Clinical trial NCT03277274
Conditions: Hepatic Impairment Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2017-11-09; Completion date: 2018-09-10
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the effect of varying degrees of hepatic function on the single dose PK of IV TAK-954.

Detailed description:
The drug being tested in this study is called TAK-954. This study will evaluate the safety and tolerability of single intravenous doses of TAK-954 in participants with varying degrees of hepatic function.

The study will enroll approximately up to 32 participants. Participants will be enrolled in one of the 4 treatment groups based on their degree of hepatic impairment which will be determined based on Child-Pugh Score as follow:

* Group 1 TAK-954 0.2 mg: Mild Hepatic Impairment (Child Pugh Class A)
* Group 2 TAK-954 0.2 mg: Moderate Hepatic Impairment (Child Pugh Class B)
* Group 3 TAK-954 0.2 mg: Severe Hepatic Impairment (Child Pugh Class C)
* Group 4 TAK-954 0.2 mg: Healthy Participants

The Child-Pugh classification will assess the severity of 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy grade) on a scale of 1 (none) to 3 (moderate). Total hepatic impairment score ranges from 5 (mild) to 15 (severe) where higher score indicates more severity.

All participants will receive a single dose of TAK-954 0.2 mg on Day 1.

This study may have a full study design, where Group 1 to Group 4 will enroll approximately 8 participants in each group or a reduced study design, where no participants will be enrolled in Group 1 and approximately 8 participants will be enrolled in Group 2 to Group 4.

This multi-center trial will be conducted in Czech Republic and Slovakia. The overall time to participate in this study is approximately 7 weeks. Participants will remain confined to the clinic for 4 days, with 2 further out-patient visits, and will make a final visit to the clinic 10-14 days after receiving their last dose of TAK-954 for a follow-up assessment.

Arms: arm 1: TAK-954 0.2 milligram (mg), intravenous, administered as 60-minute infusion, once on Day 1. arm 2: TAK-954 0.2 mg, intravenous, administered as 60-minute infusion, once on Day 1. arm 3: TAK-954 0.2 mg, intravenous, administered as 60-minute infusion, once on Day 1. arm 4: TAK-954 0.2 mg, intravenous, administered as 60-minute infusion, once on Day 1.
Interventions: intervention 1: TAK-954
Intervention descriptions: intervention 1: TAK-954 intravenous infusion.

Protocol documents:
Prot_000.pdf: 


•
Title: A Phase 1, Nonrandomized, Open-Label Trial to Evaluate the Effect of Hepatic Impairment 
on the Single Dose Pharmacokinetics of Intravenous TAK-954
NCT Number: NCT03277274
Protocol Approve Date: 06 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, Nonrandomized, Open-Label Trial to Evaluate the Effect of Hepatic Impairment 
on the Single Dose Pharmacokinetics of Intravenous TAK-954
Sponsor:
Takeda Development Center Americas, Inc. 
Takeda Development Centre Europe Ltd.
Trial Number:
TAK-954-1006
Compound:
TAK-954
Date:
06 October 2017
Version/Amendment 
Number:
01
Amendment History: 
Date
Amendment Number
Amendment Type (for 
regional European purposes 
only)
Region
23 May 2017
Initial version
Not applicable
Global
06 October 2017
01
Non-substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the trial.


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TABLE OF CONTENTS
1.0
TRIAL SUMMARY........................................................................................................6
1.1
Protocol Amendment 01 Summary of Changes ..........................................................9
2.0
TRIAL SCHEMATIC ...................................................................................................10
3.0
SCHEDULE OF TRIAL PROCEDURES......................................................................11
4.0
INTRODUCTION.........................................................................................................13
4.1
Background .............................................................................................................13
4.2
Rationale for the Proposed Trial...............................................................................14
4.3
Benefit/Risk Profile .................................................................................................14
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................16
5.1
Objectives................................................................................................................16
5.1.1
Primary Objective............................................................................................16
5.1.2
Secondary Objective........................................................................................16
5.1.3
Exploratory Objectives ....................................................................................16
5.2
Endpoints.................................................................................................................16
5.2.1
Primary Endpoint.............................................................................................16
5.2.2
Safety Endpoints..............................................................................................16
5.2.3
Exploratory Endpoints .....................................................................................16
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................18
6.1
Trial Design.............................................................................................................18
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................19
6.2.1
Rationale of Trial Design and Dose..................................................................19
6.2.2
Rationale for Endpoints ...................................................................................20
6.3
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................20
6.3.1
Critical Procedures Based on Trial Objectives: Timing of Procedures..............21
6.4
Trial Beginning and End/Completion.......................................................................21
6.4.1
Definition of Beginning of the Trial.................................................................21
6.4.2
Definition of End of the Trial...........................................................................22
6.4.3
Definition of Trial Discontinuation ..................................................................22
6.4.4
Criteria for Premature Termination or Suspension of the Trial .........................22
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............23
7.1
Inclusion Criteria .....................................................................................................23
7.2
Exclusion Criteria ....................................................................................................26
7.3
Excluded Medications, Supplements, and Dietary Products .....................................28


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7.4
Diet, Fluid, and Activity ..........................................................................................30
7.4.1
Diet and Fluid..................................................................................................30
7.4.2
Activity ...........................................................................................................30
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................30
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................31
7.7
Subject Replacement................................................................................................31
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................32
8.1
Clinical Trial Drug...................................................................................................32
8.1.1
Clinical Trial Drug Labeling............................................................................32
8.1.2
Clinical Trial Drug Inventory and Storage .......................................................32
8.1.3
Clinical Trial Drug Blinding ............................................................................32
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs.............................32
8.1.5
Ancillary Supplies ...........................................................................................32
9.0
TRIAL PROCEDURES.................................................................................................33
9.1
Administrative Procedures.......................................................................................33
9.1.1
Informed Consent Procedure............................................................................33
9.1.2
Assignment of Screening Numbers ..................................................................33
9.1.3
Inclusion and Exclusion Criteria ......................................................................33
9.1.4
Medical History/Demographics .......................................................................33
9.1.5
Prior and Concomitant Medication Review......................................................33
9.1.6
Physical Examinations.....................................................................................33
9.1.7
Vital Sign Measurements.................................................................................34
9.1.8
Height and Weight...........................................................................................34
9.1.9
BMI.................................................................................................................34
9.1.10
12-Lead ECG...................................................................................................34
9.1.11
AE Monitoring ................................................................................................35
9.1.12
Pregnancy........................................................................................................35
9.2
Laboratory Procedures and Assessments..................................................................35
9.3
PK and PGx Samples...............................................................................................37
9.3.1
PK Evaluations ................................................................................................38
9.3.2
PGx Measurements..........................................................................................38
9.4
Trial Drug Administration........................................................................................40
9.5
Confinement ............................................................................................................40
10.0
ADVERSE EVENTS ....................................................................................................41
10.1
Definitions and Elements of AEs .............................................................................41


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10.1.1
SAEs ...............................................................................................................43
10.2
AE Procedures.........................................................................................................44
10.2.1
Assigning Severity/Intensity of AEs ................................................................44
10.2.2
Assigning Causality of AEs .............................................................................44
10.2.3
Assigning Relationship to Trial Procedures......................................................44
10.2.4
Start Date.........................................................................................................44
10.2.5
Stop Date.........................................................................................................44
10.2.6
Frequency........................................................................................................44
10.2.7
Action Concerning Trial Drug .........................................................................45
10.2.8
Outcome..........................................................................................................45
10.2.9
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................45
10.2.10 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...47
11.0
STATISTICAL METHODS..........................................................................................49
11.1
Statistical and Analytical Plans ................................................................................49
11.1.1
Analysis Sets ...................................................................................................49
11.1.2
Analysis of Demographics and Other Baseline Characteristics.........................49
11.1.3
PK Analysis.....................................................................................................49
11.1.4
Safety Analysis................................................................................................50
11.2
Interim Analysis and Criteria for Early Termination ................................................51
11.3
Determination of Sample Size..................................................................................51
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................52
12.1
Trial-Site Monitoring Visits.....................................................................................52
12.2
Protocol Deviations..................................................................................................52
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................52
13.0
ETHICAL ASPECTS OF THE TRIAL .........................................................................53
13.1
IRB and/or IEC Approval ........................................................................................53
13.2
Subject Information, Informed Consent, and Subject Authorization .........................54
13.3
Subject Confidentiality ............................................................................................55
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................55
13.4.1
Publication and Disclosure...............................................................................55
13.4.2
Clinical Trial Registration................................................................................56
13.4.3
Clinical Trial Results Disclosure......................................................................56
13.5
Insurance and Compensation for Injury....................................................................56
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................57
14.1
Administrative Information......................................................................................57


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14.1.1
Trial Contact Information ................................................................................57
15.0
INVESTIGATOR AGREEMENT.................................................................................58
15.1.1
Trial-Related Responsibilities ..........................................................................58
15.1.2
List of Abbreviations .......................................................................................59
16.0
DATA HANDLING AND RECORDKEEPING............................................................61
16.1
eCRFs......................................................................................................................61
16.2
Record Retention .....................................................................................................61
17.0
REFERENCES..............................................................................................................63
18.0
APPENDICES...............................................................................................................64
LIST OF IN-TEXT TABLES
Table 6.a
Number of Subjects Based on Study Design Options..........................................18
Table 6.b
Hepatic Function Categories Based on Child-Pugh Score...................................19
Table 7.a
Inclusion Criteria ...............................................................................................24
Table 7.b
Exclusion Criteria ..............................................................................................26
Table 7.c
Excluded Medications, Supplements, and Dietary Products................................29
Table 9.a
Primary Specimen Collections ...........................................................................38
Table 10.a
Takeda Medically Significant AE List................................................................43
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................64
Appendix B
Elements of the Subject Informed Consent.........................................................66
Appendix C
Investigator Consent to Use of Personal Information..........................................69
Appendix D
Pregnancy and Contraception.............................................................................70
Appendix E
Detailed Descriptions of Amendments to Text ...................................................72


