Conditions: Healthy Volunteers
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the PK, safety and tolerability of phenylacetate and benzoate after intravenous administration of TAK-123 in Japanese healthy adult male participants.

Detailed description:
The drug being tested in this study is called TAK-123. TAK-123 is being tested in Japanese healthy adult men. This study will look at the PK, safety and tolerability of phenylacetate and benzoates of people who administered TAK-123.

The study will enroll approximately 10 participants. All participants will be administered TAK-123 intravenously at the dose level of 3.75 g/m\^2 of sodium phenylacetate and 3.75 g/m\^2 of sodium benzoate.

\- TAK-123 as 3.75 g/m\^2 of sodium phenylacetate and 3.75 g/m\^2 of sodium benzoate

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 8 days. Participants will make multiple visits to the clinic and be hospitalized for four days.

Arms:
arm 1: TAK-123 as 3.75 gram per square meter (g/m\^2) of sodium phenylacetate and 3.75 g/m\^2 of sodium benzoate, intravenous administration over 90 minutes, followed by TAK-123 as 3.75 g/m\^2 of sodium phenylacetate and 3.75 g/m\^2 of sodium benzoate, intravenous administration over 24 hours.

Interventions: intervention 1: TAK-123
Intervention descriptions: intervention 1: TAK-123 infusion

Protocol document:
Prot_000.pdf: 
Title: A Single Center, Open-Label, Phase 1 Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability of TAK-123 after Intravenous Infusion in Japanese Healthy 
Adult Male Subjects 
NCT Number: NCT04155567 
Protocol Approve Date: 10-OCT-2019 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


TAKEDA PHARMACEUTICALS 
PROTOCOL 
A Single Center, Open-Label, Phase 1 Study to Evaluate the Pharmacokinetics, Safety and 
Tolerability of TAK-123 after Intravenous Infusion in Japanese Healthy Adult Male 
Subjects 
 
 
 
Study Identifier: 
TAK-123-1001 
 
 
 
 
Compound: 
TAK-123 
 
 
 
 
Date: 
10 October 2019 
 
 
 
(English translation: 10 October 2019) 
 
 
Version/Amendment 
Number: 
Amendment 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TAK-123 
 
Study ID TAK-123-1001 
Page 2 of 66 
Protocol 
10 October 2019 
 
TABLE OF CONTENTS 
1.0 
STUDY SUMMARY...........................................................................................................6 
2.0 
STUDY SCHEMATIC ........................................................................................................9 
3.0 
SCHEDULE OF STUDY PROCEDURES .......................................................................10 
4.0 
INTRODUCTION .............................................................................................................11 
4.1 
Background ..................................................................................................................11 
4.2 
Rationale for the Proposed Study ................................................................................13 
4.3 
Benefit/Risk Profile .....................................................................................................13 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................15 
5.1 
Trial Objectives ............................................................................................................15 
5.1.1 
Trial Primary Objective .........................................................................................15 
5.1.2 
Trial Secondary Objective .....................................................................................15 
5.2 
Endpoints .....................................................................................................................15 
5.2.1 
Primary Endpoint ...................................................................................................15 
5.2.2 
Secondary Endpoints .............................................................................................15 
5.2.3 
Safety Endpoints ....................................................................................................15 
5.2.4 
Exploratory Endpoints ...........................................................................................15 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................16 
6.1 
Trial Design .................................................................................................................16 
6.2 
Rationale for Trial Design, Dose, and Endpoints ........................................................16 
6.2.1 
Rationale of Trial Design .......................................................................................16 
6.2.2 
Rationale for Dose .................................................................................................17 
6.2.3 
Rationale for Endpoints .........................................................................................17 
6.2.4 
Critical Procedures Based on Trial Objectives: Timing of Procedures .................18 
6.3 
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters ....................................................................................................................18 
6.4 
Trial Beginning and End/Completion ..........................................................................18 
6.4.1 
Definition of Beginning of the Trial ......................................................................18 
6.4.2 
Definition of End of the Trial ................................................................................18 
6.4.3 
Definition of Trial Discontinuation .......................................................................18 
6.4.4 
Criteria for Premature Termination or Suspension of the Trial .............................19 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............20 
7.1 
Inclusion Criteria .........................................................................................................20 
7.2 
Exclusion Criteria ........................................................................................................20 
7.3 
Excluded Medications, Supplements, Dietary Products ..............................................21 
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7.4 
Diet, Fluid, Activity .....................................................................................................22 
7.4.1 
Diet and Fluid ........................................................................................................22 
7.4.2 
Activity ..................................................................................................................23 
7.5 
Record of Discontinuation or Withdrawal of a Subject Before TAK-123 
Administration .............................................................................................................23 
7.6 
Criteria for Discontinuation or Withdrawal of a Subject .............................................24 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject .......................................25 
7.8 
Subject Replacement ....................................................................................................25 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................27 
8.1 
Clinical Study Drug .....................................................................................................27 
8.1.1 
Clinical Study Drug Labeling ................................................................................27 
8.1.2 
Clinical Study Drug Inventory and Storage ...........................................................27 
8.1.3 
Clinical Study Drug Blinding ................................................................................27 
8.1.4 
Randomization Code Creation and Storage ...........................................................27 
8.1.5 
Clinical Trial Blind Maintenance/Unblinding Procedure ......................................27 
8.1.6 
Accountability and Destruction of Sponsor-Supplied Drugs .................................28 
9.0 
STUDY PROCEDURES ...................................................................................................29 
9.1 
Administrative Procedures ...........................................................................................29 
9.1.1 
Informed Consent Procedure .................................................................................29 
9.1.2 
Inclusion and Exclusion .........................................................................................29 
9.1.3 
Medical History/Demography ...............................................................................29 
9.1.4 
Concomitant Medications ......................................................................................29 
9.2 
Clinical Procedures and Assessments ..........................................................................30 
9.2.1 
Full Physical Exam ................................................................................................30 
9.2.2 
Height and Weight .................................................................................................30 
9.2.3 
BMI ........................................................................................................................30 
9.2.4 
Vital Signs ..............................................................................................................30 
9.2.5 
12-Lead ECG .........................................................................................................30 
9.2.6 
Study Drug Administration ....................................................................................31 
9.2.7 
AE Monitoring .......................................................................................................31 
9.2.8 
Laboratory Procedures and Assessments ...............................................................31 
9.3 
PK Sample ...................................................................................................................33 
9.3.1 
PK Measurements ..................................................................................................33 
9.3.2 
Confinement ...........................................................................................................34 
10.0 
ADVERSE EVENTS .........................................................................................................36 
10.1 
Definitions and Elements of AEs .................................................................................36 
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10.1.1 SAEs ......................................................................................................................38 
10.1.2 Special Interest AEs ...............................................................................................39 
10.2 
AE Procedures .............................................................................................................39 
10.2.1 Assigning Severity/Intensity of AEs ......................................................................39 
10.2.2 Assigning Causality of AEs ...................................................................................40 
10.2.3 Assigning Causality of AEs to Study Procedures ..................................................40 
10.2.4 Start Date ...............................................................................................................40 
10.2.5 End Date.................................................................................................................40 
10.2.6 Pattern of Adverse Event (Frequency) ...................................................................40 
10.2.7 Action Taken with Study Treatment (Administration of TAK-123) .....................40 
10.2.8 Outcome .................................................................................................................41 
10.2.9 Collection and Reporting of AEs, SAEs, and Abnormal LFTs .............................41 
10.2.10 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities .............43 
11.0 
STATISTICAL METHODS ..............................................................................................45 
11.1 
Statistical and Analytical Plans ....................................................................................45 
11.1.1 Analysis Sets ..........................................................................................................45 
11.1.2 Analysis of Demography and Other Baseline Characteristics ...............................45 
11.1.3 PK Analysis ...........................................................................................................45 
11.1.4 Safety Analysis ......................................................................................................45 
11.2 
Interim Analysis and Criteria for Early Termination ...................................................46 
11.3 
Determination of Sample Size .....................................................................................46 
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................47 
12.1 
Study-Site Monitoring Visits .......................................................................................47 
12.2 
Protocol Deviations ......................................................................................................47 
12.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................47 
13.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................48 
13.1 
IRB Approval ...............................................................................................................48 
13.2 
Subject Information, Informed Consent, and Subject Authorization ..........................48 
13.3 
Subject Confidentiality ................................................................................................49 
13.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................50 
13.4.1 Publication and Disclosure ....................................................................................50 
13.4.2 Clinical Trial Registration ......................................................................................50 
13.4.3 Clinical Trial Results Disclosure ...........................................................................51 
13.5 
Insurance and Compensation for Injury .......................................................................51 
14.0 
ADMINISTRATIVE AND REFERENCE INFORMATION ...........................................52 
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14.1 
Administrative Information .........................................................................................52 
14.1.1 Study Contact Information .....................................................................................52 
14.1.2 Investigator Agreement ..........................................................................................52 
14.1.3 Study-Related Responsibilities ..............................................................................52 
14.1.4 List of Abbreviations .............................................................................................52 
15.0 
DATA HANDLING AND RECORDKEEPING ..............................................................54 
15.1 
eCRFs ...........................................................................................................................54 
15.2 
Record Retention .........................................................................................................54 
16.0 
REFERENCES ..................................................................................................................56 
17.0 
APPENDICES ...................................................................................................................57 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Dosage of TAK-123 ...............................................................................................16 
Table 6.b 
Dosage of ondansetron ...........................................................................................16 
Table 7.a 
Excluded Medications, Supplements, and Dietary Products .................................22 
Table 9.a 
Primary Specimen Collections ...............................................................................33 
Table 9.b 
Sampling of blood samples for PK analysis ..........................................................34 
Table 9.c 
Sampling of urine samples for PK analysis ...........................................................34 
Table 10.a 
Takeda Medically Significant AE List ..................................................................39 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Alternative-Pathway Therapy for Nitrogen Disposal by Phenylacetate and 
Benzoate .................................................................................................................13 
 
LIST OF APPENDICES 
Appendix A 
Responsibilities of the Investigator ........................................................................57 
Appendix B 
Elements of the Subject Informed Consent ...........................................................58 
Appendix C 
Investigator Consent to the Use of Personal Information ......................................61 
Appendix D 
Pregnancy and Contraception ................................................................................62 
Appendix E 
Acceptable Time Window for Study Procedure ....................................................65 
 
