3.
X
21. Are unable to refrain from or anticipates the use of:

strong CYP3A4 inhibitors or inducers 

CYP1A2 inhibitors or inducers (Group C only)

serotonin agonists or antagonists

monoamine oxidase inhibitors

noradrenergic agonists

selective serotonin reuptake inhibitors

gamma—aminobutyric acid antagonists

N-methyl-D-aspartate receptor antagonists
beginning approximately 7 days before administration of 
the trial drug, throughout the trial (including washout 
intervals between trial periods), until the Follow-up Visit.
X
22. Require any method of dialysis (except intermittent 
hemodialysis in Group E).
X
23. Have renal disease secondary to hepatic disease 
(hepatorenal syndrome).
X
24. Have hemoglobin level ≤110 g/L at Screening for the Czech 
Republic sites only.
X
25. At the discretion of the investigators, have any significant 
hepatic, cardiac, or pulmonary disease or subjects who are 
clinically nephrotic.
X
26. Have a positive urine drug screening test result at the 
Screening Visit or at check-in on Day -1.
X
27. Have a positive urine drug screening test result at the 
Screening Visit or at check-in on Day -1, unless the positive 
drug screen is due to prescription drug use and is approved 
by the investigators and the sponsor’s medical monitor.
X
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7.3
Excluded Medications, Supplements, and Dietary Products
Use of excluded agents (prescription or nonprescription) or dietary products is outline in Table 7.c.
Table 7.c
Excluded Medications, Supplements, and Dietary Products (a)
Category
Between Screening and Enrollment 
(Days -28 to Predose [Day 1])
Post-Enrollment (Day 1) to Follow-up 
Visit
Tobacco- and 
nicotine-containing 
products (a)
Completely restricted.
Completely restricted.
Cannabis products
Completely restricted.
Completely restricted.
Alcohol
Completely restricted for a minimum of 
3 days before dosing (start of infusion).
Completely restricted during the 
confinement period.
Xanthine and/or caffeine
Completely restricted 24 hours before 
dosing (start of infusion).
Completely restricted until 24 hours after 
dosing.
Medications for healthy 
subjects
Completely restricted 7 days before 
dosing (start of infusion).
Completely restricted (b).
Medications for renally 
impaired subjects
Concomitant medications allowed.
Concomitant medications allowed.
Food substance
Grapefruit /grapefruit juice
Completely restricted 7 days before 
dosing (starting of infusion).
Completely restricted.
Fruit
No restriction.
No restriction.
Fruit juice
No restriction.
Dosing will occur without consumption 
of fruit juice. Fruit juice is restricted until 
4 hours after dosing (start of infusion).
Mustard green (c)
Completely restricted 7 days before 
dosing (starting of infusion).
Completely restricted.
Charbroiled meat
Completely restricted 7 days before 
dosing (start of infusion).
Completely restricted.
(a) Subjects in Groups B through E will abstain from the use of tobacco- or nicotine-containing products 48 hours 
before to dosing and during confinement in the clinic. 
(b) If medications are required to treat an AE, certain medications may be allowed after discussion and agreement 
between the sponsor and principal investigator.
(c) Mustard green family includes kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, and mustard. 
For subjects in Groups B through E, concomitant medications may be given if they are necessary 
for the welfare of the subjects (eg, standard therapy for underlying disease), are not 
contraindicated with TAK 954, and are unlikely to interfere with the PK of TAK-954. 
Concomitant medications to treat concurrent diseases or comorbidities should be maintained at a 
stable dose and regimen from the Screening Visit throughout the trial; however, medication 
adjustments may be made by the investigators with Sponsor approval based on the subject’s 
condition and standard of care.
Occasional use of acetaminophen/paracetamol (1 g/day) or other medication as approved by 
Takeda on a case-by-case basis is allowed.
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Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigators and consultation with Takeda. However, if a 
medication is taken, it is the responsibility of the investigators to ensure that the details regarding 
the medication are recorded in full in the electronic case report form (eCRF).
7.4
Diet, Fluid, and Activity 
7.4.1
Diet and Fluid
All subjects must abstain from all food and drink (except water) at least 8 hours before any safety 
laboratory evaluations. Subjects should also abstain from all food and drink (except water) 
overnight before each dosing day. 
Water may be consumed without restrictions. Noncaffeinated drinks (except grapefruit or 
grapefruit-related citrus fruit juices) may be consumed with meals and evening snack.
Lunch and dinner will be provided approximately 4 and 9 hours after dosing (start of infusion). An 
evening snack will also be permitted.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the Screening Visit until the Follow-up Visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. The subject experiences an AE that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the AE.
2. Liver Function Test (LFT) Abnormalities 
In multidose studies, trial drug should be discontinued immediately with appropriate 
clinical follow-up (including repeat laboratory tests, until a subject’s laboratory profile has 
returned to normal/baseline status, see Section 10.2.9.4), if the following circumstances 
occur at any time during trial drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 times the 
upper limit of normal (ULN), or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio >1.5, or
–
ALT or AST >3×ULN with:

appearance of fatigue, nausea, vomiting.

right upper quadrant pain or tenderness, fever.
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
rash and eosinophilia (>5%).
3. Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
4. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
5. Voluntary withdrawal. The subject wishes to withdraw from the trial. The reason for 
withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal because of 
an AE should not be recorded in the “voluntary withdrawal” category).
6. Trial termination. The sponsor, IRB, or regulatory agency terminates the trial.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial when 
the subject meets the trial 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 trial. 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. 
7.7
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigators and sponsor.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
8.1
Clinical Trial Drug 
Details regarding the composition and extemporaneous preparation of the active ingredient are 
found in the Pharmacy Manual, and/or similar documents. Clinical trial drug will be packaged to 
support enrollment and replacement subjects as required. When a replacement subject is required, 
the sponsor needs to be contacted before dosing.
8.1.1
Clinical Trial Drug Labeling
Clinical trial drug packaging will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Trial Drug Inventory and Storage
Clinical trial drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of trial drug must be recorded by an 
authorized person at the trial site. 
8.1.3
Clinical Trial Drug Blinding
This is an open-label trial; therefore, the sponsor, investigators, and subject will know the 
treatment administered.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical trial drug received from 
the sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the conclusion of the trial. For all trial sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for clinical trial drug 
accountability, return, and destruction. 
8.1.5
Ancillary Supplies
All ancillary supplies will be provided by either the site or Takeda, based upon availability. If 
provided by Takeda, unused ancillary supplies will be accounted for and disposed of as directed by 
Takeda or a Takeda designee.
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9.0
TRIAL PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Trial Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator. For information regarding procedures that are scheduled concurrently, see 
Section 6.3.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject entering into the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2. 
In the case where subjects have screening assessments performed before the trial, the data from the 
general/site screening could be included/used in the trial for those who were enrolled, as long as 
the procedure was performed within the protocol screening/enrollment window. A generic site 
screening form may be used.
9.1.2
Assignment of Screening Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before allocation. Each subject will be assigned only 
1 screening number. Screening numbers must not be re-used for different subjects. Any subject 
who is screened multiple times will be assigned a new screening number for each screening event.
9.1.3
Inclusion and Exclusion Criteria 
Each subject is assessed according to the eligibility criteria provided in Section 7.0.
9.1.4
Medical History/Demographics
Qualified site personnel are to collect subject significant medical history (past and ongoing) per 
the site’s standard of care and appropriate clinical judgment as well as subject demographics. 
9.1.5
Prior and Concomitant Medication Review
Medications are defined as prescription and over-the-counter drugs, vitamin supplements, 
nutraceuticals, and oral herbal preparations. Qualified site personnel are to review subject 
medication use. 
9.1.6
Full Physical Examinations
Qualified site personnel will conduct physical examinations.
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9.1.7
Brief Physical Examinations
Qualified site personnel will conduct brief physical examinations.
9.1.8
Vital Sign Measurements
Body temperature will be measured with an auricular or tympanic thermometer. The same method 
(eg, oral or tympanic) must be used for all subsequent measurements for each individual subject 
and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes before having vital sign 
measurements obtained. Vital signs will include HR, respiratory rate, body temperature, and 
systolic blood pressure and diastolic blood pressure. The same method (eg, same and appropriately 
sized cuff, manual, or automated) must be used for all measurements for each individual subject 
and should be the same for all subjects. 
Subjects will continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose or other trial-related procedure. 
9.1.9
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
9.1.10 BMI
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2).
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 round down and 0.5 to 0.9 round up.
9.1.11 12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bras. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement.
QT intervals with Fridericia correction method (QTcF) will be used to calculate QT intervals in 
this trial.
A predose ECG will be obtained within approximately 30 minutes before dosing. This 
measurement will be used as the baseline. The principal investigator should arrange to have a trial 
cardiologist available as needed to review ECG tracings with abnormalities.
If a subject demonstrates an increase in QTcF interval ≥40 msec compared with a predose baseline 
measurement, the ECG will be repeated within 5 minutes. The average value of the QTcF interval 
from the 2 ECGs will represent the value at that time point. If the average QTcF interval increase 
from Baseline for any postdose time point is ≥40 msec, the subject will continue to be monitored 
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by repeat 12-lead ECGs every 60 minutes for at least 4 hours or until the QTcF is within 40 msec of 
the baseline value. If prolongation of the QTcF interval ≥40 msec persists, a consultation with a 
trial cardiologist may be appropriate and the sponsor should be notified.
If the QTcF interval is ≥500 msec, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be telemetry-monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted on 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy. 
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: HR, PR-interval, QRS-duration, QT-interval, 
QTcF-interval, and the interpretation of the ECG profile by the principal investigator.
9.1.12 AE Monitoring
AE monitoring begins after signing of informed consent. Changes in subject health status from 
baseline assessment to trial drug administration should be captured in the subject’s medical 
history. A complete description of AE collections and procedures is provided in Section 10.0.
9.1.13 Pregnancy
Women of childbearing potential will not be included in this study. If any subject is found to be 
pregnant on Day -1, she should be withdrawn from the study. 
9.2
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken after a minimum 8-hour overnight fast on the days stipulated in the Schedule 
of Trial Procedures (Section 3.0).
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9.2.1.1
Clinical Laboratory Tests
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Bicarbonate
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN, will be fractionated
Protein (total)
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute 
differential
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts.
Urine pregnancy test (hCG)
A urine pregnancy test (hCG) will be conducted on women on Day -1. For dialysis subjects who 
are anuric, a pregnancy test will be conducted via a blood sample.
Urine Drug Screen
For dialysis subjects who are anuric, the following tests will be conducted via a blood sample 
(results should be available before dosing if possible).
A urine drug screen will include the following tests:
Amphetamines
Cotinine
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Barbiturates
3,4-methylenedioxy-methamphetamine
Benzodiazepines
Methadone/metabolite
Cannabinoids
Opiates
Cocaine/metabolites
Phencyclidine
Alcohol Screen
Subjects will undergo a urine alcohol test. An alcohol breath test may be performed at the 
discretion of the investigators.
9.2.1.2
Screening
Serum
Serum evaluations will include the following tests:
HIV test
Hepatitis panel, including HBsAg and anti-HCV
Follicle-stimulating hormone (FSH)
9.3
PK and PGx Samples
Samples for PK analysis will be collected as specified in the Schedule of Trial Procedures 
(Section 3.0). Please refer to the Laboratory Manual for information on the collection, processing, 
and shipment of samples to the central laboratory. 
A portion of the DNA sample will be analyzed for the presence of allelic variants in drug 
metabolizing enzymes, drug transporters, or putative drug targets that may contribute to the 
variability in the PK of TAK-954 (Drug Metabolism Enzymes and Transporters). 
 