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1.0
TRIAL SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. 
Takeda Development Centre Europe Ltd.
Compound:
TAK-954
Study Number: TAK-954-1006
Phase: 1
Protocol Title: A Phase 1, Nonrandomized, Open-Label Trial to Evaluate the Effect of Hepatic Impairment on the 
Single Dose Pharmacokinetics of Intravenous TAK-954
Trial Design:
This is a phase 1, nonrandomized, open-label trial in male and female subjects (non–childbearing potential) with 
hepatic impairment as defined by the Child-Pugh Score. The trial is designed to investigate the effect of hepatic 
impairment on the pharmacokinetics (PK) of intravenous (IV) TAK-954. Healthy subjects will be enrolled which will 
be similar to subjects in the impaired hepatic function groups with respect to age, weight (approximately 50% of 
healthy subjects on each side of the median age and weight of all hepatically-impaired subjects grouped together), 
gender, and race. This will be decided by the investigator in discussion with Takeda.
The trial will include a Screening Visit, an in-patient period, and a Follow-up Visit. The groups will be enrolled in a 
staggered fashion, beginning with Group 2 (Child-Pugh Class B). Safety and available PK data for 2 subjects in 
Group 2, dosed at 0.2 mg, will be reviewed by Takeda personnel and the investigator to confirm or modify the 
TAK-954 dose for the remaining 6 subjects. Enrollment of healthy subjects (Group 4) may begin after the second 
moderately hepatically-impaired subject has enrolled. There will be approximately 8 healthy subjects in total. When 
Group 2 has completed, and following another assessment of the safety and available PK data, Takeda personnel and 
the investigator will decide whether to enroll subjects in Group 1 (Child-Pugh Class A) or not (reduced versus full 
study design). During this review, the dose for subjects from Group 1 (if enrolled) and/or Group 3 will be selected. 
Additional healthy subjects may be enrolled for Group 1 and/or Group 3 (mild and/or severe) if needed.
If it is a reduced study design, there will be approximately 8 subjects with moderate hepatic impairment and 
approximately 8 healthy subjects, and a maximum of 8 subjects with severe hepatic impairment with additional 
healthy subjects if needed. If it is a full study design, there will be approximately 8 subjects with moderate hepatic 
impairment, approximately 8 healthy subjects, approximately 8 subjects with mild hepatic impairment, a maximum of 
8 subjects with severe hepatic impairment, with additional healthy subjects if needed.
Subjects will reside in the clinical research unit (CRU) from Day -1 until after the PK sample collection on the 
morning of Day 3. At the discretion of the investigator, subjects may be requested to remain in the CRU longer. 
Subjects will return to the clinic for PK sample collection on Days 4 and 5. After completion of the trial (or after 
subject withdrawal), all subjects will return for a Follow-up Visit 10 to 14 days after the dose of trial drug.
Primary Objective:

To evaluate the effect of varying degrees of hepatic function on the single-dose PK of IV TAK-954.
Secondary Objectives:

To evaluate the safety and tolerability of single IV doses of TAK-954 in subjects with varying degrees of hepatic
function.
Subject Population: 
Group 1: Males and females (non-childbearing potential) with mild hepatic impairment (Child-Pugh Class A).
Group 2: Males and females (non-childbearing potential) with moderate hepatic impairment (Child-Pugh Class B).
Group 3: Males and females (non-childbearing potential) with severe hepatic impairment (Child-Pugh Class C).
Group 4: Healthy males and females (non-childbearing potential). 


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Number of Subjects:
Up to approximately 32 subjects (with 8 planned per 
group) will be enrolled in this trial.
Number of Sites:
Multiple sites
Dose Levels: 
TAK-954 0.2 mg.
Route of Administration: 
TAK-954 IV.
Duration of Treatment:
One single dose.
Period of Evaluation:
Approximately 6 to 7 weeks.
Main Criteria for Inclusion:
All subjects:
Male and female subjects (non-childbearing potential) who are aged 18 to 75 years, inclusive, with a body mass index 
(BMI) between 18 to 35 kg/m2.
Groups 1 to 3: 
Subjects with hepatic impairment who are medically stable as determined by the investigator, based on medical 
history and clinical evaluations including physical examinations, clinical laboratory tests, vital sign measurements, 
and 12-lead electrocardiograms (ECGs) performed at the Screening Visit and at check-in on Day -1.
Group 4:
Healthy subjects. 
Main Criteria for Exclusion:
Groups 1 to 3:
Subjects who have:

A history of hepatic carcinoma, hepatorenal syndrome, or presence of a liver mass by ultrasound, computed
tomography (CT) or magnetic resonance imaging (MRI), or acute liver disease caused by an infection or drug
toxicity.

Have severe hepatic encephalopathy (> Grade II Portal Systemic Encephalopathy Score).

Surgical porto-systemic shunts, including transjugular intrahepatic portosystemic shunt.

A history of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than 1 month prior to trial
entry.

Bilirubin levels above 5 times the upper limit of normal (ULN) at Screening or Day -1 for Groups 1 and 2; there is
no limit for Group 3.

Severe/advanced ascites and/or pleural effusion which requires emptying and albumin supplementation, as
judged by the investigator.

Renal creatinine clearance (CLcr) ≤50 mL/min, calculated using the Cockcroft-Gault equation
(https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc) from the serum creatinine measurement taken
at Screening.
Group 4: Subjects who have a history of clinically significant endocrine, gastrointestinal (GI) [including motility 
disorder and intestinal obstruction]), cardiovascular, hematological, hepatic, immunological, renal, respiratory, 
genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases will be 
excluded from the trial.


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Endpoints and Criteria for Evaluation:
Primary endpoints:
Plasma PK parameters (expressed as total and free; maximum plasma concentration at the end of the infusion [Cmax], 
area under the plasma concentration time curve from time zero to the last measurable time point [AUClast], and area 
under the plasma concentration time curve from time zero and extrapolated to infinity [AUC∞]).
Safety endpoints:
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and clinical laboratory 
results as well as collection of spontaneous adverse events.
Statistical Considerations:
PK:
At this stage of the development of TAK-954, the exposure-response relationship for efficacy and safety has not been 
characterized. An increase of 2.5-fold or less in TAK-954 exposures will not warrant dose adjustments. PK parameters 
will be compared between normal and hepatically-impaired groups, classified by Child-Pugh Score and summarized 
descriptively. 
Descriptive statistics (eg, mean, SD, standard error, percent coefficient of variation [%CV], minimum, median, and 
maximum) will be used to summarize concentrations of TAK-954 (
) and PK parameters 
according to the hepatic function group (mild, moderate, and severe hepatic impairment, and healthy subjects).
Linear and semi-logarithmic plots of the mean and individual concentration-time curves will be provided. Individual 
plasma concentration and PK parameter data will be presented in the data listing.
An analysis of variance will be performed on log transformed Cmax and area under the plasma concentration-time 
curve (AUC) to compare each hepatically-impaired group with the healthy subject group and 90% confidence interval 
(CI) for the ratio of geometric means from subjects with hepatic impairment versus healthy subjects will be provided. 
In addition, the effect of other factors and covariates (such as gender and body weight) on the relationship between 
TAK-954 PK parameters and level of hepatic impairment will also be investigated. 
Safety:
Safety data will be presented by hepatic function group. Treatment-emergent adverse events (TEAEs) will be 
summarized by causal relationship to the trial drug and by intensity for each hepatic 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 hepatic function group. 
Sample Size Justification:
The planned sample size of 8 subjects in each hepatic function group is in line with regulatory guidance for these types 
of studies (“Food and Drug Administration Guidance for Industry PK in Patients with Impaired Hepatic 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 Hepatic Function”). 
Subjects who drop out may be replaced at the discretion of the investigator in consultation with the sponsor. 
CCI


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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 amend the postmenopausal criteria to be
consistent with the Clinical Trial Facilitation Group “Recommendations related to contraception 
and pregnancy testing in clinical trials”, as well as to add further clarity that it is not possible for 
the Informed Consent to be signed by a legal guardian.
The amendment opportunity was taken to make additional nonsubstantial changes, including 
clarifications, additional routine safety precautions, and the removal of redundant exploratory 
endpoints.
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 number of subjects.
2. Revision of postmenopausal criteria.
3. The addition of an exclusion criteria for subjects with QTcF >450 msec.
4. The addition of an exclusion criteria for a positive human immunodeficiency virus (HIV) and 
hepatitis test for healthy subjects.
5.
6. Removal of “legal representative” language.
7. Addition of an exclusion criteria for subjects with legal incapacity or limited legal capacity.
8. Added information regarding pregnancy.
9. Added pregnancy test at check-in on Day -1. 
10. Revised exclusion criteria based on bilirubin levels.
11. Pregnancy and contraception wording changed. 
12. Clarification to altering the trial design.
13. Additional vital sign measurements added.
14. Added exclusion criteria for restricted concomitant medications.
CCI


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2.0
TRIAL SCHEMATIC
PK=pharmacokinetic.