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Study ID TAK-123-1001 
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1.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceuticals 
Compound: 
TAK-123 
Study Identifier: TAK-123-1001 
Phase: 1 
Protocol Title: A Single Center, Open-Label, Phase 1 Study to Evaluate the Pharmacokinetics, Safety and 
Tolerability of TAK-123 after Intravenous Infusion in Japanese Healthy Adult Male Subjects 
Trial Design: 
This study is a single-center, open-label, uncontrolled study. 
In this study, TAK-123 will be administered intravenously as a loading dose over 90 minutes at the dose level of 
3.75 g/m2 of sodium phenylacetate and 3.75 g/m2 of sodium benzoate under the breakfast fasting condition, followed 
by an equivalent maintenance dose over 24 hours to evaluate the pharmacokinetics (PK), safety and tolerability of 
TAK-123 in Japanese healthy adult male subjects. 
A 4 mg of dose of ondansetron will be administered intravenously 30-40 minutes before the start of TAK-123 
infusion. 
Trial Primary Objective: 
To evaluate the PK of phenylacetate and benzoate after intravenous administration of TAK-123 in Japanese healthy 
adult male subjects. 
Secondary Objectives: 
To evaluate the safety and tolerability of phenylacetate and benzoate after intravenous infusion of TAK-123 in 
Japanese healthy adult male subjects. 
Trial Subject Population: Japanese healthy adult male subjects 
Planned Number of Subjects: 
10 subjects 
Planned Number of Sites: 
1 site 
Dose Levels: 
TAK-123 will be administered intravenously via a 
peripheral vein as loading dose over 90 minutes at the 
dose level of 3.75 g/m2 of sodium phenylacetate and 
3.75 g/m2 of sodium benzoate under the breakfast 
fasting condition, followed by maintenance dose over 
24 hours at the dose level of 3.75 g/m2 of sodium 
phenylacetate and 3.75 g/m2 of sodium benzoate. 
Route of Administration: 
Intravenous infusion via a peripheral vein 
Duration of Treatment: 
Over 90 minutes followed by over 24 hours 
Planned Trial Duration: 
Screening: Day -28 to -2 
Check-in: Day -1 
Treatment Period: Day 1 to 8 
Criteria for Inclusion: 
Subjects to participate in this study should meet all the following criteria. 
1. The subject is capable of understanding and complying with protocol requirements in the opinion of the 
investigator or sub-investigator. 
2. The subject signs and dates a written informed consent form prior to the initiation of any study procedures. 
3. The subject is a Japanese healthy adult male. 
4. The subject is aged 20 to 45 years inclusive at the time of informed consent. 
5. The subject weighs at least 50.0 kg, and has a body mass index (BMI) between 18.5 and 25.0 kg/m2, inclusive, at 
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Study ID TAK-123-1001 
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10 October 2019 
 
Screening. 
6. The subject is sterile, vasectomized or agrees to use an appropriate method of contraception during the predefined 
period in this study. 
Criteria for Exclusion: 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any study drugs within 90 days before screening for this study (including the cases that at 
least 5 times the elimination half-lives of any study drugs have not yet passed). 
2. The subject previously received TAK-123, its ingredients, or related compound before participation in this study 
except for the cases where benzoic acid is ingested as a food additive. 
3. The subject is an employee of the Sponsor or the study site, or immediate family member, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, 
sibling) or who may be forced to provide consent. 
4. The subject has previous or current history of diseases considered to be inappropriate for participation in this 
study, including uncontrolled, clinically relevant neurologic, cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, endocrine, hematologic, immune, skin disease or psychiatric disorder. 
5. The subject has a history of multiple episodes or severe allergies (eg, food, drug, latex allergy), or has had an 
anaphylactic reaction or significant intolerance to prescription drugs, over-the-counter drugs or foods. 
6. The subject has had an anaphylactic reaction to active ingredients or additives of TAK-123, ondansetron or 
additives of ondansetron, or salicylic acid associated with the intravenous administration of TAK-123. 
7. The subject has a positive urine drug test at the time of screening. 
8. The subject has a history of drug abuse (defined as any illicit drug use) or has a history of alcohol dependence 
within 2 years before the start of screening or is unwilling to agree to abstain from alcohol and drugs throughout 
the study. 
9. The subject consumes 6 or more servings of caffeinated beverages (containing about 720 mg of caffeine or more) 
such as coffee, tea, cola, or energy drinks per day. 
10. The subject is a smoker who smoked cigarettes or used nicotine-containing products (such as nicotine patch) 
within 6 months before the study drug administration. 
11. The subject has a history of cancer. 
12. The subject has a positive test result for any of the following at the time of screening: hepatitis B surface antigen 
(HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, serological 
test for syphilis. 
13. The subject has poor peripheral venous access. 
14. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL 
within 12 weeks (84 days) prior to the start of study drug administration. 
15. The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to 
the start of study drug administration. 
16. The subject has undergone blood component collection within 2 weeks (14 days) prior to the start of study drug 
administration. 
17. The subject has any clinically relevant abnormality in vital signs or 12-lead ECG at screening or predose of Day 1. 
18. The subject has abnormal laboratory test values at screening or Day -1 indicating clinically relevant underlying 
disease, or showing alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5×upper limit of 
normal (ULN). 
19. The subject has been on an abnormal diet (eg, excessive drinking and eating or starvation condition) during the 4 
weeks prior to the start of study drug administration in the opinion of the investigator or sub-investigator. 
20. The subject who used or plans to use excluded concomitant medications, supplements, or dietary products (see 
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Study ID TAK-123-1001 
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Protocol 
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Table 7.a) during the predefined period in this study. 
21. The subject is unlikely to comply with the protocol requirements or is unsuitable as a subject of this study for any 
other reason in the opinion of the investigator or sub-investigator. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint of the study is: 
PK parameters: PK parameters (Cmax, AUClast, AUC∞) of phenylacetate, benzoate, and these metabolites 
(phenylacetylglutamine and hippurate). 
The secondary endpoints will be assessed through evaluation of the following parameters: 
Safety: Number of subjects with treatment-emergent adverse events (TEAEs) 
Statistical Considerations: 
PK Analysis: 
The following analyses will be performed in the PK analysis set. 
Plasma concentrations of phenylacetate, benzoate, and these metabolites (phenylacetylglutamine and hippurate) will 
be summarized over each scheduled sampling time using descriptive statistics. Plasma and urine PK parameters of 
phenylacetate, benzoate, and these metabolites (phenylacetylglutamine and hippurate) will be summarized using 
descriptive statistics. 
Safety Analysis: 
The following analyses will be performed in the safety analysis set. 
A TEAE refers to an AE that occurs on or after the start of the administration of TAK-123. The frequency of all 
TEAEs, TEAEs related to TAK-123, all TEAEs by intensity, TEAEs related to TAK-123 by intensity, TEAEs leading 
to TAK-123 discontinuation and serious TEAEs will be summarized. TEAEs will be coded using Medical Dictionary 
for Regulatory Activities Terminology (MedDRA) and summarized by system organ class (SOC) and preferred term 
For continuous variables, the observed values and changes from baseline will be summarized for each scheduled 
sampling time using descriptive statistics. For categorical variables, shift tables showing the number of subjects in 
each category at baseline and each post-baseline scheduled sampling time will be provided. 
Sample Size Justification: 
The sample size of 10 subjects is chosen to evaluate PK, safety and tolerability of TAK-123. The sample size is not 
based on statistical power considerations. 
 
 
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2.0 
STUDY SCHEMATIC 
Period 
Screening Period 
Treatment Period 
Day 
-28～-2 
-1 
1 
2 
3 
… 
8 
Visit/ 
Confinement 
Visit 
Confinement 
 
Visit 
Procedure 
Informed consent/ 
Screening tests 
Check-in/Examinations 
Administration of study 
drug 
Examinations 
Examinations/Discharge 
 
Follow-up 
 
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3.0 
SCHEDULE OF STUDY PROCEDURES 
 
Screening Period 
Treatment Period 
Study Day: 
Day -28~ Day 
-2 (At 
Screening) 
Day -1 
(Check in) 
Day 1 
Day 2 
Day 3 
(Discharge) 
Early 
Termination 
Day 8 
(Follow-up) 
Confinement 
 
X 
X 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria (a) 
X 
 
X 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
Physical examination (b) 
X 
X 
X 
X 
X 
X 
X 
Vital signs (c) 
X 
 
X 
X 
X 
X 
X 
Weight, height, and BMI (d) 
X 
 
X 
 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
(ECG) (e) 
X 
 
X 
 
X 
X 
X 
Clinical laboratory tests (f)(g) 
X 
X 
X (h) 
X 
X 
X 
X 
Blood gas tests (i) 
 
X 
X 
X 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
Immunology tests 
X 
 
 
 
 
 
 
Dosing of the Study Drug (j) 
 
 
X---------X 
 
 
 
PK blood collection (k) 
 
 
X 
X 
X 
X (l) 
 
PK urine collection (m) 
 