It is anticipated that the total blood volume drawn for the trial will be approximately 260 mL for 
healthy subjects and subjects with moderate RI, 245 mL for subjects with ESRD requiring dialysis; 
and 140 mL for subjects with severe RI or ESRD not requiring dialysis and subjects with mild RI. 
Subjects' hemoglobin will be assessed within 10-14 days of last dose in order to ensure that 
subjects do not become anemic during the study due to the blood volume loss from repeated blood 
sampling, receiving the standard of care if needed.
Property of Takeda: For n
mmercial use only and subject to the applicable Terms of Use
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Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended 
Use
Sample 
Collection
Plasma sample for TAK-954 PK
Plasma
PK measurement
Mandatory
Plasma sample for CYP substrate 
PK 
Plasma
PK measurement
Mandatory
Plasma sample for TAK-954 
protein binding
Plasma
PK measurement
Mandatory
Plasma sample for TAK-954 PK 
dialyzer arterial
Plasma
PK measurement
Mandatory
Plasma sample for TAK-954 PK 
dialyzer venous
Plasma
PK measurement
Mandatory
Dialysis fluid sample for TAK-954 
PK
Dialysis 
fluid
PK measurement
Mandatory
Urine sample for TAK-954 PK
Urine
PK measurement
Mandatory
Urine sample for CYP substrate PK
Urine
PK measurement
Mandatory
Blood sample for DNA PGx
Blood
DNA
PK measurement
Optional
Blood sample for RNA PGx
Blood
RNA
PK measurement
Optional
9.3.1
PK Evaluations
The PK parameters of TAK-954 
 will be derived using noncompartmental 
analysis methods and will be determined from the concentration-time data for all evaluable 
subjects. Actual sampling times, rather than scheduled sampling times, will be used in all PK 
computations involving sampling times. A more detailed description will be given in the CPAP.
The following PK parameters for TAK-954 will be calculated:
Plasma PK parameters (free and total):
!
Cmax.
!
AUC72.
!
AUClast.
!
AUC∞.
!
t1/2.
!
CL.
!
Vz.
Property of Takeda: For non-comm
l use only
DNA
DNA
ly and subject to the applicable Terms of Use
mple
mple
ollec
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m
Mandat
Mand
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M
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pp
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PK m
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Urine PK parameters:
!
Ae.
!
fe.
!
CLR.
Dialysate PK parameters:
!
CLD.
Other PK parameters may be calculated if deemed necessary for the interpretation of the data. All 
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
However, samples obtained within 10% of the nominal time from dosing will not be captured as a 
protocol deviation, as long as the exact time of dosing and the sample collection is noted on eCRF.
The decision as to which plasma and/or urine samples collected will be assayed for evaluation of 
PK will be determined by the sponsor. If indicated, these samples may also be assayed and/or 
pooled for assay in an exploratory manner for metabolites.
9.3.2
PGx Measurements
9.3.2.1
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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9.3.2.2
Biological Sample Retention and Destruction
In this trial, specimens for genome/gene analysis will be collected as described in the Laboratory 
Manual. The genetic material will be initially stored at the vendor, or a comparable laboratory, 
under contract to Takeda, with validated procedures in place, and then preserved and retained at 
the vendor, or a comparable laboratory with validated procedures in place, for up to but not longer 
than 15 years from the end of the trial when the trial report is signed, or if less, the maximum 
period permitted under applicable law or until consent is withdrawn.
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the trial will be stored securely with limited access 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main trial but using a code that 
is different from the code attached to the health information and other clinical test results collected 
in the trial. The sample and data are linked to personal health information with code numbers; the 
samples are stripped of all personal identifying information but a key linking the samples to 
clinical analysis data exists. This link means that the subject may be identified but only indirectly. 
The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a PD sample for DNA and RNA analysis can withdraw their 
consent at any time and request disposal of a stored sample. Any remaining sample that can be 
identified as coming from the subject will be destroyed. The investigator and sponsor may 
Property of Takeda: For non-commercial use 
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continue to use and distribute any information and test results gathered before the request to 
withdraw.
9.4
Trial Drug Administration
TAK-954
Eligible subjects in Groups A to D will be allocated to trial treatment by nonrandom assignment on 
Day 1 and will receive a single IV dose of 0.2 mg TAK-954 administered as a 60-minute infusion 
approximately between 0600 and 0900. Subjects with ESRD requiring dialysis (Group E) will 
receive 2 single IV doses of 0.2 mg TAK-954 administered as a 60-minute infusion at 
approximately the same time between 0600 and 0900. 
Subjects will continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose except to stand for the measurement of standing vital signs (if needed) or other 
trial-related procedure.
ct to the applicable Terms of Use
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9.5
Confinement
For Treatment 1/Period 1, all subjects will reside in the CRU from Day -1 until after the PK sample 
collection on the morning of Day 3, or at the discretion of the investigator. Subjects must return to 
the CRU for the remaining PK sample collections.
For Treatment 2, subjects in Groups A and C will reside in the CRU from Day -1 until after the last 
PK sample collection on the morning of Day 2. For Period 2, subjects with ESRD requiring 
dialysis (Group E) will reside in the CRU from Day -1 until after the last PK sample collection on 
the morning of Day 3, or at the discretion of the investigator. Subjects must return to the CRU for 
the remaining PK sample collections.
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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 trial; 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 underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of trial 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 to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory 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) should NOT be recorded as an AE unless related to 
a trial procedure. However, if the subject experiences a worsening or complication of such a 
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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 
trial medication or after any change in trial 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 trial medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) because of 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 trial subject, at a dose above that which is assigned to that individual subject 
according to the trial 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 eCRF, 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 the AE CRF(s) according to 
Section 10.2.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9.

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.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.2.2 Assigning Causality of AEs
The relationship of each AE to trial medication(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.2.3 Assigning Relationship to Trial Procedures
Relationship (causality) to trial procedures should be determined for all AEs.
The relationship should be assessed as “Related” if the investigator considers that there is 
reasonable possibility that an event is because of a trial procedure. Otherwise, the relationship 
should be assessed as “Not Related”.
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10.2.4 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.5 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.2.6 Frequency 
Episodic AEs (eg, headache) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.7 Action Concerning Trial Drug 

Drug withdrawn: a trial medication is stopped because of the particular AE.

Dose not changed: the particular AE did not require stopping a trial medication.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a trial medication was stopped for a reason other than the particular AE, for 
example, the trial has been terminated, the subject died, dosing with trial medication was 
already stopped before the onset of the AE.
10.2.8 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 
trial period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

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 because of hospital change or residence 
change at the end of the subject’s participation in the trial.
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10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.9.1 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 10 to 14 days after the last dose of trial medication. For subjects who discontinue 
before the administration of trial medication, AEs will be followed until the subject discontinues 
trial participation. 
10.2.9.2 Reporting AEs
At each trial 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 trial. Subjects experiencing an SAE before 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 before the first exposure to investigational 
product, related or unrelated to the trial procedure, need not be followed-up for the purposes of the 
protocol.
All subjects experiencing AEs, whether considered associated with the use of the trial 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 eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of trial 
medication(s) (related or not related).

Investigator’s opinion of the causal relationship to trial procedure(s), including the details of 
the suspected procedure.

Action concerning trial medication.

Outcome of event.

Seriousness.
10.2.9.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
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A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the trial 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 after the AE collection period should be 
reported to the sponsor if considered related to trial participation.
Reporting of SAEs that begin before the 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.
10.2.9.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.
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 10.2.9.3. 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 must also be performed. In addition, an LFT 
Increases eCRF must be completed and transmitted with the Takeda SAE form (as per 
Section 10.2.9.3). 
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10.2.10 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 trial 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 trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all trial objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the trial database, subject evaluability, or appropriateness of the 
planned statistical methods.
11.1.1 Analysis Sets
Safety Set
The safety set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
PK Set
The PK set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug and 
have at least 1 measurable TAK-954 plasma concentration. All subjects with valid PK parameter 
estimates will be included in the summaries and analyses for that parameter.
If any subject has incomplete data, a decision will be made on a case-by-case basis as to whether 
that subject should be included in the PK analyses; however, data for all subjects will be presented 
in the data listings.
11.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for all subjects. Summary statistics 
(number of subjects, mean, SD, median, minimum, and maximum) will be presented for 
continuous variables (eg, age, weight, and BMI), and the number and percentage of subjects within 
each category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristic data will be provided in the data listings.
11.1.3 PK Analysis
The Pharmacokinetic Set will be used for all summaries of PK data. Summaries will be provided 
by renal function group using Cockcroft-Gault formula (CLcr) and Modification of Diet in Renal 
Disease formula (eGFR).
Cockcroft and Gault (CG) equation:
CLcr (mL /min ) = 140 −age (years) • total body weight (kg) • (0.85 for females)
72 • serum creatinine (mg/dL)
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Modification of Diet in Renal Disease equation:
eGFR (ml/Min/1.73 m2) = 175 x Scr,std)-1.154 x (age)-0.203 x (0.742 if female) x (1.212 if African 
American)
Summary statistics will be presented for plasma concentrations of TAK-954 and any measured 
metabolites over each scheduled sampling time by renal function group. Amounts of TAK-954 
and any measured metabolites excreted in urine will also be summarized over each scheduled 
sampling interval by renal function group. Individual plasma concentrations of TAK-954 and any 
measured metabolites at each scheduled sampling time and amounts of TAK-954 and any 
measured metabolites excreted in urine at each scheduled sampling interval will be presented in 
listings.
Summary statistics will be presented for the plasma and urine PK parameters for TAK-954 and any 
measured metabolites by renal function group. Geometric means will also be presented for Cmax
and AUCs. Individual plasma and urine PK parameters will be presented in a data listing.
To evaluate the effect of RI on the PK of TAK-954 and any measured metabolites, an analysis of 
variance (ANOVA) with renal function group as a fixed effect will be performed on t1/2 and the 
natural logarithms of AUCt, AUC72, AUC∞, and Cmax for TAK-954 and any measured metabolites. 
Within the ANOVA framework, comparisons of each RI group versus the normal renal function 
group will be made using appropriate contrast statements.
The relationship between renal function and the PK of TAK-954 and any measured metabolites 
(Cmax and AUCs) will be evaluated through graphics and regression modeling with CLR included 
in the regression model as a continuous variable.
Descriptive statistics (mean, standard deviation, standard error, % coefficient of variation [%CV], 
minimum, median, and maximum) will be used to summarize concentrations 
 