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3.0
SCHEDULE OF TRIAL PROCEDURES
Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
10-14 days after the dose
Hours Postdose
0
24
48
72
96
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
X
X
Semirecumbent vital signs (heart rate [HR], 
systolic blood pressure [SBP] and diastolic 
blood pressure [DBP]
X
X
X(a)
X
X
X
X
X
Vital signs (respiratory rate, oral [at the floor 
of the mouth]/tympanic temperature) 
X
X
Height
X
Weight
X
Body mass index (BMI)
X
Standard 12-lead electrocardiogram (ECG)
X
X
X (a)
X
X
X
X
Adverse event (AE) monitoring
X----------------------------------------------------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Serum chemistry
X
X
X
X
Hematology (b) 
X
X
X
X
Urinalysis
X
X
X
X
Serum follicle-stimulating hormone (FSH)
X
Urine drug screen
X
X
Alcohol breath or urine alcohol test (c)
X
X
HIV test
X
Hepatitis panel
X
Urine pregnancy test (hCG)
X
Pharmacokinetics (PK) Evaluations
Plasma samples for TAK-954 (d)
X
X
X
X
X
Urine sample for TAK-954 PK (e)
X
X
X
Plasma sample for protein binding (f)
X
Footnotes are on last table page.


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Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
10-14 days after the dose
Hours Postdose
0
24
48
72
96
Pharmacogenomic (PGx) Evaluations
Blood sample for DNA PGx (optional)
X
Blood sample for RNA PGx (optional)
X
Drug Administration
TAK-954 dosing 
X
Other
Confinement (g)
X
X
X
X
Meals
X
(a) Assessments at predose (within 30 minutes), 1 (just after the end of infusion), 2, and 4 hours postdose (relative to TAK-954 start infusion start). Additional blood pressure and HR 
assessments will be taken at 0.5 and 12 hours after the start of infusion.
(b) Complete blood count and for Screening Visit only, coagulation screen (prothrombin time, international normalized ratio [INR], and activated partial thromboplastin time).
(c) Additional alcohol breath or urine alcohol tests may be done at the discretion of the investigator.
(d) Time points for PK blood samples for TAK-954: predose (within 30 minutes), 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 and 96 hours 
after start of infusion.
(e) Urine collected at predose, 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose (relative to TAK-954 infusion start).
(f) Plasma for protein binding: 1 and 12 hours postdose (relative to TAK-954 infusion start).
(g) Length of confinement may be extended at the investigator’s discretion.


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4.0
INTRODUCTION
4.1
Background
Critically ill patients who require enteral feeding frequently have reduced gastrointestinal (GI) 
motility, develop enteral feeding intolerance (EFI), which can lead to several complications 
including not meeting daily calorie and protein requirements [1]. The addition of malnutrition in 
these patients is associated with impairment of immunological function, increased risk of 
infection, prolongation of mechanical ventilation, increased length of intensive care unit (ICU) 
and hospital stay, and ultimately higher mortality [2,3]. 
CCI


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Please refer to the TAK-954 Investigator’s Brochure for complete information on the 
investigational product. 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirement(s).
4.2
Rationale for the Proposed Trial
This is a phase 1, nonrandomized, open-label trial in male and female subjects (non–childbearing 
potential) with hepatic impairment and healthy subjects designed to investigate the effect of 
hepatic impairment on the PK of IV TAK-954.
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.
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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 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.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of the trial is to evaluate the effect of varying degrees of hepatic function on 
the single dose pharmacokinetics of IV TAK-954.
5.1.2
Secondary Objective
The secondary objective of the trial is to evaluate the safety and tolerability of single IV doses of 
TAK-954 in subjects with varying degrees of hepatic function.
5.1.3
Exploratory Objectives
Exploratory objectives of this trial include: 
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoints of the trial are the following PK parameters (expressed as total and free):
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from time 0 to the last measurable time point, 
(AUClast).
!
Area under the concentration-time curve from time 0 to and extrapolated to infinity (AUC∞).
5.2.2
Safety Endpoints
Safety endpoints include the following: 
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and 
clinical laboratory assessments, and collection of spontaneous AEs.
5.2.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a phase 1, nonrandomized, open-label trial in males and females (non-childbearing 
potential) with hepatic impairment and healthy males and females. Table 6.a displays the number 
of subjects who will participate in the study based on design options:
Table 6.a
Number of Subjects Based on Study Design Options
Group
Number of Subjects
Total Number of 
Subjects
Reduced Study Design
Group 1 (Mild)
0
~24
Group 2 (Moderate)
Minimum of 8
Group 3 (Severe)
Maximum of 8
Group 4 (Healthy)
Minimum of 8
Full Study Design
Group 1 (Mild)
Minimum of 8
~32
Group 2 (Moderate)
Minimum of 8
Group 3 (Severe)
Maximum of 8
Group 4 (Healthy)
Minimum of 8
The groups will be enrolled in a staggered fashion, beginning with Group 2 (Child-Pugh Class B). 
After safety and PK data are available for 2 subjects in Group 2, dosed at 0.2 mg, Takeda personnel 
and the investigator will review this data and confirm or modify the TAK-954 dose for the 
remaining 6 subjects. Enrollment of healthy subjects (Group 4) may begin after the second 
moderately hepatically-impaired subject is enrolled. As much as possible, the healthy subjects 
should be comparable to the hepatic impairment groups with respect to median age and weight 
(approximately 50% of healthy subjects on each side of the median age and weight of currently 
enrolled hepatically-impaired subjects grouped together), gender, and race. This will be decided 
by the investigator in discussion with Takeda. When Group 2 has completed, and following 
another assessment of PK and safety, Takeda personnel and the investigator will decide whether to 
enroll subjects in Group 1 (Child-Pugh Class A) or not (reduced vs full trial design). During this 
review the dose for subjects from Group 1 and/or Group 3 will be selected. 


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Table 6.b
Hepatic Function Categories Based on Child-Pugh Score
Assessment Parameters
Points Scored for Observed Findings (a)
1 point
2 points
3 points
Encephalopathy grade (b)
none
1 or 2
3 or 4
Ascites
absence
slight
moderate
Serum bilirubin, mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, seconds 
prolonged
<4
4 to 6
>6
Source: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf.
(a) Classification of clinical severity:
Mild (Class A): total score 5-6 points.
Moderate (Class B): total score 7-9 points.
Severe (Class C): total score 10-15 points.
(b) Grade 0: normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second (cps) waves.
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
The trial will include a Screening Visit, an in-patient period, and a Follow-up Visit.
Safety will be assessed by monitoring for AEs, ECGs, vital signs, safety laboratory tests, and 
physical examinations throughout the trial. 
After completion of the trial (or after subject withdrawal), all subjects will return for a Follow-up 
Visit, approximately 10 to 14 days after the dose of trial drug.
6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale of Trial Design and Dose
Although TAK-954 did not appear to be extensively metabolized in clinical studies following oral 
administration, it is possible that changes in hepatic function may impact TAK-954 exposure, and 
impaired organ function is a potential complication associated with critical illness. The impact of 
hepatic impairment on TAK-954 is not yet known.
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The purpose of this trial is to investigate the effect of hepatic impairment on the PK of IV 
TAK-954. 
 
 
 
 
 
6.2.2
Rationale for Endpoints
6.2.2.1
PK 
To determine the PK of TAK-954 in hepatically-impaired subjects with similar healthy subjects, 
the primary endpoint for this trial will consist of standard PK variables (Cmax, AUClast, and AUC∞).
6.2.2.2
Safety Endpoints
Key safety endpoints will be assessed through monitoring of AEs, vital signs, ECGs, clinical 
laboratory results, and physical examinations.
6.2.2.3
Exploratory Endpoints
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 
required to achieve the scientific goals of the trial objectives and/or to ensure appropriate safety 
monitoring of the trial subjects. 
!
Decrease the dose of the trial drug administered.
!
A planned PK data review may be eliminated if agreed to by Sponsor and investigator. 
!
Addition of a PK data review.
!
The number of subjects in the severe hepatically-impaired cohort may be less than 8 subjects.
Up to an additional 50 mL of blood may be drawn for PK analyses. This may include repeat 
samples or modified PK time points based on emerging data from previous subjects/cohorts in the 
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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, etc) currently outlined in the protocol may be modified during the trial based on 
data as it is analysed 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 investigator for retention. The letter 
may be forwarded to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
at the discretion of the investigator. 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 TAK-954 (PK) are the critical procedures.

At any postdose time point, the blood samples for TAK-954 (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.

ECG and vital signs measurements should be performed before the nominal time of the 
TAK-954 (PK) if scheduled together.

The order of priority can be changed during the trial with joint agreement of the investigator 
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.