 
X 
X 
X 
 
 
AE assessment (n) 
X 
X-----------------------------------------------------------------------------X 
(a) Check of the inclusion/exclusion criteria will be done at Screening and predose (Day 1 before the administration of TAK-123). 
(b) Physical examination will be performed at Screening (Day -28 to -2), Day -1, predose, 4, 25.5 and 48 hours after the start of 
TAK-123 infusion and Day 8 or at Early Termination. 
(c) The sitting blood pressure (resting more than 5 minutes), sitting pulse rate, respiratory rate, and body temperature (axillary) will 
be measured at Screening, predose, 1.5, 4, 25.5 and 48 hours after the start of TAK-123 infusion and Day 8 or at Early 
Termination. 
(d) Weight will be measured at Screening, predose, 48 hours after the start of TAK-123 infusion and Day 8 or at Early Termination. 
Height will be measured only at Screening. 
BMI will be calculated at Screening. 
(e) The 12-lead ECG will be measured at Screening, predose, 1.5 and 48 hours after the start of TAK-123 infusion and Day 8 or at 
Early Termination. 
(f) Laboratory tests include hematology, serum chemistry, and urinalysis. Blood samples will be collected at Screening, Day -1, 
25.5 and 48 hours after the start of TAK-123 infusion and Day 8 or at Early Termination after fasting for at least 8 hours. 
(g) Glucose level will be assessed at Day -1, 1 and 1.5 hours after the start of TAK-123 infusion by a self-monitoring blood glucose 
meter. 
(h) Blood samples for laboratory tests (Na, K, Cl) will be collected at 1.5 hours after the start of TAK-123 infusion in addition to 
the time points stipulated in (f). 
(i) Blood gas tests will be performed at Day -1, 1.5 and 25.5 hours after the start of TAK-123 infusion. 
(j) A 4 mg of dose of ondansetron will be administered intravenously 30-40 minutes before the start of TAK-123 infusion. 
(k) PK blood samples will be collected at predose (from waking-up to immediately before the administration of TAK-123) and 
0.25, 0.75, 1.5, 2.5, 4.5, 6.5, 8.5, 10.5, 12.5, 16.5, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29.5, 30.5, 32.5 and 48 hours after the start 
of TAK-123 infusion. 
(l) Measured only if the subject discontinues the study within 48 hours after the start of TAK-123 infusion. 
(m) PK urine samples will be collected at predose (spot), 0-24 and 24-48 hours after the start of TAK-123 infusion. 
(n) The collection of AEs will commence from the time the subject signs the informed consent at Screening and continue until the 
follow-up examination. 
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4.0 
INTRODUCTION 
4.1 
Background 
Urea cycle disorders (UCD) is an inborn metabolic disorder caused by a deficiency of one of 
enzymes involved in the urea cycle, leading to hyperammonemia as a result of inhibited 
conversion of ammonia to urea. As clinical symptoms, non-specific neuropathies, such as 
vomiting, anorexia, multiple breathing, convulsions, disturbance of consciousness, behavior 
abnormalities, developmental disorders, etc. are observed in many patients. Especially in neonates 
with severe deficits, the disease occurs soon after birth or in the first year of life. Neonatal-onset 
UCD usually has a severe clinical course, possibly resulting in fatal cases. Thus, UCD is a serious 
disease [1]. The estimated incidence of UCD is one in 8000 to 44,000 births, and 286 patients of 
those who were registered with inborn error of metabolism (4778 patients in total) had UCD 
according to the nationwide registry survey conducted by Medical Aid Program for Chronic 
Pediatric Diseases of Specified Categories in 2011 [2]. The distribution by disease category was as 
follows: 16 patients with carbamoylphosphate synthetase (CPS) deficiency; 76 patients with 
ornithine transcarbamylase (OTC) deficiency, 120 patients with argininosuccinate synthetase 
(ASS) deficiency, 8 patients with argininosuccinate lyase (ASL) deficiency, 6 patients with 
arginase (ARG) deficiency, and 51 patients with hyperammonemia. 
Rapid reduction of blood ammonia levels is given the highest priority for the treatment of 
hyperammonemia to improve neurological abnormality such as encephalopathy and comatose and 
avoid fatal cases and irreversible neurologic damage. For the treatment of hyperammonemia in 
Japan, oral administration of sodium phenylbutyrate (Buphenyl®) and intravenous administration 
of sodium benzoate (NaBZ) by in-house preparation of reagents are performed as a drug treatment 
with a nitrogen scavenger. However, oral sodium phenylbutyrate takes time to show its efficacy 
because it undergoes an absorption process in the gastrointestinal tract. Therefore, a stable and 
immediate efficacy cannot be expected in a case of an acute attack accompanied by 
gastrointestinal symptoms. Furthermore, quite a few patients have a difficulty to take oral 
medication. Also, currently NaBZ is prepared from reagents at hospitals, and thus, it is difficult to 
assure its quality. Consequently, the current therapeutic environment for acute hyperammonemia 
is insufficient in Japan. 
TAK-123 is a sterile, concentrated, aqueous injectable solution containing 10% sodium 
phenylacetate (NaPA) and 10% NaBZ that has been marketed in the US for the treatment of acute 
hyperammonemia and associated encephalopathy in patients with UCD. In Japan, upon the written 
request for the development of new drugs submitted by the Japanese Society for Inherited 
Metabolic Diseases, the Evaluation Committee on Unapproved or Off-labeled Drugs with High 
Medical Needs publicly sought for companies to develop new drugs for UCD in May 2010, and we 
declared our intent to develop TAK-123 to the MHLW. 
The active ingredients of TAK-123 are NaPA and NaBZ. Both compounds are considered nitrogen 
scavengers; they exert their therapeutic effects by binding waste nitrogen as an alternative pathway 
to the urea cycle so that it can be excreted in the urine (Figure 4.a). NaPA conjugates with 
glutamine that is formed by 2 molecules of ammonia, being excreted as phenylacetylglutamine 
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into the urine. As a result, 2 moles of waste nitrogen are removed per mole of NaPA. NaBZ 
conjugates with glycine that is formed by one molecule of ammonia, being excreted as hippurate 
into the urine. As a result, 1 mole of waste nitrogen is removed per mole of NaBZ. TAK-123 with 
the following characteristics is expected to contribute to the improvement of the prognosis of UCD 
patients by lowering plasma ammonia concentrations more steadily and more rapidly, compared to 
the currently available pharmacotherapies for hyperammonemia in patients with UCD. 
Phenylacetate and benzoate, free-forms of NaPA and NaBZ, are nitrogen scavengers through 
different routes other than the urea cycle. Consequently, it can be expected that TAK-123 lowers 
ammonia concentrations in the plasma of UCD patients whose function of urea cycle is not 
sufficient. 
TAK-123, as an injection, can be administered in a case of an acute attack accompanied by 
gastrointestinal symptoms, and is expected to have faster onset of therapeutic effects than oral 
medicine. 
The PK, safety and tolerability of TAK-123 in non-Japanese healthy subjects after intravenous 
infusion of TAK-123 have been evaluated in 2 clinical studies (Study 951603 and Study 973600). 
In this study, the PK, safety and tolerability of NaPA and NaBZ, and these metabolites 
(phenylacetylglutamine and hippurate) after the administration of TAK-123 will be evaluated in 
Japanese healthy adult male subjects. 
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Figure 4.a 
Alternative-Pathway Therapy for Nitrogen Disposal by Phenylacetate and 
Benzoate 
 
ARG: arginase, ASL: argininosuccinate lyase, ASS: argininosuccinate synthetase, ATP: adenosine triphosphate 
CPS: carbamoyl phosphate synthetase, NAGS: N-acetylglutamate synthethase, OTC: ornithine transcarbamylase 
4.2 
Rationale for the Proposed Study 
The efficacy and safety of TAK-123 in patients with hyperammonemia were confirmed in a 
foreign clinical study involving patients with UCD. Also, the PK, safety and tolerability of NaPA 
and NaBZ (active ingredients of TAK-123) and these metabolites (phenylacetylglutamine and 
hippurate) have been reported from 2 foreign studies in healthy volunteers (Study 951603 and 
Study 973600). TAK-123 is currently on the US market for the treatment of acute 
hyperammonemia and associated encephalopathy in patients with UCD. This study was planned to 
evaluate the PK, safety and tolerability of NaPA, NaBZ and these metabolites 
(phenylacetylglutamine and hippurate) following administration of TAK-123 to Japanese healthy 
adult male subjects. 
4.3 
Benefit/Risk Profile 
There is no benefit to subjects in this clinical study since this is a healthy volunteer study. 
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Subjects who participate in this study may have adverse events and other risks associated with 
administration of the study drug. Therefore, subjects will be informed of possible risks before the 
participation in this study, and will be explained at the time of informed consent that they are free 
to withdraw from the study at any time without giving a reason. 
In a multi-center, open-label, uncontrolled study conducted in overseas for 21 years (1982 to 2003), 
316 patients with UCD comprising 1045 hyperammonemia episodes were treated with TAK-123. 
Adverse events (AEs) were reported for 52% of patients (163/316 patients) and 31% of episodes 
(319/1045 episodes). AEs with the incidence ≥6% of subjects included vomiting (9% of subjects 
and 7% of episodes; the same applies below), hypokalaemia (7% and 3%), hyperglycaemia (7% 
and 2%), seizure (6% and 2%), and mental impairment (6% and 2%). Adverse drug reactions 
(ADRs) with the incidence ≥6% of subjects included vomiting (8% and 6%) and hypokalaemia 
(6% and 2%). 
For the clinical safety information on TAK-123, please refer to the US package insert of Ammonul 
[3] and the Investigator’s Brochure of TAK-123. 
This study will be conducted in the light of the mechanism of action of TAK-123, non-clinical data, 
clinical data from foreign clinical studies conducted to date, and overseas safety information in 
order to minimize potential risks. The procedures may be changed during the study period as 
needed based on emerging safety information. 
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5.0 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1 
Trial Objectives 
5.1.1 Trial Primary Objective 
The primary objective of the study is to evaluate the PK of phenylacetate and benzoate after 
intravenous infusion of TAK-123 in Japanese healthy adult male subjects. 
5.1.2 Trial Secondary Objective 
The secondary objective of the study is to evaluate the safety and tolerability of TAK-123 after 
intravenous infusion of TAK-123 in Japanese healthy adult male subjects. 
5.2 
Endpoints 
5.2.1 Primary Endpoint 
PK parameters: 
PK parameters (Cmax, AUClast, AUC∞) of phenylacetate, benzoate, and these metabolites 
(phenylacetylglutamine and hippurate). 
5.2.2 Secondary Endpoints 
Safety: Number of subjects with treatment-emergent adverse events (TEAEs) 
5.2.3 Safety Endpoints 
Safety: TEAEs, laboratory tests, vital signs, body weight, and 12-lead ECG 
5.2.4 Exploratory Endpoints 
PK: 
• 
Plasma PK parameters (tmax, t1/2z, λz) of phenylacetate, benzoate, and these metabolites 
(phenylacetylglutamine and hippurate) 
• 
Urinary excretion amounts (Ae) and excretion ratios (fe) of phenylacetate, benzoate, and these 
metabolites (phenylacetylglutamine and hippurate) 
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6.0 
TRIAL DESIGN AND DESCRIPTION 
6.1 
Trial Design 
This study is a single-center, open-label, uncontrolled study. 
In this study, TAK-123 will be administered intravenously as a loading dose over 90 minutes at the 
dose level of 3.75 g/m2 of NaPA and 3.75 g/m2 of NaBZ under the breakfast fasting condition, 
followed by an equivalent maintenance dose over 24 hours to evaluate the PK, safety and 
tolerability of TAK-123 in Japanese healthy adult male subjects. 
A 4 mg of dose of ondansetron will be administered intravenously 30-40 minutes before the start 
of TAK-123 infusion. 
The dose of TAK-123 to be investigated is shown in Table 6.a. The dose of ondansetron to be 
administered before the administration of TAK-123 is shown in Table 6.b. 
Table 6.a 
Dosage of TAK-123 
Study drug 
Dose 
Mode of administration 
TAK-123 
3.75 g/m2 of NaPA and 
3.75 g/m2 of NaBZ 
1) Intravenous infusion (via a peripheral vein) over 90 minutes as a 
loading dose 
2) An equivalent intravenous infusion (via a peripheral vein) over 24 
hours as a maintenance dose after the completion of the above 1). 
 