 PK parameters according to the renal function group (healthy 
subjects and moderate subjects).
An ANOVA will be performed on log transformed Cmax and AUC for e
 
subjects with moderate RI (Group C) with healthy subjects (Group A). The estimated 
difference between moderate RI (Group C) and healthy subjects with normal renal function 
(Group A) will be obtained and a 90% confidence interval. This estimate and difference will then 
be exponentiated to provide an estimated ratio and 90% confidence interval for moderate RI 
relative to normal renal function for each analyte 
. Additional statistical 
analyses will be performed, if deemed appropriate. A more detailed analysis will be presented in 
the SAP.
11.1.4 Safety Analysis
The safety set will be used for all summaries of safety parameters.
Property of Takeda: For non
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11.1.4.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse event (TEAEs) 
with onset occurring within 30 days (onset date minus last date of dose +1≤30) after the last dose 
of trial drug will be included in the summary tables. All AEs will be in the listings. TEAEs will be 
summarized by SOC and PT. The following summary tables will be included in the report: 
summary of TEAEs and drug-related AEs, relationship of AEs to trial drug (related vs not related), 
severity of AEs, and related SAEs. Data listings will be provided for all AEs including TEAEs, 
AEs leading to trial drug discontinuation, and SAEs. 
11.1.4.2 Clinical Laboratory Evaluation
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized by 
regimen. All clinical laboratory data will be provided in the data listings.
11.1.4.3 Vital Signs
Baseline, postdose, and changes from Baseline in vital sign measurements will be summarized. All 
vital sign data will be provided in the data listings.
11.1.4.4 ECGs
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized by regimen. Shift tables for each will be generated to show the investigator’s ECG 
interpretations at each postdose collection by the interpretation at Baseline.
All ECG data will be provided in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
No formal interim analyses will be conducted. 
11.3
Determination of Sample Size
The planned sample size of 8 subjects in each renal function group is in line with regulatory 
guidance for these types of studies (“FDA Guidance for Industry Pharmacokinetics in Patients 
with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” 
and “EMEA Guideline on The Evaluation of the Pharmacokinetics of Medicinal Products in 
Patients with Impaired Renal Function”). 
Subjects who drop out may be replaced at the discretion of the sponsor in consultation with the 
investigator. Subjects who replace dropouts will begin the trial as a new subject. 
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Trial-Site Monitoring Visits
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and trial site guarantee access to source documents by the sponsor or its designee and 
by the IRB or IEC.
All aspects of the trial and its documentation will be subject to review by the sponsor or the 
sponsor’s designee, including but not limited to the Investigator’s Binder, trial drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator and other trial 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 trial 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 trial assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The trial 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 trial. In 
addition, there is the possibility that this trial may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the trial 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 trial documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE TRIAL
This trial 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 Conference on Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the trial 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 trial, 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 
because of 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 trial (ie, before shipment of the sponsor-supplied drug or trial-specific 
screening activity). The IRB or IEC approval must refer to the trial by exact protocol title, number, 
and version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug/notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives 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 trial 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 trial. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the trial, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before 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 trial, and (2) 
decide whether or not to participate in the trial. If the subject determines he or she will participate 
in the trial, 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 before the subject entering into the trial. 
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 before subject entering into the trial; 
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 before analysis. Notify the 
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 trial, a subject’s source data will only be linked to the 
sponsor’s clinical trial 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 trial 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 eCRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the trial. During and after the trial, only the sponsor may make trial 
information available to other trial investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical trial site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or trial results, other 
than trial recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the trial (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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13.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of the trial, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials 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 trial 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 trial insurance against the risk of injury to trial subjects. Refer to the 
trial 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 Trial Contact Information 
Contact Type/Role
Contact
SAE and pregnancy reporting
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15.0
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 trial in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of trial subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.10 of this protocol.

Terms outlined in the trial site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
15.1.1 Trial-Related Responsibilities 
The sponsor will perform all trial-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific trial-related activities 
will perform these activities in full or in partnership with the sponsor.
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15.1.2 List of Abbreviations
5-HT4
serotonin type 4
β-hCG
β–human chorionic gonadotropin
AE
adverse event
Ae
amount of drug excreted in urine
Aet
amount of drug excreted in urine from time 0 to time t
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC72
area under the plasma concentration-time curve from time 0 to 72 hours
AUClast
area under the plasma concentration-time curve from time 0 to the last measurable time 
point.
AUCt
area under the plasma concentration-time curve from time 0 to time t.
AUC∞
area under the plasma concentration-time curve from time 0 to infinity.
BMI
body mass index
CFR
Code of Federal Regulations
CG
Cockcroft and Gault
CL
Total clearance after IV administration, calculated using the observed value of the last 
quantifiable concentration
CLcr
creatinine clearance
CLD
dialysis clearance
CLR
renal clearance
Cmax
maximum observed plasma concentration
CRU
clinical research unit
CT
computed tomography
CV
coefficient of variation
CYP
cytochrome P-450
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
EFI
enteral feeding intolerance
EMA
European Medicines Agency
ESRD
end stage renal disease
fe
fraction of drug excreted in urine
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
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HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RI
renal impairment
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
Vz
volume of distribution during the terminal disposition phase after intravenous 
administration, calculated using the observed value of the last quantifiable concentration
WBC
white blood cell
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16.0
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 the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
16.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections 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 eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical trial database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator using change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits by 
trial monitors. The sponsor or its designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
16.2
Record Retention
The investigator agrees to keep the records stipulated in Section 16.1 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
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documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
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 trial 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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17.0
REFERENCES
1.
Blakey G, Lockton J, Perrett J, Norwood P, Russell M, Aherne Z, et al. Pharmacokinetic 
and pharmacodynamic assessment of a five-probe metabolic cocktail for CYPs 1A2, 3A4, 
2C9, 2D6 and 2E1 Br J Clin Pharmacol 2003;57(2):162-69.
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18.0
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 trial.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the trial 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 trial-related procedures, including trial-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations.
6. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial 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 trial, 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 
trial. 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.
10. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years after notification by the sponsor that all investigations have been discontinued or that 
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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 trial 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 trial.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the trial.
9. A description of the possible side effects of the treatment that the subject may receive.
10. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
11. 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.
12. 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.
13. 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 is authorizing such access.
14. 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.
15. The anticipated prorated payment(s), if any, to the subject for participating in the trial.
16. The anticipated expenses, if any, to the subject for participating in the trial.
17. 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.
18. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
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19. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
20. A statement that the subject 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 trial.
21. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
22. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated.
23. 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 trial. 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 trial 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 trial 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 trial results are 
published.
24. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening, throughout the duration of the trial, and for 30 days after last dose of trial 
medication. 
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25. 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 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 trial and/or other clinical studies.

Management, monitoring, inspection, and audit of the trial.

Analysis, review, and verification of the trial results.

Safety reporting and pharmacovigilance relating to the trial.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial.

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 trial medication.

Inspections and investigations by regulatory authorities relating to the trial.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of trial records.

Posting investigator site contact information, trial 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
Female Subjects and Their Male Partners
Female subjects of childbearing potential are excluded from this trial; there are no requirements 
for contraception or pregnancy avoidance. If any subject is found to be pregnant during the study, 
she should be withdrawn from the study and any Takeda-supplied drug should be immediately 
discontinued. In addition, any pregnancies in the partner of a male subject during the study 30 days 
after the last dose should also be recorded following authorization from the subject’s partner. All 
pregnancies, including female partners of male subjects, in subjects on active study drug will be 
followed up to final outcome. The outcome of the pregnancy, including any premature 
termination, must be reported to the sponsor.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 30 days after the 
last dose of trial drug, nonsterilized** male subjects who are sexually active with a female partner 
of childbearing potential must use barrier contraception (eg, condom with or without spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period. Women 
of childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception below.
** Sterilized men 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. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this trial, where medications and devices containing hormones are included, 
females of childbearing potential who are partners of male subjects are advised to use 
additional contraception chosen from the list below: 

Nonhormonal methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion. 

Hormonal methods: 
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of trial drug.
Oral. 
Intravaginal (eg, ring).
Transdermal. 
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–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of trial drug.
Oral. 
Injectable.
Implantable.
2. Since genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the 
investigational drug, additional effective methods of contraception (there may be a higher than 
1% failure rate) that may be chosen by the female partner of a male subject are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action. 
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Male 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 and 
sperm donation during the course of the trial.
5. Male subjects will receive continued guidance with respect to the avoidance of pregnancy and 
sperm donation as part of the trial procedures. Such guidance should include a reminder of the 
following:

Contraceptive requirements of the trial.

Reasons for use of barrier methods (ie, condom) in males with partners of child bearing 
potential.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit?
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Appendix E
Detailed Descriptions of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 01 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Clarification of the number of subjects included in the study.
The primary change occurs in the 1.0 TRIAL SUMMARY.
Initial 
wording:
A range of approximately 24 to 40 subjects will complete this trial.
Amended 
or new 
wording:
Up to approximately 40 subjects (with 8 planned per Group) will be enrolled in this 
trial.
Rationale for Change:
The Czech Competent Authority commented that the protocol should clearly state number of 
subjects per group and not just the total number of subjects (as per “Guideline on the evaluation of 
the pharmacokinetics of medicinal products in patients with decreased renal function”). 
Change 2: Clarification to altering the trial design.
The primary change occurs in Section 6.3 Trial Design/Dosing/Procedures Modifications 
Permitted Within Protocol Parameters: 
Initial 
wording:
This is a phase 1 assessment of TAK-954 in humans and the PK and safety profiles of 
the compound are still being elucidated. This protocol is written with some flexibility 
to accommodate the inherent dynamic nature of phase 1 clinical trials. Modifications 
to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined below may be required to achieve the scientific goals of the trial objectives 
and/or to ensure appropriate safety monitoring of the trial subjects. 
Some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose/exposure may 
not exceed those currently outlined.