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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, 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 preclinical 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 GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement.
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
Groups 
1-3 
(Hepatic 
Impaired 
ONLY)
Group 4 
(Healthy 
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.
Must have a Child-Pugh Score of Class A, B, or C (b).
X
7.
Diagnosis of cirrhosis due to parenchymal liver disease, which is confirmed 
and documented by at least 1 of the following: medical history, physical 
examination, hepatic ultrasound, computed tomography (CT) scan, 
magnetic resonance imaging (MRI), or liver biopsy.
X
8.
Should be on a stable drug regimen. If subjects are in a fluctuating treatment 
regimen, they may be considered for inclusion if the underlying disease is 
under control. However, these subjects must have sponsor approval prior to 
the dose of trial medication.
X
9.
Must be similar to subjects in the impaired hepatic function groups with 
respect to age, weight (approximately 50% of healthy subjects on each side 
of the median age and weight of all hepatically-impaired subjects grouped 
together), gender, and race. This will be decided by the investigator in 
discussion with Takeda.
X
10. Is considered to be healthy (for healthy subjects) or medically stable (for 
subjects with hepatic impairment) as determined by the investigator, 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. Subjects with 
hepatic impairment should have no clinically significant changes in medical 
history or clinical laboratory values within 30 days prior to trial drug 
administration on Day 1. If clinical laboratory tests within 30 days prior to 
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 investigator to determine the subject’s medical status.
X
11. Must be a nonsmoker who has not used tobacco- or nicotine-containing 
products (eg, nicotine patch) for at least 6 months before administration of 
the initial dose of the trial drug/invasive procedure.
X
12. Must abstain from the use of tobacco- or nicotine-containing products 
48 hours prior to dosing and during confinement in the clinic.
X
Footnotes are on last table page.


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(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) Child-Pugh Class:
–
Group 1: Subjects with mild hepatic impairment (Child-Pugh Class A).
–
Group 2: Subjects with moderate hepatic impairment (Child-Pugh Class B).
–
Group 3: Subjects with severe hepatic impairment (Child-Pugh Class C).


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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: 
Table 7.b
Exclusion Criteria
Subjects who:
All 
Subjects
Groups 1-3 
(Hepatic 
Impaired 
ONLY)
Group 4 
(Healthy 
Subjects 
ONLY)
1.
Have participated in another investigational trial within 4 weeks before 
the pretrial (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.
Are a breastfeeding woman.
X
5.
Have a QTcF > 450 msec at Baseline.
X
6.
Have a positive urine drug screening test result at the Screening Visit or at 
check-in on Day -1.
X
7.
Have a positive test result for hepatitis B surface antigen (HBsAg), 
hepatitis C antibody (HCV), or 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 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 investigator and the sponsor’s medical 
monitor.
X
9.
Ingest alcohol within 72 hours prior to trial drug administration and 
during the confinement period. 
X
10.
Ingest alcohol within 7 days prior to trial drug administration and during 
the confinement period. 
X
11.
Have a history of alcohol consumption exceeding 2 standard drinks per 
day on average (1 glass is approximately equivalent to: beer [354 mL/12 
ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] 
per day).
X
12.
Have a substance abuse disorder.
X
13.
Have a history of cancer (malignancy).
X
14.
Have a history of cancer (malignancy) with the following exceptions:
(1) Subjects with adequately treated non-melanomatous skin carcinoma 
or carcinoma in situ of the cervix may participate in the trial; (2) Subjects 
with other malignancies which have been successfully treated ≥10 years 
prior to the Screening Visit where, in the judgment of both the 
investigator and treating physician, appropriate follow-up has revealed no 
evidence of recurrence from the time of treatment through the time of the 
Screening Visit; or, (3) Subjects, who, in the opinion of the trial 
investigator, are highly unlikely to sustain a recurrence for the duration of 
the trial.
X


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Subjects who:
All 
Subjects
Groups 1-3 
(Hepatic 
Impaired 
ONLY)
Group 4 
(Healthy 
Subjects 
ONLY)
15.
Have a known hypersensitivity to any component of the formulation of 
TAK-954 or related compounds.
X
16.
Had major surgery, donated or lost 1 unit of blood (approximately 
500 mL) within 8 weeks of the first dose.
X
17.
Have a history of clinically significant endocrine, gastrointestinal 
(including motility disorder and intestinal obstruction), cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, 
or major neurological (including stroke and chronic seizures) 
abnormalities or diseases.
X
18.
Have a history of hepatic carcinoma, hepatorenal syndrome, or presence 
of a liver mass by ultrasound, CT or MRI, or acute liver disease caused by 
an infection or drug toxicity.
X
19.
Have surgical porto-systemic shunts, including transjugular intrahepatic 
portosystemic shunt.
X
20.
Have a history of gastrointestinal hemorrhage due to esophageal varices 
or peptic ulcers less than one month prior to Screening.
X
21.
Have bilirubin levels above 5 times the upper limit of normal (ULN) at 
Screening or Day -1 for Groups 1 and 2 (no limit for Group 3).
X
22.
Have bilirubin levels above 1.5 times the ULN at Screening or Day -1.
X
23.
Have severe hepatic encephalopathy (> Grade II Portal Systemic 
Encephalopathy Score).
X
24.
Have severe/advanced ascites and/or pleural effusion which requires 
emptying and albumin supplementation, as judged by the investigator.
X
25.
Have renal creatinine clearance (CLcr) ≤50 mL/min, calculated using the 
Cockcroft-Gault equation 
(https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc) from 
the serum creatinine measurement taken at Screening.
X
26.
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, and until the Follow-up Visit. See 
Section 7.3.
X
27.
Are unable to refrain from or anticipates the use of:

strong CYP3A4 inhibitors or inducers

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, until the Follow-up Visit.
X


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Subjects who:
All 
Subjects
Groups 1-3 
(Hepatic 
Impaired 
ONLY)
Group 4 
(Healthy 
Subjects 
ONLY)
28.
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
7.3
Excluded Medications, Supplements, and Dietary Products
Use of excluded agents (prescription or nonprescription) or dietary products is outline in Table 7.c.


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Table 7.c
Excluded Medications, Supplements, and Dietary Products 
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 48 hours prior to 
dosing (start of infusion).
Restricted during confinement.
Cannabis products
Completely restricted.
Completely restricted.
Alcohol (b)
Completely restricted for a minimum of 3 
and 7 days before dosing, respectively, 
for hepatically-impaired subjects and 
healthy subjects.
Completely restricted during the 
confinement period.
Xanthine and/or caffeine
Completely restricted 48 hours before 
dosing (start of infusion).
Completely restricted 48 hours after 
dosing (start of infusion).
At all other times no more than 
6 units/day.
Medications for healthy 
subjects
Completely restricted 7 days before 
dosing.
Completely restricted (c).
Medications for 
hepatically-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 (d)
Completely restricted 7 days before 
dosing (start of infusion).
Completely restricted.
Charbroiled meat
Completely restricted 7 days before 
dosing (start of infusion).
Completely restricted.
(a) Subjects in Groups 1-3 will abstain from the use of tobacco- or nicotine-containing products 48 hours prior to 
dosing and during confinement in the clinic. 
(b) Outside the confinement period, regular alcohol consumption below 24 units for males and 17 units for females per 
week (1 unit equals 354 mL/12 ounces of beer, 118 mL/4.0 ounces of wine, or 29.5 mL/1.0 ounces of spirits) is 
allowed. In addition to Screening and Day -1, subjects may undergo an alcohol breath or urine test at other time s at the 
discretion of the investigator.
(c) If medications are required to treat an AE, certain medications may be allowed after discussion and agreement 
between the sponsor and principal investigator. 
(d) Mustard green family includes kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, and mustard. 
For subjects in Groups 1, 2, and 3, 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 co-morbidities should be maintained at a stable dose and regimen from 
the Screening Visit throughout the trial; however, medication adjustments may be made by the 
investigator with Sponsor approval based on the subject’s condition and standard of care. 


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Occasional use of acetaminophen/paracetamol (≤1 g/day) or other medication is allowed as 
approved by Takeda on a case-by-case basis.
Subjects must be instructed not to take any medications, including OTC products, without first 
consulting with the investigator. However, if a medication is taken, it is the responsibility of the 
investigator 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 the dosing day. 
Water may be consumed without restrictions. Non-caffeinated drinks may be consumed with 
meals and evening snack.
Lunch and dinner will be provided approximately 4 and 9 hours, respectively, after dosing 
(starting 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. 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.
3. 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.
4. Voluntary withdrawal. The subject  wishes to withdraw from the trial. The reason for 
withdrawal, if provided, should be recorded in the eCRF. 
5. 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.


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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 investigator and sponsor. The trial site should contact the sponsor for the 
replacement subject’s treatment assignment and allocation number. 


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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, investigator, 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 6.3.1.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters 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 prior to 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
Physical Examinations
Qualified site personnel will conduct physical examinations.


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9.1.7
Vital Sign Measurements
Body temperature will be measured with an oral (temperature taken at floor of the mouth) 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, systolic blood pressure, and diastolic blood 
pressure, body temperature, and respiratory rate. 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. 
9.1.8
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
9.1.9
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.
9.1.10 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 
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.


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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.
9.1.11 AE Monitoring
AE monitoring begins after signing of informed consent. A complete description of AE collections 
and procedures is provided in Section 10.0.
9.1.12 Pregnancy
Women of childbearing potential will not be included in this trial. 
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). Females of 
childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in Appendix D containing highly effective contraception. 
If any subject is found to be pregnant during the trial, she should be withdrawn from the trial and 
any Takeda-supplied drug and should be immediately discontinued. In addition, any pregnancies 
in the partner of a male subject during the trial 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 trial drug will be followed up to final outcome. The outcome of 
the pregnancy, including any premature termination, must be reported to the sponsor.
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 Drug Screen
A urine drug screen will include the following tests: 
Amphetamines
Cotinine
Barbiturates
3,4-methylenedioxy-methamphetamine (MDMA)
Benzodiazepines
Methadone/metabolite
Cannabinoids
Opiates
Cocaine/metabolites
Phencyclidine


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Alcohol Screen
Subjects will undergo a urine alcohol test. An alcohol breath test may be performed at the 
discretion of the investigator.
Urine
Urine evaluations will include the following test:
hCG for pregnancy (all females)
9.2.1.2
Screening
Serum
Serum evaluations will include the following tests:
HIV test
Hepatitis panel, including HBsAg and anti-HCV
FSH (females only)
International normalized ratio (INR)
Prothrombin time
Activated partial thromboplastin time
9.3
PK and PGx Samples
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). 
As PGx is an evolving science, many genes and their functions are not yet fully understood. Future 
data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored 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. 
It is anticipated that the total blood volume drawn for the trial will be approximately 170 mL. 