Table 6.b 
Dosage of ondansetron 
Premedication 
Dose 
Mode of administration 
Ondansetron 
4 mg 
Slow intravenous infusion 
6.2 
Rationale for Trial Design, Dose, and Endpoints 
6.2.1 Rationale of Trial Design 
Japanese healthy adult male subjects will be enrolled in this study in order to appropriately 
evaluate the PK of TAK-123 in Japanese. An open-label, uncontrolled design is adopted for this 
study to evaluate the PK profile following intravenous infusion of TAK-123 to Japanese subjects. 
In a previous clinical PK study of TAK-123 with healthy adult volunteers conducted in the US 
(Study 951603), 2 of 3 subjects with a dose of 5.5 g/m2 experienced severe vomiting, although 
antiemetic drug, ondansetron, was co-administrated during the first 15 minutes. Therefore, all 
remaining subjects after the first 3 subjects in the same study and all subject in another clinical 
study with healthy volunteers had been pretreated with ondansetron. Although several subjects 
experienced moderate or mild nausea and/or vomiting at a dose levels of 3.75 g/m2 or 4 g/m2 under 
the pretreatment of ondansetron, subjects were generally well tolerated. Consequently, it is 
considered that pretreatment of ondansetron is needed for this study with healthy volunteers in 
consideration of ensuring the subject’s safety. 
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6.2.2 Rationale for Dose 
The dosage of TAK-123 in this study was set by referring to the approved dosage in the US and 
results from a PK study of TAK-123 in healthy volunteers conducted in the US (Study 951603). 
As for the approved dosage of TAK-123 in the US, for patients whose body weight exceeds 20 kg, 
TAK-123 is administered through a central intravenous catheter as a loading dose infusion over 90 
to 120 minutes at the dose level of 5.5 g/m2 of NaPA and 5.5 g/m2 of NaBZ, followed by an 
equivalent maintenance dose infusion over 24 hours. 
On the other hand, in the PK study (Study 951603), TAK-123 was administered intravenously as a 
loading dose infusion over 90 minutes at the start dose level of 5.5 g/m2 of NaPA and 5.5 g/m2 of 
NaBZ, followed by an equivalent maintenance dose infusion over 24 hours. However, nausea and 
vomiting were occured in all of the initial 3 subjects at the dose of 5.5 g/m2. Thus, all of the rest 
subjects were administered at the decreased dose of 3.75 g/m2. As a result, PK profiles of 
phenylacetate and benzoate in healthy volunteers were evaluated at the doses of 3.75 g/m2 in 17 
subjects and 5.5 g/m2 in 3 subjects. Even though limited PK data were available following the 
5.5 g/m2 dose, this was approved at the dose of TAK-123 in the US. 
Considering AEs observed at 5.5 g/m2 above, administration at the dose of 5.5 g/m2 to healthy 
volunteers could be difficult from the tolerability point of view also in this study. In addition, PK 
of TAK-123 will be compared between Japanese and non-Japanese by using results from this 
study in the future. Consequently, 3.75 g/m2 was selected as the dosage to be investigated in this 
study. The US package insert states that TAK-123 must be administrated through a central 
intravenous catheter. However, administration through a central line is more invasive than that via 
a peripheral line, imposing a greater burden on patients. In PK studies conducted outside Japan for 
healthy volunteers (Study 951603 and Study 973600) where TAK-123 was administered through a 
peripheral intravenous catheter, no AE related to administration site was observed. In addition, as 
described above, the healthy volunteers will be entered to this study and the result of this study will 
be compared with that of studies conducted outside Japan in the future. Thus, the administration 
route through a peripheral intravenous catheter, was chosen for this study. 
The 0.15 mg/kg of the approved dose for Ondansetron which has an indication for nausea and 
vomiting with treatment of anticancer drug in the US was pre-treated in the PK study conducted 
outside Japan. The 4 mg of Ondansetron will be pre-treated in this study according to the 
administration and dosage for Ondansetron in Japan because Ondansetron was approved in the 
dose of 4 mg. 
6.2.3 Rationale for Endpoints 
Since the primary objective of this study is to characterize the PK of TAK-123 in Japanese healthy 
adult male subjects, PK parameters (Cmax, AUClast, and AUC∞) of phenylacetate, benzoate, and 
these metabolites (phenylacetylglutamine and hippurate) were set as primary endpoints. 
Endpoints that are generally used in Phase 1 studies involving healthy adult male subjects were 
chosen as the endpoints for evaluating the safety and tolerability of TAK-123 administered as 
intravenous infusion in this study. 
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6.2.4 Critical Procedures Based on Trial Objectives: Timing of Procedures 
The objective of this section is to specify the sequence of procedures in the cases where the timing 
of each procedure overlaps. 
• Safety evaluation will be conducted within the predetermined allowance window as far as 
possible. 
• Blood samples for PK assessment will be collected at time points as close to the specified time 
as possible. 
• Other procedures must be completed at time points as close to the specified or planned hours as 
possible irrespective of before or after the specified times. 
• If the timing of blood sampling and ECG or vital signs measurement overlap, blood sampling 
should be prioritized. ECG or vital signs measurement may be performed before blood 
sampling within an acceptable time window (Appendix E). 
6.3 
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters 
The acceptable time windows for each examination/test, observation, and evaluation are defined 
(Appendix E). 
6.4 
Trial Beginning and End/Completion 
6.4.1 Definition of Beginning of the Trial 
The entire study will start when the first subject signs the informed consent form to participate in 
this study. 
6.4.2 Definition of End of the Trial 
The entire study will end when the last subject completes the last planned visit or follow-up visit or 
is withdrawn from the study or lost to follow-up (the status that the subject cannot be reached by 
the investigator or sub-investigator). 
6.4.3 Definition of Trial Discontinuation 
The study may be discontinued for reasons other than safety such as the followings: 
• 
A finding (eg, PK, pharmacodynamics, efficacy, biologic targets) from the other nonclinical 
or clinical studies results with the study drug in the study discontinuation for non-safety 
related reasons. 
• 
Data from drugs classified in the same class as the study drug, or methodologies used in this 
study become available and results in the study being stopped for a non-safety related reasons. 
• 
Study discontinuation due to non-scientific and non-safety-related reasons, such as slow 
enrollment. 
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Discontinuation of the clinical study for safety reasons: 
• 
The study is prematurely terminated because other clinical, non-clinical trials, or commercial 
use in launched regions where the study drug or other drugs of the same class are administered 
have confirmed unexpected safety concerns based on the methodology used in this study. 
6.4.4 Criteria for Premature Termination or Suspension of the Trial 
6.4.4.1 Criteria for Premature Termination or Suspension of Trial 
The study will be completed as planned unless 1 or more of the following criteria are met that 
require temporary suspension or early termination of the study. 
• 
New information or other evaluation regarding the safety or efficacy of TAK-123 that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety. 
6.4.4.2 Criteria for Premature Termination or Suspension of a Site 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise is permitted by the contractual agreement. 
6.4.4.3 Procedures for Premature Termination or Suspension of a Site 
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend of the 
entire study or the study site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by the applicable study sites during the 
course of termination or study suspension. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
7.1 
Inclusion Criteria 
Subjects to participate in this study should meet all the following criteria. 
1. The subject is capable of understanding and complying with protocol requirements in the 
opinion of the investigator or sub-investigator. 
2. The subject signs and dates a written informed consent form prior to the initiation of any study 
procedures. 
3. The subject is a Japanese healthy adult male. 
4. The subject is aged 20 to 45 years inclusive at the time of informed consent. 
5. The subject weighs at least 50.0 kg, and has a body mass index (BMI) between 18.5 and 
25.0 kg/m2, inclusive, at Screening. 
6. The subject is sterile, vasectomized or agrees to use an appropriate method of contraception 
during the predefined period in this study. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any study drugs within 90 days before screening for this study 
(including the cases that at least 5 times the elimination half-lives of any study drugs have not 
yet passed). 
2. The subject previously received TAK-123, its ingredients, or related compound before 
participation in this study except for the cases where benzoic acid is ingested as a food 
additive. 
3. The subject is an employee of the study site, or immediate family member, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, sibling) or who may be forced to provide consent. 
4. The subjects have previous or current history of diseases that may affect the participation in 
this study or study results, including uncontrolled, clinically relevant neurologic, 
cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, endocrine, hematologic, 
immune, skin disease or psychiatric disorder. 
5. The subject has a history of multiple episodes or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerance to prescription drugs, 
over-the-counter drugs or foods. 
6. The subject has had an anaphylactic reaction to active ingredients or additives of TAK-123, 
ondansetron or additives of ondansetron, or salicylic acid associated with the intravenous 
administration of TAK-123. 
7. The subject has a positive urine drug test at the time of screening. 
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8. The subject has a history of drug abuse (defined as any illicit drug use) or has a history of 
alcohol dependence within 2 years before the start of screening or is unwilling to agree to 
abstain from alcohol and drugs throughout the study. 
9. The subject consumes 6 or more servings of caffeinated beverages (containing about 720 mg 
of caffeine or more) such as coffee, tea, cola, or energy drinks per day. 
10. The subject is a smoker who smoked cigarettes or used nicotine-containing products (such as 
nicotine patch) within 6 months before the study drug administration. 
11. The subject has a history of cancer. 
12. The subject has a positive test result for any of the following at the time of screening: hepatitis 
B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus 
(HIV) antibody/antigen, serological test for syphilis. 
13. The subject has poor peripheral venous access. 
14. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) 
or at least 400 mL within 12 weeks (84 days) prior to the start of the study drug administration. 
15. The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks 
(364 days) prior to the start of the study drug administration. 
16. The subject has undergone blood component collection within 2 weeks (14 days) prior to the 
start of the study drug administration. 
17. The subject has any clinically relevant abnormality in vital signs or 12-lead ECG at screening 
or predose of Day 1. 
18. The subject has abnormal laboratory test values at screening or Day -1 indicating clinically 
relevant underlying disease, or showing alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >1.5 × upper limit of normal (ULN). 
19. The subject has been on an abnormal diet (eg, excessive drinking and eating or starvation 
condition) during the 4 weeks (28 days) prior to the start of the study drug administration in the 
opinion of the investigator or sub-investigator. 
20. The subject who used or plans to use excluded concomitant medications, supplements, or 
dietary products (see Table 7.a) during the predefined period in this study. 
21. The subject is unlikely to comply with the protocol requirements or is unsuitable as a subject of 
this study for any other reason in the opinion of the investigator or sub-investigator. 
7.3 
Excluded Medications, Supplements, Dietary Products  
Table 7.a shows excluded medications, supplements, and dietary products. 
Use of the drugs listed on Table 7.a (prescribed drugs and over-the-counter drugs), vitamins, 
supplements, and dietary products will be excluded from a specified time point to until discharge 
or the follow-up visit (Day 8) given the effect on the safety and PK. Use of prohibited concomitant 
drugs will be allowed when the investigator or sub-investigator deems it necessary to use any of 
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the concomitant drugs for reasons including treatment of an AE (eg, when nausea and/or vomiting 
occur as AEs during or after the administration of TAK-123, 4 mg of ondansetron can be used 
additionally only once for such symptoms if judged as necessary by the investigator or 
sub-investigator). 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator or sub-investigator. 
Table 7.a 
Excluded Medications, Supplements, and Dietary Products 
From 28 days before 
TAK-123 administration 
(Day 1) to the follow-up 
visit (Day 8) 
From 7 days before 
TAK-123 administration 
(Day 1) to the follow-up 
visit (Day 8) 
From 7 days before 
TAK-123 administration 
(Day 1) to the discharge 
From 24 hours before 
TAK-123 administration 
(Day 1) to the discharge 
• Prescription drugs 
• over-the-counter drugs 
• Supplements (St. 
John’s wort, ginseng, 
kava-kava, ginkgoes 
biloba, and melatonin) 
• Chinese herbal 
medicines 
• Vaccination/vaccine 
• Nicotine-containing 
products 
• Grapefruit/grapefruit 
juice 
• Char-broiled meat 
• Vitamins 
• Alcohol-containing 
products 
• Cruciferous vegetables 
(eg, kale, broccoli, 
watercress, collard 
green, kohlrabi, sprout, 
mustard) 
• Caffeine-containing 
products 
• Xanthine-containing 
products 
Note: Excludes the drug needs to be administered to treat an AE and if the investigator or sub-investigator considers 
necessary to use the drug 
7.4 
Diet, Fluid, Activity 
7.4.1 Diet and Fluid 
Diet and fluid (except water) must be ingested at least 8 hours before performing clinical 
laboratory tests. 
On the day before clinical laboratory tests, evening meal must be ingested by 21:00. 
During hospitalization, pre-specified diets must be ingested, and other diets will be prohibited. 
After discharge, excessive drinking and eating must be avoided until completion of follow-up 
period (Day 8). 