Repeat of or decrease in the dose of the trial drug administered.

Entire cohorts may be omitted.

A planned PK data review may be eliminated if agreed to by sponsor and 
investigators and if no further increases in total daily dose occur. 

Addition of a PK data review.

Instructions to take trial drug with or without food or drink may also be modified 
based on newly available data, ie, food effect is known.
The PK sampling scheme currently outlined in the protocol may be modified during 
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the trial based on newly available PK or PD data (eg, to obtain data closer to the time 
of peak plasma concentrations). If indicated, these collected samples may also be 
assayed in an exploratory manner for metabolites and/or additional PD markers.
Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This 
may include repeat samples or modified PK/PD time points based on emerging data. 
The total blood volume withdrawn from any single subject will not exceed the 
maximum allowable volume during his or her participation in the entire trial. 
The timing of planned procedures for assessment of safety procedures (eg, vital signs, 
ECG, safety laboratory tests) currently outlined in the protocol may be modified 
during the trial based on newly available safety, tolerability, PK, or PD data (eg, to 
obtain data closer to the time of peak plasma concentrations). These changes will not 
increase the number of trial procedures for a given subject during his/her participation 
in the entire trial. 
Additional laboratory safety tests may be added to blood samples previously drawn to 
obtain additional safety information (eg, adding creatinine kinase to serum chemistry 
panel that was already drawn). 
It is understood that the current trial may employ some or none of the alterations 
described above. Any alteration made to this protocol to meet the trial objectives must 
be detailed by the Sponsor in a letter to the Trial File and forwarded to the 
investigators for retention. The letter may be forwarded to the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) at the discretion of the 
investigators.
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Amended 
or new 
wording:
This is a phase 1 assessment of TAK-954 in humans and the PK and safety profiles of 
the compound are still being elucidated. This protocol is written with some flexibility 
to accommodate the inherent dynamic nature of phase 1 clinical trials. Modifications 
to the dose, dosing regimen, and/or clinical or laboratory procedures currently
outlined below may be required to achieve the scientific goals of the trial objectives 
and/or to ensure appropriate safety monitoring of the trial subjects. 
Some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose/exposure may 
not exceed those currently outlined.

Repeat of or Decrease in the dose of the trial drug administered.

Entire cohorts may be omitted.

A planned PK data review may be eliminated if agreed to by sponsor and 
investigators and if no further increases in total daily dose occur.

Addition of a PK data review (eg, the decision to start enrolment of Group B 
(mild RI) after Group C (moderate RI) data is available, or the decision to 
start enrolment of Group E (subjects with ESRD requiring dialysis) after 
Group D (severe RI or ESRD not requiring dialysis) data is available).

The number of subjects in Group D (severe RI or ESRD not requiring 
dialysis) and Group E (subjects with ESRD requiring dialysis) may be less 
than 8 subjects.

Instructions to take trial drug with or without food or drink may also be modified 
based on newly available data, ie, food effect is known.
The PK sampling scheme currently outlined in the protocol may be modified during 
the trial based on newly available PK or PD data (eg, to obtain data closer to the time 
of peak plasma concentrations). Based on emerging PK data, the actual PK 
sampling times may change but the number of samples will remain the same. If 
indicated, these collected samples may also be assayed in an exploratory manner for 
metabolites and/or additional PD markers.
Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This 
may include repeat samples or modified PK/PD time points based on emerging data 
from previous subjects/cohorts in the study as per protocol. The total blood 
volume withdrawn from any single subject will not exceed the maximum allowable 
volume during his or her participation in the entire trial. 
The timing of planned procedures for assessment of safety procedures (eg, vital signs, 
ECG, safety laboratory tests) currently outlined in the protocol may be modified 
during the trial based on newly available safety, tolerability, PK, or PD data as it is 
analyzed per protocol from previous subjects/cohorts in the study (eg, to obtain 
data closer to the time of peak plasma concentrations). These changes will not increase 
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the number of trial procedures for a given subject during his/her participation in the 
entire trial. 
Additional laboratory safety tests may be added to blood samples previously drawn to 
obtain additional safety information (eg, adding creatinine kinase to serum chemistry 
panel that was already drawn). 
It is understood that the current trial may employ some or none of the alterations 
described above. Any of these per protocol alterations (part of trial design made to 
this protocol to meet the trialits objectives) must be detailed by the Sponsor in a letter 
to the Trial File and forwarded to the investigators for retention. The letter may be 
forwarded to the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) at the discretion of the investigators. Any other changes, if considered 
substantial, will be documented in a protocol amendment which will require 
approval before they are implemented.
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TAK-954
Study No. TAK-954-1007
Page 84 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Rationale for Change:
The Czech Competent Authority commented that some changes listed are considered by the 
Institute to be substantial, and hence prior to the implementation of such a change the sponsor 
should submit a substantial amendment to the protocol which is subjected to the Institute’s 
approval. The protocol has been revised to remove changes and make it obvious what limited 
changes are within remit as per protocol design and clarify that any other changes will not occur 
without a prior approval of a substantial amendment by the Institute.
Change 3:
The primary change occurs in Section 5.1 Objectives:
Deleted 
text:
A sub-set of this study will be to explore the potential for renal insufficiency to affect 
non-renal clearance mechanisms using different CYP probes including caffeine, 
tolbutamide, and midazolam. 
Rationale for Change:
To address comment of the Czech Competent Authority, one of the cocktail probe drugs, 
tolbutamide, is being removed due to concerns with hypoglycemia in subjects with compromised 
renal function, in addition to sourcing issues.
The following sections also contain this change:
!
Section 1.0 TRIAL SUMMARY.
!
Section 4.3 Benefit/Risk Profile.
!
Section 6.1 Trial Design.
!
Section 6.2.1 Rationale of Trial Design and Dose.
!
Section 9.4 Trial Drug Administration.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-954
Study No. TAK-954-1007
Page 85 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Change 4 The addition of an exclusion criteria for subjects with QTcF >450 msec.
The primary change occurs in Table 7.b
Exclusion Criteria.
Added text:The following exclusion criteria was added for all subjects:
Have a QTcF > 450 msec at Baseline.
Rationale for Change:
This standard exclusion criteria was inadvertently omitted during protocol development.
Change 5: Added section for pregnancy.
The primary change occurs in Section 9.1.13 Pregnancy:
Description 
of change:
A section was added to address pregnancy concerns as a pregnancy test on Day -1 was 
added.
Added text: 9.1.13 Pregnancy
Women of childbearing potential will not be included in this study. If any subject 
is found to be pregnant on Day -1, she should be withdrawn from the study.
Rationale for Change:
Additional routine precaution. 
Change 6: Added pregnancy test on Day -1.
The primary change occurs in Section 3.0 Schedule of Trial Procedures.
Description 
of change:
Urine pregnancy test (hCG) was added to the Day -1 Visit.
Section 9.2.1.1 Clinical Laboratory Tests also contains this change.
Rationale for Change:
Additional routine precaution.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 86 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Change 7: Revision of postmenopausal criteria for women.
The primary change occurs in Table 7.a
Inclusion Criteria (footnote a):
Initial 
wording:
–
Is a female subject with no childbearing potential, defined by at least 1 of the following criteria:

Postmenopausal (for healthy subjects defined as 12 months of spontaneous amenorrhea in 
females aged >45 years or approximately 6 months of spontaneous amenorrhea in females 
aged ≤45 years with serum FSH levels >40 mIU/mL and for renally impaired subjects defined 
as 12 months of spontaneous amenorrhea in females with serum FSH levels >40 mIU/mL). 
Appropriate documentation of FSH levels is required.
Amended 
or new 
wording:
–
Is a female subject with no childbearing potential, defined by at least 1 of the following criteria:

Postmenopausal (for healthy subjects defined as 12 months of amenorrhea without an 
alternative medical cause) in females aged >45 years or approximately 6 12 months of 
spontaneous amenorrhea in females aged ≤45 years with serum FSH levels >40 mIU/mL for 
healthy subjects and for renally impaired subjects defined as 12 months of spontaneous 
amenorrhea in females with serum FSH levels >40 mIU/mL for renally impaired subjects). 
Appropriate documentation of FSH levels is required.
Rationale for Change:
To align with criteria set in the Clinical Trial Facilitation Group “Recommendations related to 
contraception and pregnancy testing in clinical trials”.
Change 8: Removal of “legal representative” language.
The primary change occurs in Section 13.2 Subject Information, Informed Consent, and Subject 
Authorization. 
Deleted 
text:
The informed consent form, subject authorization form (if applicable), and subject 
information sheet (if applicable) must be written in a language fully comprehensible to 
the prospective subject. It is the responsibility of the investigator to explain the 
detailed elements of the informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of 
rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable 
laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the trial, and (2) decide whether or not to 
participate in the trial. If the subject, or the subject’s legally acceptable representative,
determines he or she will participate in the trial, then the informed consent form and 
subject authorization form (if applicable) must be signed and dated by the subject, or 
the subject’s legally acceptable representative, at the time of consent and before the 
subject entering into the trial. The subject or the subject’s legally acceptable 
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TAK-954
Study No. TAK-954-1007
Page 87 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the 
informed consent form and subject authorization (if applicable) at the time of consent 
and before subject entering into the trial; however, the sponsor may allow a designee 
of the investigator to sign to the extent permitted by applicable law.
Two copies of the informed consent are signed by the subject, 1 of which, along with 
the 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 
or the relevant subject’s legally acceptable representative in the same manner as the 
original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the 
revised informed consent form. 
Rationale for Change:
To further clarify that only subjects who are able to provide an informed consent and whose legal 
capacity is not restricted can participate in the clinical trial.
The following sections also contain this change:

Section 7.5 Criteria for Discontinuation or Withdrawal of a Subject. 

Appendix A
Responsibilities of the Investigator.