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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 measurements
Mandatory
Urine sample for TAK-954 PK
Urine
PK measurements
Mandatory
Blood sample for DNA PGX
Blood
DNA
PGx measurements
Optional
Blood sample for RNA PGX
Blood
RNA
PGx measurements
Optional
Plasma for protein binding
Plasma
PK measurement
Mandatory
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 clinical pharmacology analysis 
plan (CPAP).
The following plasma PK parameters (free and total) for TAK-954 will be calculated: 
!
Cmax
!
AUC∞
!
AUClast
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.
9.3.2
PGx Measurements
9.3.2.1
Blood Sample for DNA and RNA PGx Measurements
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, 
CCI


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distribution, metabolism, and excretion), PD (pharmacologic effects), and/or the clinical outcome 
(efficacy and/or safety).
PGx research in this trial may be conducted to understand how individual genetic variation in 
subjects impacts their trial drug treatment response. This information may be also be used, for 
example, to develop a better understanding of the safety and efficacy of TAK-954 and other trial 
drugs, to increase understanding of the disease/condition being studied and other related 
conditions, gain a better understanding of the drug pharmacology and for generating information 
needed for research, development, and regulatory approval of tests to predict response to 
TAK-954. 
Whole blood samples for DNA and RNA isolation will be collected from each consented subject in 
the trial. If necessary and feasible, a second aliquot of blood may be taken at a later time point if 
isolation of DNA from the first sample was not successful or possible.
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
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 site, 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 PGx 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 trial doctor and sponsor may 
continue to use and distribute any information and test results gathered before the request to 
withdraw.


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9.4
Trial Drug Administration
Eligible subjects 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. 
Subjects will continue to rest in a semirecumbent position from the time of dosing (start of 
infusion) until 4 hours postdose except to stand for the measurement of standing vital signs (if 
needed) or other trial-related procedure. 
9.5
Confinement
Subjects will reside in the CRU from Day -1 until after the PK sample collection on the morning of 
Day 3. At the discretion of the investigator, subjects may be requested to remain in the CRU 
longer. Subjects discharged on Day 3 will return to the clinic for PK sample collection on Days 4 
and 5.


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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.

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).
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


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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”.
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.


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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.
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 10-14 days after the dose of TAK-954. 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 


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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:
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.


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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 (Group 4 only)
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 as described in Section 9.2 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). 
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 
Independent Ethics Committees (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 


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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 and for each hepatic 
function group. 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
At this stage of the development of TAK-954, the exposure-response relationship for efficacy and 
safety has not been characterized. An increase of 2.5-fold or less in TAK-954 exposures will not 
warrant dose adjustments. PK parameters will be compared between normal and 
hepatically-impaired groups, classified by Child-Pugh Score and summarized descriptively. 
Descriptive statistics (e.g. mean, standard deviation, standard error, % coefficient of variation 
[CV], minimum, median and maximum) will be used to summarize concentrations of TAK-954 


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) and PK parameters (expressed as free and total) according to the 
hepatic function group [healthy subjects and mild, moderate, severe hepatic impairment].
Linear and semi-logarithmic plots of the mean and individual concentration-time curves will be 
provided. Individual plasma concentration and pharmacokinetic parameter data will be presented 
in the data listing.
An analysis of variance will be performed on log transformed Cmax and AUC to compare each 
hepatically-impaired group with the normal hepatic function group and 90% confidence intervals 
for the ratio of geometric means from each hepatic impairment group versus normal function 
group will be provided. In addition, the effect of other factors and covariates (such as gender and 
body weight) on the relationship between TAK-954 PK parameters and level of hepatic 
impairment will also be investigated. 
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.
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). TEAEs with onset occurring within 30 days 
(onset date minus last date of dose +1≤30) after the 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 with a 
breakdown for each hepatic function group and overall. 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.
CCI
CCI


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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 hepatic function group is in line with regulatory 
guidance for these types of studies (“FDA Guidance for Industry Pharmacokinetics in Patients 
with Impaired Hepatic 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 Hepatic Function”). The sample size of 8 healthy subjects 
allows for healthy subjects to be represented for a comparator or reference.
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 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.
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 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
PPD


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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.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting 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
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to the last measurable time point.
AUCt
area under the concentration-time curve from time 0 to time t.
AUC∞
area under the concentration-time curve from time 0 to infinity.
BMI
body mass index
CFR
Code of Federal Regulations
Cmax
maximum observed concentration
CRU
clinical research unit
CT
computed tomography
CV
coefficient of variation
CPAP
clinical pharmacology analysis plan
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
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HR
heart rate
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
C
CI
CCI
C
C
I


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MTD
maximum tolerated dose
PD
pharmacodynamic(s)
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
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
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell
C
C
I


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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.
Barton RG. Nutrition support in critical illness. American Society for Parenteral and Enteral 
Nutrition 1994;168:659-64.
2.
Harrington L. Nutrition in critically ill adults: key processes and outcomes. Crit Care Nurs 
Clin North Am 2004;16(4):459-65.
3.
Slone DS. Nutritional support of the critically ill and injured patient. Crit Care Clin 
2004;20(1):135-57.
4.
Beattie DT, Armstrong SR, Vickery RG, Tsuruda PR, Campbell CB, Richardson C, et al. The 
Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with 
Gastrointestinal Prokinetic Properties. Front Pharmacol 2011;2:25.


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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 the 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. If any subject is found to be 
pregnant during the trial, she should be withdrawn from the trial and any Takeda-supplied drug 
and should be immediately discontinued. In addition, any pregnancies in the partner of a male 
subject during the trial 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 trial 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 
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 males should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
1. 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. 
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of trial drug.


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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, postovulation 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 number of subjects.
The primary change occurs in Section 6.1 Trial Design.
Initial 
wording:
A range of approximately 16 to 32 subjects will be enrolled in this trial (Table 6.a).
Amended 
or new 
wording:
Table 6.a displays the number of subjects who will participate in the study based on 
design options:
Rationale for Change:
To clarify the number of subjects in the trial.
Section 1 Clarification of number of subjects. also contains a change. 
Change 2: Clarification of number of subjects.
Revision of postmenopausal criteria.
The 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 hepatically 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 months of spontaneous amenorrhea in 
females aged ≤45 years with serum FSH levels >40 mIU/mL). and for hepatically 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.
Rationale for Change:
The Czech Competent Authority, State Institute for Drug Control, requested an amendment to the 
protocol for the postmenopausal criteria to be consistent with the Clinical Trial Facilitation Group 
“Recommendations related to contraception and pregnancy testing in clinical trials”.


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Change 3: 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 4: The addition of an exclusion criteria for a positive human immunodeficiency virus 
(HIV) and hepatitis test for healthy subjects.
The primary change occurs in Table 7.b
Exclusion Criteria: 
Added text:The following exclusion criteria was added for Group 4 (healthy subjects only):
Have a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C 
antibody (HCV), or 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.
Rationale for Change:
This exclusion criteria was inadvertently omitted during protocol development.
Change 5:
The primary change occurs in deleted Section 9.3.2 PD Assessments.
Deleted 
text:
9.3.2
PD Assessments
Rationale for Change:
The following sections also contain this change:
!
Section 3.0 Schedule of Trial Procedures.
!
Section 5.1.3 Exploratory Objectives
!
Section 5.2.3 Exploratory Endpoints.
CCI
CCI
CCI


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
Section 6.1 Trial Design.

Section 6.2.2.3 Exploratory Endpoints.

Section 6.3 Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters.
Change 6: 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 
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 


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recorded in the subject’s medical record, and the subject should receive a copy of the 
revised informed consent form.
Rationale for Change:
To address the following comment from the Czech Competent Authority (State Institute for Drug 
Control): It is required that only subjects who are able to provide an informed consent with 
participation in the trial and whose legal capacity is not restricted participate in the clinical trial. In 
compliance with Section 52 of Act No 378/2007 Coll. (“Act on Pharmaceuticals”), participation of 
persons with restricted capacity to carry out legal acts in a clinical trial is permissible only in cases 
where a preventive or therapeutic benefit from the trial is expected. The Institute requires that this 
information be included in the inclusion criteria as well as in chapter 13.2 “Subject Information, 
Informed Consent, and Subject Authorization” of the protocol. With respect to this comment, it is 
not possible for the Informed Consent to be signed by a legal guardian.
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 7: Addition of an exclusion criteria for subjects with legal incapacity or limited legal 
capacity.
The primary change occurs in Table 7.b
Exclusion Criteria.
Description 
of change:
Added exclusion criteria to all subjects: Have legal incapacity or limited legal 
capacity.
Rationale for Change:
To address request from the Czech Competent Authority (State Institute for Drug Control) to 
exclude subjects who cannot provide consent (see rationale for change above).
Change 8: Added information regarding pregnancy.
The primary change occurs in Section 9.1.12 Pregnancy. 
Description 
of change:
A section was added to further clarify dealing with pregnancy.