Subjects will be instructed to fast from at least 8 hours before the start of TAK-123 infusion to 4 
hours after the start of TAK-123 infusion. 
Subjects will take low-fat/high-carbohydrate diets after the start of TAK-123 infusion to the 
discharge. Subjects will take the first and second meals approximately 4 and 9 hours after the start 
of TAK-123 infusion, respectively, and at appropriate times thereafter. 
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Note: For low-fat/high-carbohydrate diet, the energy produced by lipid will account for ≤20% 
of the total calorie, and the remaining calorie will be supplemented by carbohydrate to 
compensate for an equivalent total calorie of ordinary diet. 
If meals and tests or blood sampling are scheduled at the same time, subjects will take meals after 
tests or blood sampling are completed. 
7.4.2 Activity 
Smoking is prohibited during the study. 
Excessive exercise is prohibited during the study. 
Blood donation is prohibited for at least 12 weeks (84 days) from completion of the last test for the 
study. 
If a subject visits another medical institution during the study period, the investigator or 
sub-investigator should be informed of the visit in advance whenever possible, and should be 
reported the circumstances and therapy after visit. The investigator or sub-investigator should 
communicate that medical institution about the subject’s participation in the study. 
7.5 
Record of Discontinuation or Withdrawal of a Subject Before TAK-123 
Administration 
The investigator or sub-investigator is responsible for all subjects who signed the informed 
consent form. If a subject is withdrawn from the study before the start of the administration of 
TAK-123, the investigator or sub-investigator will complete the electronic case report form 
(eCRF) to record the details. 
The primary reason for the withdrawal before the start of the administration of TAK-123 will be 
recorded in the eCRF using the following categories: 
• 
Death 
• 
Adverse events (AEs) 
• 
Screen failure (The subject did not meet the inclusion criteria or did meet the exclusion 
criteria.) <Specify the reason.> 
• 
Protocol deviation 
• 
Lost to follow-up 
• 
Withdrawal by subject <Specify the reason.> 
• 
Study terminated by the Sponsor 
• 
Sample size sufficient 
• 
Other <Specify the reason.> 
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7.6 
Criteria for Discontinuation or Withdrawal of a Subject 
Primary reasons for discontinuation or withdrawal of a subject from the study or study drug should 
be recorded in the eCRF using the following categories. For the subject who is withdrawn from the 
study before the administration of TAK-123, refer to Section 7.5. 
1. Death 
A subject died on study. 
Note: If the subject dies on study, the event will be considered as a serious adverse event (SAE). 
See Section 10.2.9.3 for the reporting procedures. 
2. AE 
The subject has experienced 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. 
TAK-123 will be immediately discontinued if a condition meets any following criteria during the 
treatment, and appropriate follow-up will be performed (clinical laboratory tests will be repeatedly 
performed until the clinical laboratory test profiles have normalized or returned to baseline, refer 
to Section 9.2.8.1): 
• Liver Function Test Abnormalities 
‒ ALT or AST >8 × ULN, or 
‒ ALT or AST >5 × ULN and persists for more than 2 weeks, or 
‒ ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
‒ ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) 
• Hyperglycemia 
‒ Fasting glucose level after the administration of TAK-123 >500 mg/dL, or 
‒ The investigator or sub-investigator considered inappropriate to continue the study 
because of obvious hyperglycemia 
• Metabolic acidosis 
‒ Diagnosed or suspected metabolic acidosis (eg, pH <7.25, or pH <7.35 and HCO3- 
<22 mEq/L persist) and the investigator or sub-investigator considered inappropriate to 
continue the study 
If metabolic acidosis was suspected, the investigator or sub-investigator should consider to 
perform a blood gas test with arterial blood or other laboratory tests to confirm the 
diagnosis and take an appropriate treatment or intervention. 
• QT/QTcF interval prolonged 
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‒ If at least one remarkable prolonged QT interval was observed on 12-lead ECG (eg, 
absolute value of QTcF intervals >500 msec or an increase >60 msec from baseline), 
and the investigator or sub-investigator considered inappropriate to continue the study. 
• Nausea and/or vomiting 
If nausea and/or vomiting occur after the administration of TAK-123 and unacceptable 
nausea and/or vomiting are continuing after the administration of antiemetics. 
3. Protocol deviation 
The discovery after the administration of TAK-123 that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health. 
4. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented in the subject’s source documentation. 
5. Withdrawal by subject 
The subject wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE 
should not be recorded in the “voluntary withdrawal” category). 
6. Study terminated by the Sponsor 
The Sponsor terminates the study. 
7. Other 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or sub-investigator may discontinue a subject’s study participation at any time 
during the study if the subject meets the study termination criteria described in Section 7.6. In 
addition, a subject may discontinue his or her participation without giving a reason at any time 
during the study. Should a subject’s participation be discontinued, the primary criterion for 
termination must be recorded by the investigator or sub-investigator. In addition, efforts should be 
made to perform all procedures scheduled for the Early Termination Visit. 
7.8 
Subject Replacement 
This study can have a few reserve subjects considered eligible for participation in the study based 
on screening test. If a subject has not received TAK-123 as scheduled during the study owing to 
any reason occurring before the administration of TAK-123, a reserve subject will be allowed to 
participate in the study. 
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If a subject withdraws from the study after initiation of TAK-123, the subject will not be replaced 
with a reserve subject. 
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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
8.1 
Clinical Study Drug 
[Test drug] 
Code name: TAK-123 
Dosage form and strength: 
TAK-123 is an injection containing 5 g NaPA and 5 g of NaBZ per vial (50 mL). 
[Premedication (concomitant drug)] 
Ondansetron (product name: Ondansetron INJ 4 mg SYRINGE “HK”) 
Ondansetron will be provided for clinical trial use by the Sponsor. Refer to the package insert for 
the drug details. 
8.1.1 Clinical Study Drug Labeling 
Study drug labeling will show name of the study drug, quantity and storage condition of the study 
drug, manufacture number, expiration date, protocol number, name and address of the Sponsor, 
and statement the drug is for clinical trial use only. 
8.1.2 Clinical Study Drug Inventory and Storage 
TAK-123 is stored at 25°C with the permissible range of 15 to 30°C. 
Ondansetron is stored at room temperature and protected from light. 
Study drug must be kept in an appropriate, limited-access, secure place until it is used, or returned 
to the Sponsor or its designee. Study drug must be stored under the conditions specified on the 
label, and remain in the original container until dispensed. 
8.1.3 Clinical Study Drug Blinding 
This study was designed as an open-label study since the primary objective is to characterize the 
PK of TAK-123. 
8.1.4 Randomization Code Creation and Storage 
The randomization table/schedule will not be created since TAK-123 is to be administered to all 
the subjects at the same dosage and administration in this study. 
8.1.5 Clinical Trial Blind Maintenance/Unblinding Procedure 
Not applicable since this is an open-label study. 
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8.1.6 Accountability and Destruction of Sponsor-Supplied Drugs 
The on-site pharmacist (a site designee) will receive the pharmacy manual created by the Sponsor, 
and follow the procedures for managing the Sponsor-supplied drug supplies. A copy of these 
procedures will be provided to the investigator as well. The manual will provide instructions on 
ensuring appropriate receipt, handling, storage, management, and dispensation of the 
Sponsor-supplied drug. The manual will also describe procedures for the collection of unused 
medications from the subject and their return to the Sponsor, or the destruction of any unused 
supplies. 
The on-site pharmacist (a site designee) will immediately return any unused study drugs in a sealed 
package to the Sponsor after the study is closed at the study site. 
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9.0 
STUDY PROCEDURES 
The investigator or sub-investigator should collect data according to the procedures described in 
the following sections. For each procedure, subjects are to be assessed by the same investigator, 
sub-investigator or site designee whenever possible. The Schedule of Study Procedures is located 
in Section 3.0. 
9.1 
Administrative Procedures 
9.1.1 Informed Consent Procedure 
The requirements of informed consent are described in Section 13.2. 
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures (including the fasting for laboratory tests) are performed. 
9.1.1.1 Assignment of Subject Identification Number 
A unique subject identification number will be assigned to each subject at the time that informed 
consent is explained; this subject identification number will be used throughout the study. 
9.1.1.2 Study Drug Assignment 
No study drug will be assigned in this study. 
9.1.2 Inclusion and Exclusion 
Each subject will be assessed according to the eligibility criteria provided in Section 7.1 and 7.2. 
9.1.3 Medical History/Demography 
Demographic information to be obtained will include date of birth, sex, height, weight, caffeine 
use, alcohol use, and smoking status of the subject. 
Medical history to be obtained will include determining whether the subject has any clinically 
significant conditions or diseases that resolved within 1 year prior to the signing of informed 
consent. Ongoing conditions will be considered concurrent medical conditions. Medication history 
information to be obtained will include any medication relevant to eligibility criteria and safety 
evaluations stopped at or within 4 weeks (28 days) prior to the signing of informed consent. 
9.1.4 Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Subjects will be asked whether they 
have taken any medication other than the study drug (used from the signing of informed consent 
through Day 8), and all medication including vitamin supplements, over-the-counter drugs, and 
oral herbal preparations, must be recorded in the eCRF. Documentation will include generic 
medication names, route of administrations, start and end dates, and reasons for use. 
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Pay attention to using the drugs which stipulated in the Section “Precautions for Co-administration” 
in the package insert of ondansetron. 
9.2 
Clinical Procedures and Assessments 
Each observation and test/examination item will be performed and evaluated in accordance with 
the Schedule of Study Procedures in Section 3.0. 
9.2.1 Full Physical Exam 
A physical examination will consist of the following body systems. 
(1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) 
nervous system; (10) lymph nodes; and (11) other. 
9.2.2 Height and Weight 
Each subject should have a height and weight measured. Height will be recorded in centimeters 
without decimal places (rounding off the first decimal place). Weight will be collected in 
kilograms (kg) with the first decimal place (rounding off the second decimal place). 
9.2.3 BMI 
BMI is calculated using the formula provided below. The values should be calculated to the first 
decimal place (rounding off the second decimal place). When the BMI is used as entry criteria, 
then this determination must be made after rounding. BMI will not be described in eCRF. 
BMI=weight (kg)/(height [m] ×height [m]) 
9.2.4 Vital Signs 
Vital signs will include body temperature (axilla measurement), respiratory rate, sitting blood 
pressure (systolic and diastolic, after resting more than 5 minutes), and pulse (beats per minute). 
9.2.5 12-Lead ECG 
A standard 12-lead ECG will be recorded. Subjects should be resting in a recumbent position for at 
least 5 minutes before each ECG measurement 
The investigator or sub-investigator (or a qualified observer at the study site) will interpret the 
ECG using one of the following categories: normal or abnormal. 
If an ECG is abnormal, the investigator or sub-investigator (or a qualified observer at the study 
site) will judge clinical significance of the abnormality. The time that the ECG was performed will 
be recorded. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, 
RR interval, PR interval, QT interval, QRS interval, and QTcF interval (calculated by Fridericia’s 
formula). 
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9.2.6 Study Drug Administration 
TAK-123 must be diluted with 10% glucose injection to the concentration of 400 mL/m2 before 
administration, then, administered intravenously as a loading dose infusion over 90 minutes 
(peripheral intravenous infusion) at the dose level of 3.75 g/m2 of NaPA and 3.75 g/m2 of NaBZ, 
followed by an equivalent maintenance dose infusion over 24 hours (peripheral intravenous 
infusion) under the breakfast fasting condition (subjects will be fasted from at least 8 hours before 
the start of TAK-123 infusion to 4 hours after the start of TAK-123 infusion [see Section 7.4.1]). 
A 4 mg of dose of ondansetron will be administered intravenously 30-40 minutes before the start 
of TAK-123 infusion. 
Subjects should be resting for a period from the start of TAK-123 infusion to 2.5 hours after the 
start of TAK-123 infusion. 
9.2.7 AE Monitoring 
AE monitoring will begin after the signing of informed consent. A complete description of AE 
collections and procedures is provided in Section 10.2. 
9.2.8 Laboratory Procedures and Assessments 
The following laboratory tests will be conducted in the study site. Samples for laboratory tests will 
be collected following a minimum 8-hour fast on the days stipulated in the Schedule of Study 
Procedures in Section 3.0. See Appendix E for the amount of blood samples. 
The investigator or sub-investigator will take responsibility for evaluation of the clinical 
laboratory test results and storage. The investigator will maintain a copy of the reference ranges for 
the laboratory used. 
9.2.8.1 Clinical Laboratory Tests 
Hematology 
Hematology evaluations will consist of the following tests: 
Red blood cell (RBC) 
White blood cell (WBC) 
WBC and differential (neutrophil, basophil, eosinophil, lymphocyte, and monocyte) (%) 
Hemoglobin 
Hematocrit 
Platelet 
PT/INR 
aPTT 
 