Appendix B
Elements of the Subject Informed Consent
Change 9: Addition of an exclusion criteria for subjects with legal incapacity or limited legal 
capacity.
The primary change occurs in Section 7.2 Exclusion Criteria.
Description 
of change:
Added exclusion criteria for all subjects: Have legal incapacity or limited legal 
capacity.
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TAK-954
Study No. TAK-954-1007
Page 88 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Rationale for Change:
To further clarify that only subjects who are able to provide an informed consent and whose legal 
capacity is not restricted can participate in the clinical trial.
Change 10: Pregnancy and contraception wording changed.
The primary change occurs in Appendix D
Pregnancy and Contraception.
Initial 
wording:
Female Subjects and Their Male Partners
Female subjects of childbearing potential are excluded from this trial; there are no 
requirements for contraception or pregnancy avoidance.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 
half-lives PLUS 90 days after the dose of trial drug, nonsterilized** male subjects who 
are sexually active with a female partner of childbearing potential must use barrier 
contraception (eg, condom with or without spermicidal cream or jelly). In addition, 
they must be advised not to donate sperm during this period. Women of childbearing 
potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective/effective contraception 
below.
Amended 
or new 
wording:
Female Subjects and Their Male Partners
Female subjects of childbearing potential are excluded from this trial; there are no 
requirements for contraception or pregnancy avoidance. If any subject is found to be 
pregnant during the study, she should be withdrawn from the study and any 
Takeda-supplied drug and should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study 30 days after the 
last dose should also be recorded following authorization from the subject’s 
partner. All pregnancies, including female partners of male subjects, in subjects 
on active study drug will be followed up to final outcome. The outcome of the 
pregnancy, including any premature termination, must be reported to the 
sponsor.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 
half-lives PLUS 90 30 days after the dose of trial drug, nonsterilized** male subjects 
who are sexually active with a female partner of childbearing potential must use 
barrier contraception (eg, condom with or without spermicidal cream or jelly). In 
addition, they must be advised not to donate sperm during this period. Women of 
childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective 
contraception below.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 89 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Rationale for Change:
1) Text added to further clarify dealing with pregnancy.
2) Period for male subjects to use barrier contraception: Given that TAK-954 did not exhibit 
genotoxic potential in the standard battery of genotoxicity assays and the short half-life, 30 days is 
considered acceptable. This is in line with the CTFG “Recommendations related to contraception 
and pregnancy testing in clinical trials” that only require contraception during treatment and until 
the end of relevant systemic exposure in the male subject plus a 90 day period in case of 
genotoxicity findings (and no additional time required in case of no genotoxicity).
The following sections also contain this change:

Table 7.a Inclusion Criteria (footnote a).

Appendix B
Elements of the Subject Informed Consent.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 90 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Change 11: Removal of waste dialysis fluid concentration sample collection and associated 
pharmacokinetic parameters.
The primary change occurs in Section 6.2.2.1 PK.
Initial 
wording:
The primary endpoint for this trial consists of standard PK variables (Cmax, AUClast, 
AUC72, and AUC∞, in plasma; Ae, fe, CLR in urine; and CLD and AeD in dialysate) to 
determine the PK of TAK-954 in renally-impaired subjects with matching healthy 
subjects.
If TAK-954 concentrations can be sufficiently measured in dialysate, the total AeD
should be determined and CLD calculated from the following equation:
CLD = Amount recovered/AUCt0-tl
where t0 marks the start time and tl the termination of the hemodialysis session. 
If TAK-954 concentrations cannot be measured in dialysate, other equations will be 
considered.
Amended 
or new 
wording:
The primary endpoint for this trial consists of standard PK variables (Cmax, AUClast, 
AUC72, and AUC∞, in plasma; Ae, fe, CLR in urine; and CLD and AeD in dialysate (as 
determined by extraction from blood) to determine the PK of TAK-954 in 
renally-impaired subjects with matching healthy subjects.
If TAK-954 concentrations can be sufficiently measured in dialysate, the total AeD
should be determined and CLD calculated from the following equation:
CLD = Amount recovered/AUCt0-tl
where t0 marks the start time and tl the termination of the hemodialysis session. 
If TAK-954 concentrations cannot be measured in dialysate, other equations will be 
considered.
In addition to dialysate clearance (CLD), other parameters may be calculated as 
appropriate and as described in the clinical pharmacology analysis plan (CPAP).
Rationale for Change:
Due to operational restrictions at the sites, a sample of waste dialysis for measurement of 
TAK-954 dialysate concentrations cannot be collected.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 91 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
The following sections also contain this change:

Section 1.0 TRIAL SUMMARY.

Section 3.0 Schedule of Trial Procedures.

Section 5.2.1 Primary Endpoint.

Section 6.1 Trial Design.

Table 9.a Primary Specimen Collections.

Section 9.3.1 PK Evaluations
Change 12 Added clarification that subjects who are anuric, urine laboratory tests may be 
conducted with a blood sample.
The primary change occurs in Section 9.2.1.1 Clinical Laboratory Tests:
Added text:For dialysis subjects who are anuric, the following tests will be conducted via a 
blood sample sample (results should be available before dosing if possible).
Rationale for Change:
Inadvertently omitted in the original protocol.
Change 13: Add further safety monitoring and measure with regards to potential risk of anemia 
(in particular in renal impaired subjects) due to blood withdrawals. 
The primary change occurs in Section 9.3 PK and PGx Samples.
Added text:Subjects' hemoglobin will be assessed within 10-14 days of last dose in order to 
ensure that subjects do not become anemic during the study due to the blood 
volume loss from repeated blood sampling, receiving the standard of care if 
needed.
Rationale for Change:
To address safety concerns of the Czech Competent Authority, additional safety monitoring was 
added.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 92 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Change 14: Blood collection timepoint for protein binding edited.
The primary change occurs in Section 3.0 Schedule of Trial Procedures.
Description 
of change:
Deleted sampling for protein binding for Groups A and C in Treatment 2.
Rationale for Change:
Erroneously included protein binding analysis for Groups A and C during Treatment 2.
Change 15: Removed the PK parameter of tmax.
The primary change occurs in Section 11.1.3 PK Analysis.
Deleted 
text:
Wilcoxon Rank Sum test will be used to compare tmax between each RI group and the 
normal renal function group.
Rationale for Change:
This was added in error in the original protocol.
Section 1.0 TRIAL SUMMARY also contains this change. 
Change 16 Added an exclusion criteria for subjects with hemoglobin levels ≤110 g/L at Screening 
for the Czech Republic site only.
The primary change occurs in Section 7.2 Exclusion Criteria:
Description 
of change:
An exclusion criteria for Groups B-E (Renally impaired subjects only) was added: 
Have hemoglobin level ≤110 g/L at Screening for the Czech Republic site only. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study No. TAK-954-1007
Page 93 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Rationale for Change:
An exclusion criteria was added at the request of the Czech Competent Authority.
The concern raised regards the potential risk of anemia in particular in subjects with compromised 
renal function due to blood volume loss form repeated blood sampling. To address the concern, 
further safety monitoring and safety measures were added to the protocol (see Change 13 Add 
further safety monitoring and measure with regards to potential risk of anemia (in particular in 
renal impaired subjects) due to blood withdrawals.). However, as the Czech Competent Authority 
specifically requested this exclusion criteria, it has been added to the Czech site.
Change 17: Additional vital sign measurements added.
Added information on cocktail drug administration.
The primary change occurs in Section 3.0 Schedule of Trial Procedures.
Description 
of change:
Added additional vital sign measurements. 
Rationale for Change:
Additional vital sign measurements were added to align with PK measurements to help further 
evaluate any potential tachycardia or hypotension. 
Change 18: Added information on cocktail drug administration.
The primary change occurs in Section 9.4 Trial Drug Administration.
Initial 
wording:
Eligible subjects in Groups A to D will be allocated to trial treatment by nonrandom 
assignment on Day 1 and will receive a single IV dose of 0.2 mg TAK-954 
administered as a 60-minute infusion approximately between 0600 and 0900. 
Subjects with ESRD requiring dialysis (Group E) will receive 2 single IV doses of
0.2 mg TAK-954 administered as a 60-minute infusion at approximately the same 
time between 0600 and 0900.
During Treatment 2, healthy subjects (Group A) and subjects with moderate RI 
(Group C) 
 
 
 
 
Subjects will continue to rest in a semirecumbent position from the time of dosing 
until 4 hours postdose or other trial-related procedure.
Property of Takeda: For non-commerc
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TAK-954
Study No. TAK-954-1007
Page 94 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Amended or 
new 
wording
TAK-954
Eligible subjects in Groups A to D will be allocated to trial treatment by nonrandom 
assignment on Day 1 and will receive a single IV dose of 0.2 mg TAK-954 
administered as a 60-minute infusion approximately between 0600 and 0900. 
Subjects with ESRD requiring dialysis (Group E) will receive 2 single IV doses of 0.2 
mg TAK-954 administered as a 60-minute infusion at approximately the same time 
between 0600 and 0900.
Subjects will continue to rest in a semirecumbent position from the time of dosing 
until 4 hours postdose except to stand for the measurement of standing vital signs (if 
needed) or other trial-related procedure.
Property of Take
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TAK-954
Study No. TAK-954-1007
Page 95 of 95
Protocol Incorporating Amendment No. 01
09 October 2017
Rationale for Change:
Added in response to the Czech Competent Authority requesting the information from the 
referenced study manual. There is no “Study manual” but a ”Pharmacy manual” instead.  The 
reference to a “Study manual” has been deleted and the relevant information for administration 
 
 has also been included.
Change 19 Added exclusion criteria based on bilirubin levels.:
The primary change occurs in Section 7.2 Exclusion Criteria.
Added text:Added the following exclusion criteria for healthy subjects: Have bilirubin levels 
above 1.5 times the ULN at Screening or Day -1.
Rationale for Change:
Standard exclusion criteria inadvertently omitted in initial protocol version. 
Change 20: Added exclusion criteria for restricted concomitant medications.
The primary change occurs in Section 7.2 Exclusion Criteria.
Description 
of change:
Added an exclusion criteria for Groups B through E: Are unable to refrain from or 
anticipates the use of:
!
strong CYP3A4 inhibitors or inducers 
!
CYP1A2 inhibitors or inducers (Group C only)
!
serotonin agonists or antagonists
!
monoamine oxidase inhibitors
!
noradrenergic agonists
!
selective serotonin reuptake inhibitors
!
gamma—aminobutyric acid antagonists
!
N-methyl-D-aspartate receptor antagonists
beginning approximately 7 days before administration of the trial drug, 
throughout the trial (including washout intervals between trial periods), until 
the Follow-up Visit.
Rationale for Change:
Restricted concomitant medications (in Section 7.3 Excluded Medications, Supplements, and 
Dietary Products and others added to minimize the risk of serotonin syndrome) were inadvertently 
omitted from exclusion criteria in the original protocol.
Section 7.3 Excluded Medications, Supplements, and Dietary Products also contains this change.
Property of Takeda: For non-commercial use only a
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal Impairment 
and Dialysis Treatment on the Pharmacokinetics of a Single Intravenous Dose of TAK-954
NCT Number: NCT03296787
SAP Approve Date: 12 December 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-954-1007
A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal Impairment and 
Dialysis Treatment on the Pharmacokinetics of a Single Intravenous Dose of TAK-954
PHASE 1
Version: Final
Date: 12 December 2018
Prepared by:
Based on:
Protocol Version: Amendment 1
Protocol Date: 09 October 2017
Property of Takeda: F
mmercial use only and subject to the applicable Terms of Use
t of Ren
t of Ren
avenous 
venous
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Fin
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ece
:
Proto
Prot
P
PPD