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Added text: 9.1.12 Pregnancy
Women of childbearing potential will not be included in this trial. 
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). Females of childbearing potential who are partners 
of male subjects are also advised to use additional contraception as shown in 
Appendix D containing highly effective contraception. 
If any subject is found to be pregnant during the trial, she should be withdrawn 
from the trial and any Takeda-supplied drug and should be immediately 
discontinued. In addition, any pregnancies in the partner of a male subject 
during the trial 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 trial drug will be followed up to 
final outcome. The outcome of the pregnancy, including any premature 
termination, must be reported to the sponsor.
Rationale for Change:
Text added to further clarify contraception and dealing with pregnancy.
Change 9: Added pregnancy test at check-in 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 check-in (Day -1) Visit.
Section 9.2.1.2 Screening also contains this change.
Rationale for Change:
Routine/standard test omitted from the initial protocol. 
Change 10: Revised exclusion criteria based on bilirubin levels.
The primary change occurs in Table 7.b Exclusion Criteria. 
Description 
of change:
Changed exclusion criteria for hepatically impaired subjects: Have bilirubin levels 
above 5 times the upper limit of normal (ULN) at Screening or Day -1 for Groups 1 
and 2 and 4 (no limit for Group 3).
Added exclusion criteria for healthy subjects: Have bilirubin levels above 1.5 times 
the ULN at Screening or Day -1.


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Rationale for Change:
To clarify the normal range in healthy volunteers which is different than levels allowed for 
subjects with hepatic impairment.
Section 1.0 TRIAL SUMMARY also contains this change. 
Change 11: 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 


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contraception below.
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.
Change 12: 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, PD, 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. 
!
Decrease the dose of the trial drug administered.
!
A planned PK data review may be eliminated if agreed to by Sponsor and 
investigator and if no further increases in total daily dose occur. 
!
Addition of a PK data review.
!
The number of subjects in the severe hepatically-impaired cohort may be less than 
8 subjects.
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/her participation in the entire trial. 
CCI


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The timing of planned procedures for assessment of safety procedures (eg, vital signs, 
ECG, safety laboratory tests, etc) 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 investigator 
for retention. The letter may be forwarded to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) at the discretion of the investigator.
Amended 
or new 
wording:
This is a phase 1 assessment of TAK-954 in humans, and the PK, PD, 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. 
•
Decrease the dose of the trial drug administered.
•
A planned PK data review may be eliminated if agreed to by Sponsor and investigator 
and if no further increases in total daily dose occur. 
•
Addition of a PK data review.
•
The number of subjects in the severe hepatically-impaired cohort may be less than 8 
subjects.
The PK/PD 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/her 
participation in the entire trial. 
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, 
safety laboratory tests, etc) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, PK, or PD data as it is analysed per protocol 
from previous subjects/cohorts in the study(eg, to obtain data closer to the time of peak 


TAK-954
Study No. TAK-954-1006
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Protocol Incorporating Amendment No. 1
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CONFIDENTIAL
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 Any of these per protocol alterations (part of trial design to 
this protocol to meet the trial objectives its objectives) must be detailed by the Sponsor in a 
letter to the Trial File and forwarded to the investigator for retention. The letter may be 
forwarded to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) at 
the discretion of the investigator. Any other changes, if considered substantial, will be 
documented in a protocol amendment which will require approval before they 
are implemented.
Rationale for Change:
This section has been revised to clarify changes that can be done within the remit of the protocol 
and those that would require a protocol amendment. Wording pertinent to oral dosing (time of 
peak plasma concentrations) has also been removed given that is not applicable to the TAK-954 
formulation used in the study.
Change 13: Additional vital sign measurements added.
The primary change occurs in Section 3.0 Schedule of Trial Procedures.
Description 
of change:
Additional blood pressure and heart rate assessments were added on Day 1 at 0.5 and 
12 hours after the start of the infusion and on Day 5.
Rationale for Change:
The additional vital sign measurements added are aligned with PK measurements taken at same 
timepoints and will add to the evaluation of any potential tachycardia or hypotension. 
Change 14: Added exclusion criteria for restricted concomitant medications.
The primary change occurs in Section 7.2 Exclusion Criteria.
Description 
of change:
Added the following exclusion criteria for Groups 1 through 3: Are unable to refrain 
from or anticipates the use of:

strong CYP3A4 inhibitors or inducers

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, 


TAK-954
Study No. TAK-954-1006
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Protocol Incorporating Amendment No. 1
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CONFIDENTIAL
throughout the trial, 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.


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PPD

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, Nonrandomized, Open-Label Trial to Evaluate the Effect of Hepatic 
Impairment on the Single Dose Pharmacokinetics of Intravenous TAK-954
NCT Number: NCT03277274
SAP Approve Date: 05 September 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-954-1006
A Phase 1, Nonrandomized, Open-Label Trial to Evaluate the Effect of Hepatic 
Impairment on the Single Dose Pharmacokinetics of Intravenous TAK-954
PHASE 1
Version: Final
Date: 05 September 2018
Prepared by:
Based on:
Protocol Version: Amendment 01
Protocol Date: 06 October 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


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1.2
Approval Signatures
Electronic signatures can be found on the last page of this document.


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.2
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objective......................................................................................................6
4.2
Secondary Objective..................................................................................................6
4.3
Exploratory Objectives ..............................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1
Primary Endpoints .....................................................................................................8
5.2
Safety Endpoints........................................................................................................8
5.3
Exploratory Endpoints ...............................................................................................8
6.0
DETERMINATION OF SAMPLE SIZE.........................................................................9
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
7.1
General Principles....................................................................................................10
7.1.1
Study Definitions ...............................................................................................10
7.1.2 Definition of Study Days ............................................................................................10
7.1.2
Definition of Study Visit Windows ....................................................................10
7.1.3
Conventions for Missing Adverse Event Dates...................................................10
7.1.4
Conventions for Missing Concomitant Medication Dates...................................11
7.1.5
Conventions for Missing Data............................................................................11
7.2
Analysis Sets ...........................................................................................................11
7.3
Disposition of Subjects ............................................................................................11
7.4
Demographic and Other Baseline Characteristics.....................................................11
7.5
Medical History and Concurrent Medical Conditions...............................................12
7.6
Medication History and Concomitant Medications...................................................12
7.7
Study Drug Exposure and Compliance.....................................................................12
7.8
Efficacy Analysis.....................................................................................................13
7.9
Pharmacokinetic Analysis........................................................................................13
7.9.1
Summary of Concentrations in Plasma...............................................................13
7.9.2
Analysis of Pharmacokinetic Parameters............................................................13
7.10
Other Outcomes.......................................................................................................14
7.11
Safety Analysis........................................................................................................14


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7.11.1 Adverse Events ..................................................................................................14
7.11.2 Clinical Laboratory Evaluations .........................................................................16
7.11.3 Vital Signs .........................................................................................................16
7.11.4 12-Lead ECGs ...................................................................................................17
7.11.5 Other Observations Related to Safety.................................................................17
7.12
Interim Analysis ......................................................................................................17
7.13
Changes in the Statistical Analysis Plan...................................................................17
8.0
BASED ON CONSULTATION WITH PHARMACOVIGILANCE, THE
CORRECTED CALCIUM WILL BE SUMMARIZED, RATHER THAN CALCIUM 
AS STATED IN THE PROTOCOL. REFERENCES.....................................................18
LIST OF IN-TEXT TABLES
Table 4.a
Number of Subjects Based on Study Design Options............................................6
Table 4.b
Hepatic Function Categories Based on Child-Pugh Score.....................................7
LIST OF APPENDICES
Appendix A
Criteria for Abnormal Changes from Baseline of Vital Signs..............................19
Appendix B
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters ......20
Appendix C
Schedule of Trial Procedures..............................................................................21


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
ANCOVA
analysis of covariance
AUC
area under the concentration-time curve
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration 
CI
confidence interval
CL
clearance
Cmax
maximum observed concentration
CPAP
clinical pharmacology analysis plan
CRF
case report form
CV
coefficient of variation
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
HR
heart rate
LLN
lower limit of normal
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
PGx
pharmacogenomics
PK
pharmacokinetics
PT
Preferred term
PTE
Pretreatment adverse event
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
System organ class
TEAE
treatment-emergent adverse event
WHODrug
World Health Organization Drug Dictionary
CCI
CCI
CCI
CCI


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4.0
OBJECTIVES
4.1
Primary Objective
The primary objective of the trial is to evaluate the effect of varying degrees of hepatic function 
on the single dose pharmacokinetics of IV TAK 954.
4.2
Secondary Objective
The secondary objective of the trial is to evaluate the safety and tolerability of single IV doses of 
TAK 954 in subjects with varying degrees of hepatic function.
4.3
Exploratory Objectives
Exploratory objectives of this trial include: 
4.4
Study Design
This is a phase 1, nonrandomized, open-label trial in males and females (non-childbearing 
potential) with hepatic impairment and healthy males and females. Table 4.a displays the number 
of subjects who will participate in the study based on design options:
Table 4.a
Number of Subjects Based on Study Design Options
Group
Number of Subjects
Total Number of 
Subjects
Reduced Study Design
Group 1 (Mild)
0
~24
Group 2 (Moderate)
Minimum of 8
Group 3 (Severe)
Maximum of 8
Group 4 (Healthy)
Minimum of 8
Full Study Design
Group 1 (Mild)
Minimum of 8
~32
Group 2 (Moderate)
Minimum of 8
Group 3 (Severe)
Maximum of 8
Group 4 (Healthy)
Minimum of 8
The groups will be enrolled in a staggered fashion, beginning with Group 2 (Child-Pugh Class 
B). After safety and PK data are available for 2 subjects in Group 2, dosed at 0.2 mg, Takeda 
personnel and the investigator will review this data and confirm or modify the TAK-954 dose for 
the remaining 6 subjects. Enrollment of healthy subjects (Group 4) may begin after the second 
moderately hepatically-impaired subject (Group 2) is enrolled. As much as possible, the healthy 
CCI