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Serum Chemistry 
Serum chemistry evaluations will consist of the following tests: 
ALT 
BUN 
Albumin 
Creatine kinase 
ALP 
GGT 
AST 
Potassium 
Total bilirubin 
Sodium 
Direct bilirubin 
Glucose assessed by a self-monitoring blood glucose 
meter (under fasting) 
Total protein 
Chloride 
Creatinine 
Calcium 
 
Urinalysis 
Urinalysis will consist of the following tests: 
pH 
Specific gravity 
Qualitative: (Protein, glucose, occult blood, nitrite, and urobilinogen) 
Sediment (RBC, WBC, and Casts)* 
*Urine sediment will be performed if urinalysis is abnormal. 
 
Other 
Immunological tests 
HIV antibody and antigen tests 
Hepatitis screen (HBs antigen, HCV antibody) 
Syphilis test (antibody) 
Urine/blood 
Blood gas measurement (pH, HCO3-) in venous blood 
Urine drug screening (phencyclidine, benzodiazepines, 
cocaines, stimulants, cannabinoids, morphines, 
barbiturates, and tricyclic antidepressants) 
HIV: Human immunodeficiency virus, HBs: Hepatitis B surface, HCV: Hepatitis C virus 
Note: The investigator or sub-investigator will report the results of “immunology” and “urine drug screening” directly 
to subjects. The Sponsor will confirm the overall test results (“Positive” or “All negative”), rather than detailed 
results, for subjects (including reserve subjects) to be administered TAK-123. 
 
Consideration for the clinical laboratory tests 
• If subjects experience an ALT or AST of >3×ULN (except the tests at Screening) after the 
administration of TAK-123, follow-up laboratory tests (at a minimum, ALP, ALT, AST, total 
bilirubin, GGT, and INR) should be performed within a maximum of 7 days and preferably 
within 48 to 72 hours after the abnormality was noted. 
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• Refer to Section 7.6 and Section 10.2.9.5 for the discontinuation or withdrawal criteria of a 
subject and the appropriate guidance on reporting abnormal liver function tests as SAEs, 
respectively. 
• The glucose test by a self-monitoring blood glucose meter will be performed by the 
investigator, sub-investigators or study collaborators. If subjects experience an obvious 
hyperglycemia (eg, fasting blood glucose >300 mg/dL) in the glucose test by a self-monitoring 
blood glucose meter 1.5 hours or over after the start of the TAK-123 infusion, the subjects 
should be carefully monitored for clinical signs and symptoms, and glucose test should be 
repeated after 30 minutes. Follow-up tests should be performed repeatedly until abnormality of 
fasting blood glucose recovers or improves. 
• If subjects experience a pH <7.35 and HCO3- <22 mEq/L in the blood gas test after the 
administration of TAK-123, remeasurement should be performed after 30 minutes. 
9.3 
PK Sample 
Primary specimen collection for PK analysis are provided in Table 9.a. 
Samples for PK will be collected according to the Schedule of Study Procedures (Section 3.0). 
Separated procedures describe the details of sampling, handling, and transferring to central 
laboratory. See Appendix E for the amount of blood samples. The actual sampling time for PK 
analyses will be documented in the subject’s source documents and eCRF. 
Table 9.a 
Primary Specimen Collections 
Specimen Name 
Primary 
Specimen 
Primary 
Specimen 
Derivative 
Description of Intended Use 
Sample 
Collection 
Plasma sample for PK 
Blood 
Plasma 
Plasma sample for PK analysis 
Mandatory 
Urine sample for PK 
Urine 
Urine 
Urine sample for PK analysis 
Mandatory 
9.3.1 PK Measurements 
The following PK parameters will be calculated from plasma and urine concentrations of 
phenylacetate, benzoate, and these metabolites (phenylacetylglutamine and hippurate), unless 
otherwise stated: 
• AUClast: Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration 
• 
AUC∞: Area under the plasma concentration-time curve from time 0 to infinity 
• 
Cmax: Maximum observed concentration (measured values) 
• 
tmax: Time of first occurrence of Cmax 
• 
t1/2z: Terminal elimination half-life 
• 
λz: Terminal elimination rate constant 
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• 
Vz: Volume of distribution during the terminal elimination phase (only for phenylacetate and 
benzoate) 
• 
CL: Total clearance after intravenous infusion (only for phenylacetate and benzoate) 
The following PK parameters will be calculated from urine concentrations of phenylacetate, 
benzoate, and these metabolites (phenylacetylglutamine and hippurate), unless otherwise stated: 
• 
Aet: Urinary excretion amount from time 0 to t 
• 
fet: Urinary excretion rate from time 0 to t 
9.3.1.1 Plasma for PK Measurements 
Blood samples for PK analysis of TAK-123 (NaPA and NaBZ) and these metabolites will be 
collected according to Table 9.b. 
Table 9.b 
Sampling of blood samples for PK analysis 
Analyzed substances 
Samples 
Study date 
Blood sampling time (hours) 
Note 
TAK-123 (NaPA and NaBZ) 
and these metabolites 
Plasma 
Day 1 
Day 1: Predose (from the wake-up time to 
immediately before the start of TAK-123 infusion), 
0.25, 0.75, 1.5, 2.5, 4.5, 6.5, 8.5, 10.5, 12.5, 16.5, 
25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29.5, 30.5, 32.5 and 
48 hours after the start of TAK-123 infusion 
Note: If a subject is withdrawn within 48 hours after the start of the TAK-123 infusion, samples should be collected 
also at the early termination visit. 
9.3.1.2 Urine for PK Measurements 
Urine samples for measurements of TAK-123 (NaPA and NaBZ) and these metabolites will be 
collected according to Table 9.c. 
Table 9.c 
Sampling of urine samples for PK analysis 
Analyzed substances 
Samples 
Study date Time from the start of infusion(hours) 
TAK-123 (NaPA and NaBZ) 
and these metabolites 
Urine 
Day 1 
Day 1: Predose (spot urine), 0 to 24 hours and 24 to 48 
hours after the start of infusion 
 
The details of the processing and shipment of samples are described in the separately prepared 
laboratory manual. 
9.3.2 Confinement 
4 days (admission on Day -1 and discharge on Day 3) 
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Subjects will be admitted to the study site during a period from Day -1 to Day 3 and discharged 
from the study site if no clinically significant abnormalities were found at the physical 
examinations and tests on Day 3, and confirmed by the investigator or sub-investigator. 
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10.0 
ADVERSE EVENTS 
Collection of AEs will commence at the time the subject signs the informed consent and continue 
until the follow-up visit (Day 8). 
10.1 
Definitions and Elements of AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily required to have a causal 
relationship with the treatment (including the study drug). 
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 treatment (including the study drug) or the study procedure. 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.) 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in dose of study drug or a concomitant medication. 
• 
Be considered unfavorable by the investigator or sub-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 may be considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator or 
sub-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 
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evaluation (eg, laboratory test, ECG, X-ray, etc.) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators or sub-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 or sub-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 or sub-investigators should ensure that the 
AE term recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• 
If the subject experiences a worsening or complication of an AE after the first administration 
of study drug (TAK-123) or after any change in study drug, the worsening or complication 
should be recorded as a new AE. Investigators or sub-investigators should ensure that the AE 
term recorded captures the change in the condition (eg, “worsening of…”). 
Changes in severity of AEs: 
• 
If the subject experiences a change in the severity of an AE that is not associated with a change 
in study drug (TAK-123), the event should be captured once with the maximum severity 
recorded. 
Preplanned surgeries or procedures: 
• 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• 
Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Overdose: 
• 
An overdose is defined as a known deliberate or accidental administration of study drug 
(TAK-123), to or by a study subject, at a dose above that which is assigned to that individual 
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subject according to the study protocol. It is up to the investigator or sub-investigator 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 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0. 
• 
Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9. 
• 
In the event of drug overdose, the subject should be treated symptomatically. 
10.1.1 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
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Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory  
distress syndrome (ARDS) 
Acute liver failure 
Anaphylactic shock 
Torsade de pointes / ventricular fibrillation /  
ventricular tachycardia 
Acute renal failure 
Pulmonary hypertension 
Malignant hypertension 
Pulmonary fibrosis 
Convulsive seizures 
(including convulsion and epilepsy) 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Agranulocytosis 
Spontaneous abortion / stillbirth and fetal death 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis /Stevens-Johnson syndrome 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
Hepatic necrosis 
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements. 
 