TAK-954-1007
Page 2 of 27
Statistical Analysis Plan {Final}
12 December 2018
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Study Title:
A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal 
Impairment and Dialysis Treatment on the Pharmacokinetics of a Single 
Intravenous Dose of TAK-954
Approvals:
Date
Date
Date
Date
Property of Takeda: For 
e applicable Terms of Use
t of Ren
t of R
f a Singl
a Sing
PPD


TAK-954-1007
Page 3 of 27
Statistical Analysis Plan {Final}
12 December 2018
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Appendices....................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1.1
Primary Endpoints .............................................................................................10
5.1.2
Safety Endpoints................................................................................................10
5.1.3
Exploratory Endpoints .......................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Study Definitions ...............................................................................................13
7.1.2
Definition of Study Days....................................................................................13
7.1.3
Definition of Study Visit Windows ....................................................................13
7.1.4
Conventions for Missing Adverse Event Dates...................................................13
7.1.5
Conventions for Missing Concomitant Medication Dates...................................13
7.1.6
Conventions for Missing Data............................................................................13
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................15
7.8.1
Primary Efficacy Endpoint(s).............................................................................15
7.8.2
Secondary Efficacy Endpoint(s).........................................................................15
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................16
7.9.1
Pharmacokinetic Analysis ..................................................................................16
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Page 4 of 27
Statistical Analysis Plan {Final}
12 December 2018
7.9.2
Pharmacodynamic Analysis ...............................................................................19
7.10
PGx Measurement ...................................................................................................19
7.11
Safety Analysis........................................................................................................19
7.11.1 Adverse Events ..................................................................................................20
7.11.2 Clinical Laboratory Evaluations .........................................................................21
7.11.3 Vital Signs .........................................................................................................21
7.11.4 12-Lead ECGs ...................................................................................................22
7.11.5 Physical Examinations .......................................................................................22
7.12
Interim Analysis ......................................................................................................22
7.13
Changes in the Statistical Analysis Plan...................................................................22
8.0
REFERENCES..............................................................................................................23
LIST OF IN-TEXT APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................24
Appendix B
Criteria for Identification of Markedly Abnormal Vital Signs.............................26
Appendix C
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters ......27
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TAK-954-1007
Page 5 of 27
Statistical Analysis Plan {Final}
12 December 2018
3.0
LIST OF ABBREVIATIONS
5-HT4
serotonin type 4
β-hCG
β–human chorionic gonadotropin
AE
adverse event
Ae
amount of drug excreted in urine
Aet
amount of drug excreted in urine from time 0 to time t
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC72
area under the plasma concentration-time curve from time 0 to 72 hours
AUClast
area under the plasma concentration-time curve from time 0 to the last measurable time 
point.
AUCt
area under the plasma concentration-time curve from time 0 to time t.
AUC∞
area under the plasma concentration-time curve from time 0 to infinity.
BMI
body mass index
CFR
Code of Federal Regulations
CG
Cockcroft and Gault
CL
Total clearance after IV administration, calculated using the observed value of the last 
quantifiable concentration
CLcr
creatinine clearance
CLD
dialysis clearance
CLR
renal clearance
Cmax
maximum observed plasma concentration
CRU
clinical research unit
CT
computed tomography
CV
coefficient of variation
CYP
cytochrome P-450
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
EFI
enteral feeding intolerance
EMA
European Medicines Agency
ESRD
end stage renal disease
fe
fraction of drug excreted in urine
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
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TAK-954-1007
Page 6 of 27
Statistical Analysis Plan {Final}
12 December 2018
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RI
renal impairment
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
Vz
volume of distribution during the terminal disposition phase after intravenous 
administration, calculated using the observed value of the last quantifiable concentration
WBC
white blood cell
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TAK-954-1007
Page 7 of 27
Statistical Analysis Plan {Final}
12 December 2018
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives of the trial are to evaluate the effect of varying degrees of renal function 
on the PK of TAK-954 following single-dose IV administration and to investigate the impact of 
hemodialysis on the PK of single IV doses of TAK-954.
4.2
Secondary Objectives
To evaluate the safety and tolerability of TAK-954 following single-dose IV administration in 
subjects with varying degrees of renal function.
4.3
Additional Objectives
Not applicable.
4.4
Study Design
This is a phase 1, open-label, parallel group trial in subjects with normal renal function as well as 
subjects with mild, moderate, and severe renal impairment (RI) and end stage renal disease 
(ESRD) as defined in the table below.
Group
Description of Subjects
Estimated Creatinine 
Clearance (CLcr) Range 
(mL/min)
Treatment Regimen
A
Normal renal function (healthy)
≥90
Treatment 1: 0.2 mg TAK-954
Treatment 2: 
B
Mild RI
60-<90
Treatment 1: 0.2 mg TAK-954
C
Moderate RI
30-<60
Treatment 1: 0.2 mg TAK-954
Treatment 2: 
D
Severe or ESRD not requiring 
dialysis
<30
Treatment 1: 0.2mg TAK-954
E
ESRD requiring dialysis
<15
Period 1:
0.2 mg TAK-954 (1 hour after 
dialysis)
Period 2: 
0.2 mg TAK-954 (2 hours before 
dialysis)
At the Screening Visit, for baseline categorization purposes, subjects will be stratified into 
groups by the degree of RI calculated using the Cockcroft and Gault (CG) equation below:
CLcr (mL /min ) = [140 −age (years)] • total body weight (kg) • (0.85 for females)
72 • serum creatinine (mg/dL)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-954-1007
Page 8 of 27
Statistical Analysis Plan {Final}
12 December 2018
Subjects will receive a single dose of 0.2 mg TAK-954 administered as a 60-minute intravenous 
(IV) infusion. For standardization purpose, trial drugs will be administered following an 8-hour 
fast. For Groups A (healthy), C (moderate RI), and E (ESRD with dialysis), the trial will include 
a Screening Visit, 2 treatment periods, and a Follow-up Visit. For Groups B (mild RI) and D 
(severe RI or ESRD not requiring dialysis), the trial will include a Screening Visit, 1 treatment 
period, and a Follow-up Visit.
Enrollment will be staggered, beginning with moderate RI (Group C) and severe RI or ESRD not 
requiring dialysis (Group D) subjects. The enrollment of healthy subjects (Group A) will begin 
after approximately 25% of the subjects from moderate and/or subjects with severe RI or ESRD 
not requiring dialysis have been enrolled. The enrollment of mild RI subjects (Group B) and 
subjects with ESRD requiring dialysis (Group E) will depend on available safety and 
pharmacokinetic (PK) data from subjects with moderate RI (Group C) and severe RI or ESRD 
not requiring dialysis (Group D). Takeda personnel and the investigators will review safety and 
PK data from the subjects with moderate RI and severe RI or ESRD not requiring dialysis and 
confirm or modify the TAK-954 dose and decide whether or not to enroll subjects with mild RI 
and/or subjects requiring dialysis. Additional healthy subjects may be enrolled if necessary.
Healthy (Group A) and moderate RI (Group C) subjects:
Healthy and moderate RI subjects will receive a single dose of TAK-954 0.2 mg (Treatment 1). 
Blood samples for the assessment of TAK 954 and its metabolites will be collected before the 
start of the TAK 954 infusion and through 120 hours after the start of the infusion. TAK-954 and 
its metabolites will be assayed in urine. Plasma protein binding of TAK 954 will also be 
assessed. 
 
 
 
 
 
For Treatment 1, subjects will be confined from Day -1 until the completion of the last PK 
sample collection on the morning of Day 3, or at the discretion of the investigator. For Treatment 
2, subjects will be confined from Day -1 until completion of the last PK sample collection on the 
morning of Day 2. After completion of the trial (or following subject withdrawal), all subjects 
will return for a follow-up visit, 10 to 14 days after their last dose of trial drug.
Mild RI (Group B) and severe RI or ESRD not requiring dialysis (Group D):
Subjects with mild RI (if enrolled) and severe RI or ESRD not requiring dialysis will receive a 
single dose of TAK-954 0.2 mg (Treatment 1). Blood samples for the assessment of TAK 954 
and its metabolites will be collected before the start of the TAK 954 infusion and through 120 
hours after the start of the infusion. TAK-954 and its metabolites will be assayed in urine. 
Plasma protein binding of TAK 954 will also be assessed. 
For Treatment 1, subjects will be confined from Day -1 until the completion of the last PK 
sample collection on the morning of Day 3, or at the discretion of the investigator. After 
Property of Takeda: For non-c
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TAK-954-1007
Page 9 of 27
Statistical Analysis Plan {Final}
12 December 2018
completion of the trial (or following subject withdrawal), all subjects will return for a follow-up 
visit, 10 to 14 days after their last dose of trial drug.
Subjects with ESRD requiring dialysis (Group E):
For subjects requiring dialysis, the trial will consist of 2 treatment periods. In Period 1, subjects 
will receive TAK-954 1 hour after the end of hemodialysis. In Period 2, subjects will receive 
TAK-954 2 hours before the start of a standard 4-hour of hemodialysis. In both periods, blood 
samples for the assessment of TAK 954 and its metabolites will be collected before the start of 
the infusion and through 72 hours after the start of the infusion. Urine will be collected for 24 
hours for the determination of TAK-954 and its metabolites, provided the subject is not anuric. 
Plasma protein binding of TAK 954 will also be assessed. All PK blood samples must be 
collected before the start of subjects’ next hemodialysis session. 
For Period 2, samples from the dialysis fluid (dialysate) and blood will be obtained 
simultaneously immediately after start of dialysis, during dialysis, and end of dialysis from 
arterial and venous lines to the dialyzer. The 2 treatment periods will be separated by a minimum 
of 13 days from Day 1 in Period 1 and Day 1 of Period 2.
The total volume of dialysate used in the dialysis should be recorded. Blood flow, dialysate flow 
during the dialysis, the make and model of the dialyzer, and type of dialysis membrane (high-
flux, low-flux) should be recorded. 
Subjects will be confined from Day -1 until after the last PK sample collection on the morning of 
Day 3 for both Periods 1 and 2, or at the discretion of the investigator. After completion of the 
trial (or following subject withdrawal), all subjects will return for a follow-up visit, 10 to 14 days 
after their last dose of trial drug.
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TAK-954-1007
Page 10 of 27
Statistical Analysis Plan {Final}
12 December 2018
5.0
ANALYSIS ENDPOINTS
5.1.1
Primary Endpoints
The primary endpoints of the trial will include the following:
Plasma PK parameters will be collected predose and up to 120 hours postdose:
!
Cmax.
!
Area under the plasma concentration-time curve from time 0 to 72 hours (AUC72).
!
Area under the plasma concentration-time curve from time 0 to the last measurable time 
point, (AUClast).
!
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞).
Urine PK parameters will be collected predose and up to 24 hours postdose:
!
Amount of drug excreted in urine (Ae).
!
Fraction of drug excreted in urine (fe).
!
Renal clearance (CLR).
Dialysate PK concentrations will be collected predose and up to 4 hours postdose:
!
Dialysate clearance (CLD).
5.1.2
Safety Endpoints
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and 
laboratory assessments, and collection of spontaneous AEs.
5.1.3
Exploratory Endpoints
commercial use only and subject to the applicable Terms of Use
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Page 11 of 27
Statistical Analysis Plan {Final}
12 December 2018
Property of Takeda: For non-commercial use only and subject to 
of Use
CCI