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subjects should be comparable to the hepatic impairment groups with respect to median age and 
weight (approximately 50% of healthy subjects on each side of the median age and weight of 
currently enrolled hepatically-impaired subjects grouped together), gender, and race. This will be 
decided by the investigator in discussion with Takeda. When Group 2 has completed, and 
following another assessment of PK and safety, Takeda personnel and the investigator will 
decide whether to enroll subjects in Group 1 (Child-Pugh Class A) or not (reduced vs full trial 
design). During this review the dose for subjects from Group 1 and/or Group 3 will be selected. 
Table 4.b
Hepatic Function Categories Based on Child-Pugh Score
Assessment Parameters
Points Scored for Observed Findings (a)
1 point
2 points
3 points
Encephalopathy grade (b)
none
1 or 2
3 or 4
Ascites
absence
slight
moderate
Serum bilirubin, mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, seconds 
prolonged
<4
4 to 6
>6
Source: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf.
(a) Classification of clinical severity:
Mild (Class A): total score 5-6 points.
Moderate (Class B): total score 7-9 points.
Severe (Class C): total score 10-15 points.
(b) Grade 0: normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second (cps) waves.
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
The trial will include a Screening Visit, an in-patient period, and a Follow-up Visit.
Blood for free and total plasma concentration and urine samples for assessment of TAK-954 
concentrations will be collected before the start of the TAK-954 infusion and at intervals up to 
96 hours after the start of the infusion. Samples may be assayed for TAK-954 metabolites. TAK-
954 and its metabolites may also be assayed in urine, data permitting and if deemed possible. 
Plasma protein binding of TAK-954 will also be assessed.
Whole blood samples for DNA PGx analysis and RNA isolation will be collected predose on 
Day 1. 
Safety will be assessed by monitoring for AEs, ECGs, vital signs, safety laboratory tests, and 
physical examinations throughout the trial. 
After completion of the trial (or after subject withdrawal), all subjects will return for a Follow-up 
Visit, approximately 10 to 14 days after the dose of trial drug.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints of the trial are the following PK parameters (expressed as total and free):
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from time 0 to the last measurable time point, 
(AUClast).
!
Area under the concentration-time curve from time 0 to and extrapolated to infinity (AUC∞).
5.2
Safety Endpoints
Safety endpoints include the following: 
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and 
clinical laboratory assessments, and collection of spontaneous AEs.
5.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
PK parameters:
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
The planned sample size of 8 subjects in each hepatic function group is in line with regulatory 
guidance for these types of studies (“FDA Guidance for Industry Pharmacokinetics in Patients 
with Impaired Hepatic 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 Hepatic Function”). The sample size of 8 healthy subjects 
allows for healthy subjects to be represented for a comparator or reference.
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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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using the following: number of subjects (N), mean, 
standard deviation (SD), median, minimum, and maximum, where appropriate. Where indicated, 
coefficient of variation (%CV) and geometric mean will also be included in the summary of 
continuous data. Categorical data will be summarized using the number and percentage of 
subjects for each category where appropriate.
Unless otherwise stated, Baseline will be defined as last observation prior to administration of 
the study drug.
All statistical tests will be two-tailed at α=0.05 level for significance unless otherwise stated. P-
values (when rounded to three digits) less than or equal to α are reported as “significant”. “No 
statistically significant difference” means that all p-values for the tests are greater than α. All 
computations will be performed prior to rounding.
In general, the presentation of decimal points will follow the following rules as appropriate: 
minimum and maximum values will be presented using the same number of decimal places as 
the recorded data. Arithmetic means, geometric means, and medians will be presented to 1 more 
decimal place than the recorded data, and SDs will be presented to 2 more decimal places than 
the recorded data. The confidence interval (CI) for a parameter estimate will be presented using 
the same number of decimal places as the parameter estimate. Percentage will be presented to 1 
decimal place (e.g., 80.1%). All p-values will be rounded to 3 decimal places prior to assessment 
of statistical significance.
All statistical analyses will be performed using the 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 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) dosing page. Other study days are defined relative to Study Day 1, with 
Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. 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}. 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 + 1}.
7.1.2
Definition of Study Visit Windows
There will be no visit windowing.
7.1.3
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.


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7.1.4
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.
7.1.5
Conventions for Missing Data
There will be no imputation of incomplete or missing data. Inclusion of subjects who are 
noncompliant with the dosing or who have incomplete data, will be made on a case-by-case 
basis. Plasma or urine 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.
They will be flagged in the data listings; however, deviations from this convention may be
considered on a case-by-case basis.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data: 

Safety Set: The safety set will consist of all subjects who are enrolled and receive the study 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics, and 
safety summaries.

Pharmacokinetic (PK) Set: The PK set will consist of all subjects who are enrolled and 
receive the appropriate dose of trial drug and have at least 1 measurable plasma concentration
or amount of drug in the urine for TAK-954. All subjects with valid PK parameter estimates 
will be included in the summaries and analyses for that parameter. The subjects receive 
inappropriate dose will not be included in PK set, but the data from those subjects will be 
listed and flagged.
7.3
Disposition of Subjects
The number and percentage of subjects who are enrolled, complete study drug and study visits, 
and who prematurely discontinue study drug and/or study visits will be summarized by hepatic 
function group (healthy subjects, mild, moderate and severe hepatic impairment) and overall. 
Subjects’ study completion data, including reasons for premature termination, will be listed.
Additionally, disposition information for screen failures will be listed. A listing of inclusion/ 
exclusion criteria not met will be provided for subjects who did not meet at least one inclusion 
criterion.
Significant protocol deviations will be listed and summarized. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for subjects in the safety set. 
Summaries will be presented by all subjects and each hepatic function group. Summary statistics 
(number of subjects (N), mean, SD, median, minimum, and maximum) will be presented for 
continuous variables (e.g., age, weight, and BMI), and the number and percentage of subjects 
within each category will be presented for categorical variables (e.g., sex, ethnicity, and race). 
Individual subject demographic and baseline characteristic data will be provided in the data 


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listings. In addition, baseline hepatic function parameters and Child-Pugh scores will be 
summarized by group. 
Demographic variables for screen failure subjects and reasons for screen failures will be
summarized for subjects who are screened but not enrolled in the study.
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant conditions or 
diseases that are present or ongoing at signing of informed consent.
Medical history and concurrent medical conditions will be coded by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA, version 20.0 or 
higher). No summary statistics for medical history and concurrent medical conditions will be 
provided. 
Medical history and concurrent medical conditions will be listed by site and subject number. The 
listing will contain subject identifier, hepatic function 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.
There will be no inferential analysis of medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 30 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 from signing of 
informed consent through the end of the study. No summary statistics for medication history and 
concomitant medications will be provided.
All medication history and concomitant medications will be listed by site and subject number. 
The listings will contain subject identifier, hepatic function 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 2018 March 
DDE B2 or higher.
7.7
Study Drug Exposure and Compliance
The date, start and end of infusion time of study drug administration in each group for each 
subject will be reported in the data listings. Summaries of TAK-954 PK data will be provided for 
each group, details can be found in section 7.9. No other summary statistics for the extent of 
exposure to study drug or compliance calculations will be performed.


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7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic Analysis
All PK summaries and analyses will be based on the PK set. 
PK blood for plasma concentration and urine samples for TAK-954 (and metabolites, if 
possible), and plasma protein binding will be collected as specified in the Schedule of Trial 
Procedures (See Appendix C). 
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.
7.9.1
Summary of Concentrations in Plasma
Descriptive statistics (e.g. mean, standard deviation, standard error, %CV, minimum, median and 
maximum) will be used to summarize concentrations of TAK-954 (and metabolites, if possible) 
according to the hepatic function group (healthy subjects and mild, moderate, severe hepatic 
impairment). If applicable, the amount of TAK-954 excreted in urine will also be summarized by 
hepatic function group using descriptive statistics. For protein binding data, concentration, 
unbound percentage, bound percentage and recovery percentage will be summarized according 
to hepatic function group using descriptive statistics.
Linear and semi-logarithmic plots of the mean and individual concentration-time curves will be 
provided. 
Individual concentration data will be presented in the data listing.
7.9.2
Analysis of Pharmacokinetic Parameters
PK parameters will be compared between normal and hepatically-impaired groups, classified by 
Child-Pugh Score and summarized descriptively. 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. 
The following plasma PK parameters (free and total) for TAK 954 will be calculated: 

Cmax

AUC∞

AUClast.
Specific or additional PK parameters may be added as appropriate per the Clinical Pharmacology 
Analysis Plan (CPAP).