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.2.9.3). 
10.1.2 Special Interest AEs 
Not applicable 
10.2 
AE Procedures 
10.2.1 Assigning Severity/Intensity of AEs 
The severity/intensity for AEs are classified and defined as follows: 
Mild: 
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate: 
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
Severe: 
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
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10.2.2 Assigning Causality of AEs 
The relationship of each AE to study drug (TAK-123) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a 
drug (TAK-123) (including the course after withdrawal of the drug), or for 
which a causal relationship is at least a reasonable possibility, ie, the 
relationship cannot be ruled out, although factors other than the drug, such as 
underlying diseases, complications, concomitant drugs and concurrent 
treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration 
of a drug (TAK-123) and/or that can reasonably be explained by other factors, 
such as underlying diseases, complications, concomitant medications and 
concurrent treatments. 
10.2.3 Assigning Causality of AEs to Study Procedures 
The causality of each AE to study procedures (including the ondansetron treatment) will be 
assessed.The causality should be assessed as Related if the investigator or sub-investigator 
considers that there is reasonable possibility that an event is due to a study procedure. Otherwise, 
the causality 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 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.2.6 Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.2.7 Action Taken with Study Treatment (Administration of TAK-123) 
• 
Drug withdrawn – a study drug (administration of TAK-123) is stopped due to the particular 
AE. 
• 
Dose not changed – the particular AE did not require stopping a study drug (administration of 
TAK-123). 
• 
Unknown – only to be used if it has not been possible to determine what action has been taken. 
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• 
Not applicable – a study drug (administration of TAK-123) was stopped for a reason other 
than the particular AE eg; the study has been terminated, the subject died, dosing with study 
drug (administration of TAK-123) had not yet started or dosing with study drug 
(administration of TAK-123) 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 study period has become worse than when it started 
‒ an irreversible congenital anomaly 
‒ the subject died from another cause with the particular AE state remaining “Not 
recovered/not resolved.” 
• 
Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left 
with permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• 
Fatal – an AE that is considered as the cause of death. 
• 
Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 
10.2.9 Collection and Reporting of AEs, SAEs, and Abnormal LFTs 
10.2.9.1 Collection Period 
Collection of AEs (ie, AEs, SAEs, and Abnormal LFTs) will commence at the time the subject 
signs the informed consent. Routine collection of AEs will continue until the follow-up visit on 
Day 8. For subjects who discontinue prior to the administration of TAK-123, AEs will be followed 
until the subject discontinues study participation. 
10.2.9.2 Reporting AEs 
At each study visit, the investigator or sub-investigator will assess whether any subjective AEs 
have occurred. A neutral question, such as “How have you been feeling since your last visit?” may 
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be asked. Subjects may report AEs occurring at any other time during the study. Subjects 
experiencing an SAE prior to the first exposure to TAK-123 must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to TAK-123, related or unrelated to the study procedure, need not be followed-up for the purposes 
of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of TAK-123 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 treatment of TAK-123. The following information will be 
documented for each event: 
• 
Event term. 
• 
Start and end date and time. 
• 
Pattern of AE (frequency). 
• 
Severity/Intensity. 
• 
Investigators’ opinion of the causal relationship between the event and administration of 
TAK-123. 
• 
Investigators’ opinion of the causal relationship between the event and the study procedure(s) 
(including the ondansetron treatment) (The details of study procedure(s) that may cause the 
event should also be provided). 
• 
Action taken with TAK-123. 
• 
Outcome of the event. 
• 
Seriousness. 
• 
Timing of occurrence (after administration of TAK-123). 
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: 
An SAE should be reported by the investigator or sub-investigator to the Sponsor (see Protocol 
Annex 1) within 1 business day of the first onset or notification of the SAE, along with any 
relevant information. The investigator should submit a detailed SAE Form to the Sponsor within 
10 calendar days. 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. 
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• 
Investigator’s or sub-investigator’s name. 
• 
Causality assessment. 
The SAE form should be transmitted within 1 business day to the attention of the contact listed in 
Section 14.1.1. 
Any SAE spontaneously reported to the investigator or sub-investigator following the AE 
collection period should be reported to the Sponsor if considered related to study participation. 
Reporting of SAEs that begin before first administration of TAK-123 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 or sub-investigator should complete a follow-up SAE form or provide other written 
documentation immediately to the Sponsor. 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 Special Interest AEs 
Not applicable 
10.2.9.5 Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. 
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 9.2.8 must also be 
performed. 
10.2.10 Safety Reporting to Investigators, IRBs, 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, as 
applicable, in accordance with national regulations in the countries where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The Sponsor 
will also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of TAK-123 or that would be sufficient to consider changes in the 
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administration of TAK-123 or in the overall conduct of the trial. The study site also will forward a 
copy of all expedited reports to his or her IRB 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 by the analysis personnel prior to 
database lock. This document will provide further details regarding the definitions of analysis 
variables, and analysis methodologies to address all study objectives. 
11.1.1 Analysis Sets 
In this study, the safety analysis set and the PK analysis set will be used as analysis sets. The 
detailed definitions of each analysis set will be separately described in the SAP. 
The Sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. If necessary, the SAP will be supplemented 
with new handling rules that were not discussed at the planning stage. The SAP must be finalized 
prior to database lock. 
11.1.1.1 Safety Analysis Set 
The safety analysis set will be defined as all subjects who received at least one dose of TAK-123. 
11.1.1.2 PK Analysis Set 
The PK analysis set will be defined as all subjects who received at least one dose of TAK-123 and 
provided sufficient PK measurements available to estimate PK parameters, at least 1 estimable PK 
parameter. 
11.1.2 Analysis of Demography and Other Baseline Characteristics 
Major demographics and other baseline characteristics will be summarized using the safety 
analysis set. 
11.1.3 PK Analysis 
The following analyses will be performed in the PK analysis set. 
Plasma concentrations of phenylacetate, benzoate, and these metabolites (phenylacetylglutamine 
and hippurate) will be summarized for each scheduled sampling time using descriptive statistics. 
Furthermore, plasma and urine PK parameters of phenylacetate, benzoate, and these metabolites 
(phenylacetylglutamine and hippurate) will be summarized using descriptive statistics. 
11.1.4 Safety Analysis 
The following analyses will be performed in the safety analysis set. 
11.1.4.1 AEs 
A TEAE is defined as an AE that occurs on or after the start of the administration of TAK-123. 
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The analyses of TEAEs will be conducted for the followings. TEAEs will be coded using the 
Medical Dictionary for Regulatory Activities Terminology (MedDRA) and summarized by the 
System Organ Class (SOC) and the Preferred Term. 
• 
The frequency of all TEAEs 
• 
The frequency of TEAEs related to TAK-123 
• 
The frequency of all TEAEs by intensity 
• 
The frequency of TEAEs related to TAK-123 by intensity 
• 
The frequency of TEAEs leading to TAK-123 discontinuation 
• 
The frequency of serious TEAEs 
11.1.4.2 Clinical Laboratory Evaluation 
For continuous variables, the observed values and changes from baseline will be summarized for 
each scheduled sampling time using descriptive statistics. For categorical variables, shift tables 
showing the number of subjects in each category at baseline and each post-baseline scheduled 
sampling time will be provided. 
11.1.4.3 Vital Signs 
The observed values and the changes from baseline will be summarized for each scheduled 
sampling time using descriptive statistics. 
11.1.4.4 Other Safety Parameters 
ECG parameters will be summarized as follows: For continuous variables, the observed values and 
changes from baseline will be summarized for each scheduled sampling time using descriptive 
statistics. For categorical variables, shift tables showing the number of subjects in each category at 
baseline and each post-baseline scheduled sampling time will be provided. 
The details of statistical methods for other endpoints will be described in the SAP. 
11.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
11.3 
Determination of Sample Size 
The sample size was determined as 10 subjects that are considered to be sufficient to evaluate the 
PK and safety of TAK-123. 
The sample size is not based on considerations of statistical power. 
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12.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (CRO) and by the IRB. 
All aspects of the study 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, study drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator or sub-investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process. 
12.2 
Protocol Deviations 
The investigator or sub-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 or sub-investigator 
should consult with the Sponsor or designee (and IRB, as required) to determine the appropriate 
course of action. There will be no exemptions (a prospectively approved deviation) from the 
inclusion or exclusion criteria. 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments [eg, the Food and Drug Administration (FDA), the United Kingdom 
Medicines and Healthcare products Regulatory Agency (MHRA), the Pharmaceuticals and 
Medical Devices Agency of Japan (PMDA)]. If the study site is contacted for an inspection by a 
regulatory body, the Sponsor should be notified immediately. The investigator guarantees access 
for quality assurance auditors to all study documents as described in Section 12.1. 
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13.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Harmonised Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix A. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
13.1 
IRB Approval 
IRBs 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. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained. 
The Sponsor or designee will supply relevant documents for submission to the respective IRB 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 for approval. The IRB’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the Sponsor or designee before commencement of the study (ie, 
before shipment of the Sponsor-supplied drug or study specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. The 
Sponsor will ship drug/notify site once the Sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the Sponsor has received permission from competent 
authority to begin the trial. Until the site receives drug/notification no protocol activities, including 
screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB All IRB 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 and Sponsor. 
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 
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applicable laws and regulations. The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he is 
free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care. 
The investigator or sub-investigator is responsible for the preparation, content, and IRB approval 
of the informed consent form. The informed consent form must be approved by both the IRB and 
the Sponsor prior to use. 
The informed consent form must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator or sub-investigator to explain the detailed 
elements of the informed consent form, to the subject. Information should be given in both oral and 
written form whenever possible and in the manner deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study, and (2) 
decide whether or not to participate in the study. If the subject, determines he will participate in the 
study, then the informed consent form must be signed and dated by the subject, or the subject’s 
legally acceptable representative, at the time of consent and prior to the subject entering into the 
study. The subject or the subject’s legally acceptable representative should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator or 
sub-investigator must also sign and date the informed consent form at the time of consent and prior 
to subject entering into the study. 
Once signed, the original informed consent form will be stored in the investigator’s site file. The 
investigator or sub-investigator must document the date the subject signs the informed consent in 
the subject’s medical record. Copies of the signed informed consent form, 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. 
13.3 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth 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 
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regulatory authority (eg, FDA, MHRA, PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 13.2). 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s 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 study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
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 study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with the facility name, investigator’s city, country, and recruiting status 
will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The study 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. 
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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 study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator or sub-investigator has questions regarding this policy, he or she should 
contact the Sponsor or Sponsor’s designee. 
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14.0 
ADMINISTRATIVE AND REFERENCE INFORMATION 
14.1 
Administrative Information 
14.1.1 Study Contact Information 
A separate contact information list (Protocol attachment 1) will be provided to the study site. 
14.1.2 Investigator Agreement 
The investigator and Sponsor will sign the protocol or alternative document to confirm the 
consensus that investigator will conduct the study in compliance with the protocol. 
14.1.3 Study-Related Responsibilities 
A separate contact information list (Protocol attachment 1) will be provided to the study site. 
14.1.4 List of Abbreviations 
Aet 
amount of drug excreted in urine from time 0 to time t 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
ARG 
arginase 
ASL 
argininosuccinate lyase 
ASS 
argininosuccinate synthetase 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC∞ 
area under the plasma concentration-time curve from time 0 to infinity 
AUClast 
area under the plasma concentration-time curve from time 0 to the last measurable 
concentration 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CL 
total clearance after intravenous infusion 
Cmax 
maximum observed concentration 
CPS 
carbamoylphosphate synthetase 
FDA 
Food and Drug Administration 
fet 
fraction of administered dose of drug excreted in urine from time 0 to time t 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HBsAg 
hepatitis B virus antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
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ICH 
International Council for Harmonisation 
INR 
international normalized ratio 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NaBZ 
sodium benzoate 
NAGS 
N-acetylglutamate synthase 
NaPA 
sodium phenylacetate 
OTC 
ornithine transcarbamylase 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PT 
prothrombin time 
SAE 
serious adverse event 
SOC 
System Organ Class 
t1/2z 
terminal elimination half-life 
TEAE 
treatment emergent adverse event 
tmax 
time of first occurrence of Cmax 
UCD 
Urea Cycle Disorders 
Vz 
volume of distribution during the terminal elimination phase 
λz 
terminal elimination rate constant 
 