TAK-954-1007
Page 12 of 27
Statistical Analysis Plan {Final}
12 December 2018
6.0
DETERMINATION OF SAMPLE SIZE
The planned sample size of 8 subjects in each renal function group is in line with regulatory 
guidance for these types of studies (“Food and Drug Administration Guidance for Industry 
Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and 
Impact on Dosing and Labeling” and “European Medicines Agency Guideline on the Evaluation 
of the PK of Medicinal Products in Patients with Impaired Renal Function”).
Subjects who drop out may be replaced at the discretion of the investigators in consultation with 
the sponsor.
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TAK-954-1007
Page 13 of 27
Statistical Analysis Plan {Final}
12 December 2018
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percent of subjects for each category, where appropriate.
Unless otherwise stated, baseline value is defined as the last observed value before the first dose 
of study medication.
All data analyses and figures will be generated using SAS System® Version 9.4 or higher.
7.1.1
Study Definitions
There are no study-specific definitions.
7.1.2
Definition of Study Days
Study day will be calculated relative to the date of the first dose of the study drug. Study days
prior to the first dose of study drug will be calculated as: {date of assessment/event – date of first 
dose of study drug of the subject}. Study days on or after the first dose of study drug will be 
calculated as: {date of assessment/event – date of first dose of study drug of the subject + 1}.
7.1.3
Definition of Study Visit Windows
There will be no visit windows.
7.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.
7.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.
7.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 
7.2
Analysis Sets
Safety set
The safety set will consist of all subjects who are enrolled and receive at least 1 dose of trial 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics, and 
safety summaries.
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TAK-954-1007
Page 14 of 27
Statistical Analysis Plan {Final}
12 December 2018
PK Set
The PK set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug 
and have at least 1 measurable TAK-954 plasma concentration. All subjects with valid PK 
parameter estimates will be included in the summaries and analyses for that parameter.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in 
the PK analyses; however, data for all subjects will be presented in the data listings.
7.3
Disposition of Subjects
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data.
Summaries will be presented by renal impairment group and overall.
Disposition of all enrolled subjects will be tabulated by renal impairment group and overall:

All subjects received at least one dose of study drug (denominator).

Subjects who completed the study drug.

Subjects who prematurely discontinued study drug.

Subjects who completed all study visits.

Subjects who prematurely discontinued study visits.
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. Reasons for premature discontinuation of study drug/study visit 
will be presented for each subject in listings. 
Disposition of screen failure subjects will be summarized descriptively. Primary reasons for 
failure will be summarized and will be presented in a data listing.
Significant protocol deviations will be listed and summarized. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized using the safety set by renal 
impairment group.
Summary statistics will be presented for continuous variables (age, height, weight, and body 
mass index [BMI]). The number and percentage subjects within each category will be presented 
for categorical variables (for example, gender, race, etc.). Creatinine clearance and eGFR values 
will also be summarized.
Individual subject demographic and baseline characteristic data will be listed.
Demographic variables of screen failure subjects will be summarized overall for subjects who 
are screened but not enrolled in the study.
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TAK-954-1007
Page 15 of 27
Statistical Analysis Plan {Final}
12 December 2018
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 18 or higher) coding system. 
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Concurrent medical conditions are 
those significant ongoing conditions or diseases present at signing of informed consent.
All medical history and concurrent medical condition data will be listed by site (study center) 
and subject number. The listing will contain subject identifier, renal impairment group, system 
organ class (SOC), preferred term (PT), whether there was any medical history or concurrent 
condition, and, if yes, a detail of the medical history or concurrent condition. No inferential 
statistics will be presented.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medications are recorded on 
the eCRF and include any medications, other than study drug, taken at any time between 
informed consent and the end of the study. 
All medication history and concomitant medications will be listed by site (study center) and 
subject number. The listings will contain subject identifier, renal impairment group, World 
Health Organization Drug Dictionary (WHODrug) preferred medication name, dose, unit, 
frequency, route, start date, stop date, whether the medication was ongoing, and reason for use. 
No inferential statistics will be presented. 
Medication history and concomitant medications will be coded using the WHODrug Version 
01March 2015 or higher.
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in a data listing. Summaries of 
TAK-954 PK concentration data will be provided (See Section 7.9.1). No other summary 
statistics for the extent of exposure to study drug or compliance calculations will be performed 
for this study.
7.8
Efficacy Analysis
Not applicable.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable.
7.8.2
Secondary Efficacy Endpoint(s)
Not applicable.
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Page 16 of 27
Statistical Analysis Plan {Final}
12 December 2018
7.9
Pharmacokinetic/Pharmacodynamic Analysis
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero in 
the summarization of concentration values and derivation of PK parameters. These values will be 
flagged in the data listings and deviations from this convention may be considered on a case-by-
case basis as deemed appropriate.
7.9.1
Pharmacokinetic Analysis
The PK set will be used for all summaries of PK data. Summaries will be provided by renal 
function group using Cockcroft-Gault formula (CLcr) and Modification of Diet in Renal Disease 
formula (eGFR).
Cockcroft and Gault (CG) equation:
CLcr (mL /min ) = [140 −age (years)] • total body weight (kg) • (0.85 for females)
72 • serum creatinine (mg/dL)
Modification of Diet in Renal Disease equation:
eGFR (mL/min/1.73 m2) = 175 x (Scr,std)-1.154 x (age)-0.203 x (0.742 if female) x (1.212 if African 
American),
where Scr,std is serum creatinine measured with a standardized assay.
7.9.1.1
Pharmacokinetic Concentrations
Samples for PK analysis will be collected as specified in the Schedule of Trial Procedures (see 
Section 3.0 in Protocol). 
7.9.1.2
Summary of Concentrations in Plasma, Urine and Dialysate
For each renal impairment group (Group A-D), descriptive statistics (number of subjects (N), 
mean, standard deviation (SD), standard error (SE), coefficient of variation (%CV), minimum, 
median, and maximum) will be used to summarize the plasma (total and free for TAK-954 only), 
urine concentrations of TAK-954 and any measured metabolites by collection timepoint. 
For Group E (ESRD requiring dialysis), descriptive statistics (number of subjects (N), mean, 
standard deviation (SD), standard error (SE), coefficient of variation (%CV), minimum, median, 
and maximum) will be summarized for the plasma (total and free, arterial and venous for TAK-
954), urine and dialysis fluid sample concentrations of TAK-954 and volume of urine collected 
and any measured metabolites at each collection timepoint by treatment period. Individual 
plasma concentrations of TAK-954 (total and free, arterial and venous), dialysate concentrations 
of TAK-954 and any measured metabolites at each scheduled sampling time and volume of urine 
collected and amounts of TAK-954 and any measured metabolites (if available) excreted in urine 
at each scheduled sampling interval will be presented in listings.
For Group A (healthy) and Group C (moderate RI), subjects 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-954-1007
Page 17 of 27
Statistical Analysis Plan {Final}
12 December 2018
7.9.1.3
Pharmacokinetics Parameters 
The PK parameters of TAK-954 
 will be derived using noncompartmental 
analysis methods and will be determined from the concentration-time data for all evaluable 
subjects. Actual sampling times, rather than scheduled sampling times, will be used in all PK 
computations involving sampling times. A more detailed description will be given in the CPAP.
The following PK parameters for TAK-954 will be calculated:
Plasma PK parameters (free and total):
!
Cmax.
!
AUC72.
!
AUClast.
!
AUC∞.
!
t1/2z.
!
CL.
!
Vz.
Urine PK parameters:
!
Aelast.
!
fe.
!
CLR.
Dialysate PK parameters:
!
CLD.
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TAK-954-1007
Page 18 of 27
Statistical Analysis Plan {Final}
12 December 2018
Descriptive statistics (N, mean, SD, SE, %CV, median, minimum, and maximum) will be used to 
summarize the plasma (for both free and total), urine, and dialysate (for Group E) PK parameters 
for TAK-954 and its measured metabolites by renal impairment group. In addition, geometric 
means will be computed for AUC72, AUClast, AUC∞, and Cmax. Individual plasma (both free and 
total for TAK-954), urine and dialysate PK parameters will be presented in a data listing.
For Group A (healthy) and Group C (moderate RI), descriptive statistics (N, mean, SD, SE, 
%CV, median, minimum, and maximum) will also be used to summarize the plasma and urine 
PK parameters
 
 In addition, geometric means will be computed for 
AUClast, AUC∞, and Cmax. Individual plasma and urine PK parameters will also be presented in a 
data listing.
Additionally, for each renal impairment group (Group A-E), descriptive statistics (number of 
subjects (N), mean, SD, SE, %CV, minimum, median, and maximum) will be used to summarize 
the plasma protein binding (concentration data from donor (plasma) side and receiver (dialysate) 
side, % unbound, % bound, and % recovery) of TAK-954. Individual plasma protein binding of 
TAK-954 will be presented in listings.
 