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Descriptive statistics (e.g. mean, standard deviation, standard error, %CV, minimum, median and 
maximum) will be used to summarize PK parameters (expressed as free and total) according to 
the hepatic function group (healthy subjects and mild, moderate, severe hepatic impairment). In 
addition, geometric means will be calculated for Cmax and AUCs. 
All pharmacokinetic parameters will be provided in a data listing.
An analysis of variance (ANOVA) will be performed on log transformed Cmax, AUCs (total and 
free) and CL to compare each hepatically-impaired group with the normal hepatic function group 
and 90% confidence intervals for the ratio of central values from each hepatic impairment group 
versus normal function group will be provided. In addition, an analysis of covariance 
(ANCOVA) with hepatic function group as a fixed effect, age, gender and body weight as 
covariates will be performed on log transformed Cmax, AUCs (total and free) and CL to 
investigate effect of covariates on the relationship between TAK-954 PK parameters and level of 
hepatic impairment. Tests will be performed on all covariates, 0.05 significance level will be 
used.
In addition, the relationship between Child-Pugh scores, baseline serum bilirubin, serum
albumin, prothrombin time and TAK-954 Cmax, Cmaxu, AUClast, AUClastu, AUC∞and AUC∞u will 
be evaluated graphically. Regression approaches will be used to evaluate these relationships if 
appropriate.
Additional analyses will be included, if appropriate. Any deviation from the analysis plan will be 
reported in the Clinical Study Report.
Individual pharmacokinetic parameter data will be presented in the data listing.
7.10
Other Outcomes
Subject must sign a PGx informed consent/be consented for sampling of whole blood for PGx 
analysis to occur. PGx sampling is optional.
Whole blood samples for DNA and RNA isolation will be collected from each consented subject 
in the trial. If necessary and feasible, a second aliquot of blood may be taken at a later time point 
if isolation of DNA from the first sample was not successful or possible.
The sample collection information for PGx will be listed.
7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory evaluations, vital sign results, 12-lead ECG 
results, and other safety parameters. The safety set will be used for all summaries of safety 
parameters.
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 drug; it does not necessarily have to have a causal relationship with 


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study participation. A treatment-emergent adverse event (TEAE) is defined as any sign, 
symptom, syndrome, or new illness, regardless the relationship to study drug, which occurs on or 
after the administration of the study drug and no more than 30 days after receiving the study drug 
(onset data minus date of dose +1 ≤30). A TEAE may also be a pretreatment AE or a concurrent 
medical condition diagnosed prior to the date of study drug that increases in severity after the 
start of dosing. Any event with partially or completely missing onset date information will be 
considered treatment emergent unless the available information indicates that the onset occurred 
outside the window (onset data - date of dose +1 ≤30).
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA, version 20.0 or higher).
AEs are recorded in the eCRF as being related or not related to study drug and study procedure. 
AEs that are recorded as related to study drug and/or study procedure will be summarized 
separately. AEs will also be presented by intensity/severity (mild, moderate, and severe). 
When calculating the frequency and percentage of subjects who reported AEs, a subject will be 
counted only once for each SOC or PT when multiple AEs are coded to the same SOC or PT. For 
the intensity or relatedness summaries, if a subject reports multiple AEs coded to the same SOC 
or PT, the AE 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.
The TEAE summary tables will include numbers and percentages of subjects experiencing at 
least one TEAE by SOC and PT and will be tabulated by hepatic function groups and overall.
The following is a list of TEAE summary tables to be generated: 

Overview of TEAEs.

TEAEs by SOC and PT

Subject Mappings for TEAEs.

TEAEs by PT.

Serious TEAEs by SOC and PT

Most Frequent Non-Serious TEAEs by PT (>=5% subjects in any group)

Drug-Related TEAEs by SOC and PT.

Relationship of TEAEs to Study Drug by SOC and PT (related vs not related). 

Intensity of TEAEs by SOC and PT.

Intensity of Drug-Related TEAEs by SOC and PT. 

PTE by SOC and PT.


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Data listings will be provided for all AEs including TEAEs, AEs leading to trial drug 
discontinuation, and SAEs. 
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests consist of chemistry, hematology, urinalysis, and other tests. 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. Refer to Appendix C for 
scheduled clinical laboratory test measurements.
Clinical laboratory variables will be summarized by hepatic function group with descriptive 
statistics (N, mean, median, SD, minimum and maximum) for Baseline, postdose, and change 
from Baseline to postdose values. Instead of Calcium, corrected Calcium will be summarized. 
Corrected Calcium can be calculated via the following formulas.

In conventional units: Corrected Calcium [mg/dL] = (0.8 * (4[mg/dL] – Albumin[mg/dL])) + 
Calcium[mg/dL].

In SI units: Corrected Calcium [mmol/L] = (0.02 * (40[g/L] – Albumin[g/L])) + 
Calcium[mmol/L].
Here 4mg/L and 40g/L represent normal Albumin levels.
Only the scheduled measurements will be included in the summary. The baseline value will be 
defined as the pretreatment assessment immediately prior to administration of study drug. No 
inferential statistics will be presented. 
All clinical laboratory data in SI and conventional Units will be presented in the data listings.
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. No inferential statistics will be presented. 
For each vital sign parameter, boxplots for predose/ postdose values and the change from the 
predose by hepatic function group will be prepared.
Individual results of vital signs that meet Takeda’s markedly abnormal criteria (see Appendix A) 
will be summarized and provided in the data listings. If a subject has a MAV for a particular vital 
sign parameter, all visits for that subject for that parameter will be listed. The number and 
percentage of subjects with at least 1 postdose MAV signs measurement will be summarized by 
hepatic function group. The mapping of the subjects who meet the MAV criteria will be listed as 
a table. All observations, including ones at unscheduled visits, will be included in the MAV 
evaluation and summaries.
All vital sign results for all subjects in the Safety Set will be listed by subject in the data listings 
and markedly abnormal values will be flagged.


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7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix C. The ECG 
parameters include heart rate, PR-interval, QRS-duration, QT-interval, QTcF interval, and the 
interpretation of the ECG profile by the principal investigator. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters will 
be presented for baseline, each post-baseline visit, and changes from Baseline in quantitative 
ECG parameters to each post-baseline visit. Only the scheduled measurements will be included 
in the summary. If more than 1 ECG parameter is measured at the same scheduled time point, the 
latest value will be used. No inferential statistics will be presented.
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that meet 
Takeda’s markedly abnormal criteria (see Appendix B) will be provided in the data listings. Shift 
tables will be generated to show the investigator’s ECG interpretations at each postdose 
collection by the interpretation at Baseline.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5 Other Observations Related to Safety
Physical examination findings will be presented in the data listings.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan


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8.0
BASED ON CONSULTATION WITH PHARMACOVIGILANCE, THE 
CORRECTED CALCIUM WILL BE SUMMARIZED, RATHER THAN 
CALCIUM AS STATED IN THE PROTOCOL. REFERENCES
1. A Phase 1, Nonrandomized, Open-Label Trial to Evaluate the Effect of Hepatic 
Impairment on the Single Dose Pharmacokinetics of Intravenous TAK-954, Takeda 
Development Center Americas, Inc. and Takeda Development Centre Europe Ltd., 
Amendment 01, Trial No. TAK-954-1006, dated 06 October, 2017.


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Appendix A
Criteria for Abnormal Changes from Baseline of Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Heart Rate
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
<35.6
>37.7


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Appendix B
Criteria for Identification of Markedly Abnormal 12-Lead ECG Parameters
Parameter
Unit
Lower Criteria
Upper Criteria
HR
bpm
<50
>120 
QTcF-interval
msec
≤50
≥500 OR
≥30 change from baseline and
≥450 


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Appendix C
Schedule of Trial Procedures
Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
10-14 days after the dose
Hours Postdose
0
24
48
72
96
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
X
X
Semirecumbent vital signs (heart rate [HR], 
systolic blood pressure [SBP] and diastolic 
blood pressure [DBP]
X
X
X(a)
X
X
X
X
X
Vital signs (respiratory rate, oral [at the floor 
of the mouth]/tympanic temperature) 
X
X
Height
X
Weight
X
Body mass index (BMI)
X
Standard 12-lead electrocardiogram (ECG)
X
X
X (a)
X
X
X
X
Adverse event (AE) monitoring
X---------------------------------------------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Serum chemistry
X
X
X
X
Hematology (b) 
X
X
X
X
Urinalysis
X
X
X
X
Serum follicle-stimulating hormone (FSH)
X
Urine drug screen
X
X
Alcohol breath or urine alcohol test (c)
X
X
HIV test
X
Hepatitis panel
X
Urine pregnancy test (hCG)
X
Footnotes are on last table page.


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Assessment
Screening
Trial Days
Follow-up/Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
10-14 days after the dose
Hours Postdose
0
24
48
72
96
Pharmacokinetics (PK) Evaluations
Plasma samples for TAK-954 (d)
X
X
X
X
X
Urine sample for TAK-954 PK (e)
X
X
X
Plasma sample for protein binding (f)
X
Pharmacogenomic (PGx) Evaluations
Blood sample for DNA PGx (optional)
X
Blood sample for RNA PGx (optional)
X
Drug Administration
TAK-954 dosing 
X
Other
Confinement (g)
X
X
X
X
Meals
X
(a) Assessments at predose (within 30 minutes), 1 (just after the end of infusion), 2, and 4 hours postdose (relative to TAK-954 start infusion start). Additional blood pressure and 
HR assessments will be taken at 0.5 and 12 hours after the start of infusion.
(b) Complete blood count and for Screening Visit only, coagulation screen (prothrombin time, international normalized ratio [INR], and activated partial thromboplastin time).
(c) Additional alcohol breath or urine alcohol tests may be done at the discretion of the investigator.
(d) Time points for PK blood samples for TAK-954: predose (within 30 minutes), 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 and 96 
hours after start of infusion.
(e) Urine collected at predose, 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose (relative to TAK-954 infusion start).
(f) Plasma for protein binding: 1 and 12 hours postdose (relative to TAK-954 infusion start).
(g) Length of confinement may be extended at the investigator’s discretion.


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