All pharmacokinetic parameters estimated will be provided in a listing.
7.9.1.4
Evaluating the Effect of Varying Renal Function on TAK-954 Pharmacokinetics
Regression models will be used to evaluate the relationship between renal function and the 
following PK parameters of TAK-954 and its metabolites: Cmax, AUC72, AUClast, AUC∞, CL 
(total and free) and CLR, tmax and λz. Two separate models will be performed: one with CLcr as 
the renal function included in the model as the independent continuous variable, and one with 
eGFR as the renal function included in the model as the independent continuous variable. 
Analysis will be performed using the first period data with and without Group E (ESRD 
requiring dialysis) subjects. Linear and quadratic regressions will be performed. If the quadratic 
term is not statistically significant, then linear regression will be the final model.
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TAK-954-1007
Page 19 of 27
Statistical Analysis Plan {Final}
12 December 2018
The results from regression model will be presented in table (parameter estimates, standard error, 
overall p-value, and R-squares). Predicted value of the PK parameters of TAK-954 and its 
associated 95% CI in each renal impairment group will be presented in the table. Scatter plots of 
TAK-954 PK parameters, Cmax, AUC72, AUClast, AUC∞, CL (total and free) and CLR and its 
metabolites will be plotted against CLcr, and eGFR. Regression line and 95% CI will be 
presented on the graphs.
To evaluate the effect of renal impairment on the PK of TAK-954 and any measured metabolites, 
an analysis of variance (ANOVA) with renal function group as a fixed effect will be performed 
on t1/2 and the natural logarithms of AUCt, AUC72, AUC∞, Cmax, CL and CLR for TAK-954 and 
any measured metabolites. Within the ANOVA framework, comparisons of each renal 
impairment group versus the normal renal function group will be made using appropriate 
contrast statements.
Additional pharmacokinetic analysis will be performed if appropriate.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
PGx Measurement
Subject must sign a PGx informed consent/be consented in order for sampling of whole blood for 
PGx analysis to occur. PGx sampling is optional.
PGx is the study of variations of DNA and RNA characteristics as related to drug response. 
There is increasing evidence that an individual’s genetic background may impact the PK 
(absorption, distribution, metabolism, and excretion), PD (pharmacologic effects), and/or the 
clinical outcome (efficacy and/or safety).
Whole blood samples for DNA and RNA isolation will be collected from each consented subject 
in the trial, and will be listed in the data listings, if collected.
7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory parameters, vital sign parameters, 12-lead ECG 
results, and other safety parameters. The safety set will be used for all summaries of safety 
parameters. The safety endpoints will be presented by regimen related to TAK-954 only in each 
renal impairment group.
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TAK-954-1007
Page 20 of 27
Statistical Analysis Plan {Final}
12 December 2018
7.11.1 Adverse Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study, but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. PTE and AE verbatim terms will be coded by SOC and PT using MedDRA (version 
19 or later).
TEAEs will be defined as any sign, symptom, syndrome, or new illness, regardless of 
relationship to study drug, that occur after the first dose of study drug and up to 30 days (onset 
date – last date of dose + 1 ≤30) after the last dose of study drug or early termination.
TEAEs are recorded in the eCRF as being related or not related to study drug and study 
procedure. TEAEs that are recorded as related to study drug and/or study procedure will be 
summarized separately. TEAEs will also be presented by intensity/severity (mild, moderate, and 
severe). Serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to 
death will also be summarized using SOC and PT. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
In general, AEs will be tabulated at the following levels: overall summary (subjects with at least 
1 AE in any dose or regimen), the MedDRA SOC, and the MedDRA PT. The tables will include 
the number and percentage (N[%]) of subjects. The following summary tables will be generated: 

Overview of Treatment-Emergent Adverse Events.

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.

Treatment-Emergent Adverse Events by Preferred Term.

Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.

Most Frequent (>5% or >=2 subjects) Non-Serious Adverse Events by Preferred Term.

Most Frequent (>5% or >=2 subjects) Non-Serious Adverse Events by System Organ Class 
and Preferred Term.

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term.
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TAK-954-1007
Page 21 of 27
Statistical Analysis Plan {Final}
12 December 2018

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.

Drug-Related Treatment-Emergent Adverse Events by Preferred Term.

Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.

Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term.

Pretreatment Adverse Events by System Organ Class and Preferred Term.
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
SAEs, and AEs that resulted in death.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. 
All laboratory test parameters will be displayed in individual subject data listings in SI units (and 
conventional (CV) units, if available). For test results not in SI units, the conversion to SI units 
will be done in derived analysis data sets using the known conversion factors. If necessary, SI 
units from the central laboratory may be converted to Takeda’s preferred SI units in the derived 
dataset. All summaries and analyses will be based on the values using these preferred SI units.
Only observations within 14 days of the last dose of study drug will be included in the tables. No 
inferential statistics will be presented unless otherwise stated. List of all the clinical laboratory 
evaluations can be found in Protocol Section 9.2.1.1.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values will be presented by renal function groups. Study baseline will be 
used for change from baseline. Note that “character” urinalysis tests will only be listed.
Listings of all clinical safety laboratory data will be provided in the listings and will be presented 
in SI units (and CV units, if available). Laboratory data outside of the normal reference range 
will be indicated in the listings. In addition, MAVs, identified by the criteria defined in Appendix 
A, will be flagged.
7.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Only observations within 7 days of the study drug will be included in 
the tables. For each vital sign variable, boxplots for predose/postdose values and the change from 
the predose by renal impairment group will be prepared.
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TAK-954-1007
Page 22 of 27
Statistical Analysis Plan {Final}
12 December 2018
Vital sign MAVs, identified by the criteria defined in Appendix B, will be listed. If a subject has 
a MAV for a particular vital signs parameter, all visits for that subject for that parameter will be 
listed. All observations, including ones at unscheduled visits, will be included in the MAV 
evaluation.
Listings of all vital signs data will be provided in the listings, and vital sign MAVs will be 
flagged. 
7.11.4 12-Lead ECGs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters, 
including heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc interval 
(Fredericia’s correction, will be presented for baseline, each post-baseline visit, and change from 
baseline to each post-baseline visit. Only the scheduled measurements will be included in the 
summary. Only observations within 7 days of the study drug will be included in the tables. No 
inferential statistics will be presented.
ECG MAVs, identified by the criteria defined in Appendix C, will be listed. If a subject has a 
MAV for a particular 12-lead ECG parameter, all visits for that subject for that parameter will be 
listed. All observations, including ones at unscheduled visits, will be included in the MAV 
evaluation.
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant) is collected by eCRF at baseline and at each scheduled post-baseline visit. 
Shifts in ECG interpretation will be presented as cross-tabulations (baseline versus each post-
baseline visit) of numbers of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant interpretations with missing, if applicable, and total categories by 
regimen.
Listings of all 12-lead ECG data will be provided in listings, and MAVs will be flagged.
7.11.5 Physical Examinations
Physical examination findings will be presented in the data listings. No summary tables will be 
provided.
7.12
Interim Analysis
No interim analysis is planned. 
7.13
Changes in the Statistical Analysis Plan 
No changes.
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TAK-954-1007
Page 23 of 27
Statistical Analysis Plan {Final}
12 December 2018
8.0
REFERENCES
1. A Phase 1, Open-Label, Parallel Group Trial to Evaluate the Effect of Renal Impairment and 
Dialysis Treatment on the Pharmacokinetics of a Single Intravenous Dose of TAK-954, 
Takeda Development Center Europe, Ltd., Protocol Amendment 1, No. TAK-954-1007,
dated 9 October, 2017.
2. Guidance for Industry “Pharmacokinetics in Patients with Impaired Renal Function”, FDA, 
March 2010, Rev. (Draft).
3. Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with 
Decreased Renal Function, EMA, August 2014.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954-1007
Page 24 of 27
Statistical Analysis Plan {Final}
12 December 2018
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 × LLN
>1.5 × ULN
Platelet count
Conventional
<100 × 103/L
>450 × 103/L
SI
<100 × 109/L
>450 × 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry – Criteria for Markedly Abnormal Values (SI units)
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3 × ULN
AST
Both
--
>3 × ULN
GGT
Both
--
>2.5 x ULN if baseline was normal; 
> 2.5 x baseline if baseline was 
abnormal
Alkaline phosphatase
Both
--
>2.5 x ULN if baseline was normal; 
>2.5 x baseline if baseline was 
abnormal
Calcium (corrected)
Conventional
Corrected serum calcium 
of <LLN - 8.0 mg/dL; 
<LLN - 2.0 mmol/L; 
Ionized calcium <LLN -
1.0 mmol/L
Corrected serum calcium of >ULN 
- 11.5 mg/dL; >ULN - 2.9 mmol/L; 
Ionized calcium >ULN - 1.5 
mmol/L
SI
<1.75 mmol/L
>2.88 mmol/L
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
Total bilirubin
Conventional
--
>ULN - 1.5 x ULN if baseline was 
normal; > 1.0 - 1.5 x baseline if 
baseline was abnormal
SI
--
>34.2 mol/L
Albumin
Conventional 
<LLN - 3 g/dL; <LLN - 30 
g/L
--
SI 
<25 g/L
--
Total protein
Both
<0.8 × LLN
>1.2 × ULN
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>5.5 mEq/L
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TAK-954-1007
Page 25 of 27
Statistical Analysis Plan {Final}
12 December 2018
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
<LLN - 55 mg/dL
>180 mg/dL
SI
<LLN - 3.0 mmol/L
>10 mmol/L
Bicarbonate
Conventional
<8.0 mEq/L
--
SI
<8.0 mmol/L
--
Creatine kinase
Conventional
--
>ULN - 2.5 x ULN
SI
--
>ULN - 2.5 x ULN
Total Cholesterol
Conventional
--
>300 mg/dL
SI
--
>7.72 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.
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TAK-954-1007
Page 26 of 27
Statistical Analysis Plan {Final}
12 December 2018
Appendix B
Criteria for Identification of Markedly Abnormal Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Heart Rate
bpm
<60 
>120
Systolic blood pressure
mm Hg
<90
>140 
Diastolic blood pressure
mm Hg
<60
>90
Body temperature
oC
<35.6
>37.7
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TAK-954-1007
Page 27 of 27
Statistical Analysis Plan {Final}
12 December 2018
Appendix C
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters
Parameter
Unit
Lower Criteria
Upper Criteria
HR
bpm
<60
>120 
PR-interval
msec
≤80
≥200
QRS-interval
msec
≤80
≥120
QTcF-interval
msec
≥500 OR
≥30 change from baseline and
≥450 
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