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15.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary. 
15.1 
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The Sponsor or its designee will supply study sites with access to eCRFs. The Sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the Sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections 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. 
The 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. 
The following data will not be recorded in the eCRF: 
• Laboratory results (including blood gas tests and glucose test by a self-monitoring blood 
glucose meter) 
• Drug concentration measurement results 
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator or sub-investigator with use of change and 
modification records of the eCRFs. The 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 study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor. 
15.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
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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 
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 study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and Sponsor. 
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents. 
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16.0 
REFERENCES 
1. Japanese Society for Inherited Metabolic Diseases. Diagnostic criteria for urea cycle disorders. 
Revised on November 25 2013. 
2. Health and Labour Sciences Research Grants in FY 2012 Shared research report of “Research 
on registration, management, analysis, and information provision of specific pediatric chronic 
diseases”. Registration of research on treatment for specific pediatric chronic diseases in Japan 
in FY 2011. 
3. AMMONUL- sodium phenylacetate and sodium benzoate injection, solution, concentrate [pre 
scribing information]. USA: Ucyclyd Pharma Inc., 2018 Jan. 
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17.0 
APPENDICES 
Appendix A Responsibilities of the Investigator 
1. Conduct the appropriate study in accordance with the protocol and GCP considering the rights, 
safety and wellbeing of human subjects. 
2. When a part of the important activities related to the study are delegated to a sub-investigator 
or the study collaborator, prepare the lists of activities to be delegated and responsible 
personnel, submit the lists to the head of the study site in advance to get them accepted. 
3. Prepare a written informed consent form and other written information, and update as 
appropriate. 
4. Confirm the contents of the clinical study agreement. 
5. Provide necessary information on the protocol, medications and responsibilities of individual 
personnel to the sub-investigator and study collaborator, and provide guidance and 
supervision. 
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the 
study in writing and obtain the written consent. 
7. Assume responsibility for all the medical judgement related to the study. 
8. Ensure in collaboration with the head of the study site that sufficient medical care for all 
clinically significant AEs related to the study are provided to subjects throughout and beyond 
the period when subjects participate in the study, upon obtaining consent from the subject. 
9. If a subject consults other medical institution or other department, notify the physician of the 
medical institution or department of the subject’s participation in the study, as well as the end 
and termination of the study in writing, and document such records. 
10. In case of urgent report of a SAE, immediately notify the head of the study site and the Sponsor 
in writing. 
11. Prepare correct and complete eCRFs, and submit them to the Sponsor with electronic 
signature. 
12. Check and confirm the contents of eCRFs prepared by the sub-investigator or transcribed from 
the source data by the study collaborator, and submit them to the Sponsor with electronic 
signature. 
13. Discuss any proposal from the Sponsor including update of the protocol. 
14. Notify the head of the study site of the end of the study in writing. 
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Appendix B Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment. 
10. A description of the possible side effects of the treatment that the subject may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject. 
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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Study ID TAK-123-1001 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. 
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated. 
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the subject’s identity will remain confidential in the event that study results are 
published. 
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25. Subjects must use highly effective contraception (as defined in the informed consent) from the 
beginning of screening throughout the duration of the study and for 91 days after the last dose 
of TAK-123. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 
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Appendix C Investigator Consent to the Use of Personal Information  
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
• Takeda, its affiliates, and licensing partners. 
• Business partners assisting Takeda, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug. 
• Inspections and investigations by regulatory authorities relating to the study. 
• Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above. 
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Appendix D Pregnancy and Contraception 
Contraception and Pregnancy Avoidance Procedure 
Male Subjects and Their Female Partners 
From signing of informed consent, throughout the duration of the study, and for 91 days after last 
dose of TAK-123, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception. In addition, they must be advised not to 
donate sperm during this period. Females of childbearing potential who are partners of male 
subjects are also advised to use additional contraception as shown in the list containing highly 
effective/effective contraception below. 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
* A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to 
confirm a post-menopausal state in younger women (eg, those <45 year old) or women who are 
not using hormonal contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
The following procedures apply for contraception and pregnancy avoidance. 
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 study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are: 
• Non-Hormonal Methods: 
‒ Intrauterine device (IUD). 
‒ Bilateral tubal occlusion. 
‒ Vasectomised partner (the vasectomised partner has received medical assessment of 
the surgical success). 
• Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method. 
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‒ Combined pill (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months; 
‒ Contraceptive pill (combined hormonal contraception) 
2. Unacceptable methods of contraception are: 
• Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods). 
• Spermicides only. 
• Withdrawal. 
• No method at all. 
• Use of female and male condoms together. 
• Cap/diaphragm/sponge without spermicide and without condom. 
• Sexual abstinence is NOT an acceptable method of contraception. 
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study. 
General Guidance With Respect to the Avoidance of Pregnancy 
Such guidance should include a reminder of the following: 
• contraceptive requirements of the study. 
• reasons for use of barrier methods (ie, condom) in males with pregnant partners. 
• 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? 
– Is there a chance your partner could be pregnant? 
Pregnancy 
If any pregnancies in the partner of a male subject during the study or for 91days after the last dose 
of TAK-123, should also be recorded following authorization from the subject’s partner. 
If the female partner of a male subject agrees to the primary care physician being informed, the 
investigator should notify the primary care physician that the female partner of the subject was 
participating in a clinical study at the time she became pregnant and provide details of the study 
drug the subject received (blinded or unblinded, as applicable). 
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All pregnancies in female partners of male subjects on active study drug will be followed up to 
final outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the Sponsor. An evaluation 
after the birth of the child will also be conducted. 
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Appendix E Acceptable Time Window for Study Procedure 
Specified in the protocol 
Acceptable window 
Variables 
Timing of procedures 
Demographics, medical 
history, and medication 
history 
Screening 
Days -28 to -2 
Immunology tests and urine 
drug screen 
Screening 
Days -28 to -2 
Physical examination 
Screening 
Days -28 to -2 
Day -1 
The day before the study 
drug administration 
Day 1 predose of TAK-123 
From awakening to 
immediately prior to dose 
4 hours postdose of TAK-123 
Within ± 60 minutes 
25.5 hours postdose of TAK-123 
Within ± 60 minutes 
48 hours postdose of TAK-123 
Within ± 60 minutes 
Day 8 
± 1 day 
Height 
Screening 
Days -28 to -2 
Weight 
Screening 
Days -28 to -2 
Day 1 predose of TAK-123 
From awakening to 
immediately prior to dose 
48 hours postdose of TAK-123 
Within ± 60 minutes 
Day 8 
± 1 day 
Vital signs 
(body temperature, sitting 
blood pressure, respiratory 
rate, sitting pulse rate) 
Screening 
Days -28 to -2 
Day 1 predose of TAK-123 
From awakening to 
immediately prior to dose 
1.5 hours postdose of TAK-123 
Within ± 15 minutes 
4 hours postdose of TAK-123 
Within ± 60 minutes 
25.5 hours postdose of TAK-123 
Within ± 60 minutes 
48 hours postdose of TAK-123 
Within ± 60 minutes 
Day 8 
± 1 day 
12-lead ECG 
Screening 
Days -28 to -2 
Day 1 predose of TAK-123 
From awakening to 
immediately prior to dose 
1.5 hours postdose of TAK-123 
Within ± 15 minutes 
48 hours postdose of TAK-123 
Within ± 60 minutes 
Day 8 
± 1 day 
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Study ID TAK-123-1001 
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Specified in the protocol 
Acceptable window 
Variables 
Timing of procedures 
Clinical laboratory tests 
Screening 
Days -28 to -2 
Day -1 
The day before the study 
drug administration 
1 hour postdose of TAK-123 (glucose assessed by a 
self-monitoring blood glucose meter only) 
Within ± 15 minutes 
1.5 hours postdose of TAK-123 (Na, K, Cl, glucose 
assessed by a self-monitoring blood glucose meter 
only) 
Within ± 15 minutes 
25.5 hours postdose of TAK-123 
Within ± 60 minutes 
48 hours postdose of TAK-123 
Within ± 60 minutes 
Day 8 
± 1 day 
Blood gas tests 
Day -1 
The day before the study 
drug administration 
1.5 hours postdose of TAK-123 
Within ± 5 minutes 
25.5 hours postdose of TAK-123 
Within ± 60 minutes 
PK blood collection 
Day 1 predose of TAK-123 
From awakening to 
immediately prior to dose 
0.25, 0.75, 1.5 ,2.5 hours postdose of TAK-123 
Within ± 3 minutes 
4.5, 6.5, 8.5, 10.5, 12.5, 16.5 hours postdose of 
TAK-123 
Within ± 5 minutes 
25.5, 26, 26.5, 27 hours postdose of TAK-123 
Within ± 3 minutes 
27.5, 28, 28.5, 29.5, 30.5, 32.5, 48 hours postdose of 
TAK-123 
Within ± 5 minutes 
PK urine collection 
Day 1 predose of TAK-123 (spot) 
From awakening to 
immediately prior to dose 
0 to 24 hours postdose of TAK-123 
Not applicable 
24 to 48 hours postdose of TAK-123 
Not applicable 
 
Whole blood volume collected from each subject is indicated below. 
Blood Volume Table 
Sample Type 
Sample Volume 
(mL) 
Number of Samples 
Total Volume 
(mL) 
Screening 
Treatment 
Safety laboratory samples (hematology, 
serum chemistry), Blood gas tests, and 
Immunology tests 
5 - 9.8 
1 
5 
51 
PK samples 
2 
- 
22 
44 
Total Blood Sampling Volume (approximately) 
95 
In addition, the volume of blood sampling by self-meter for blood glucose: 0.8 µL/time (3 times in total) 
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SAP_001.pdf: 
Title: A Single Center, Open-Label, Phase 1 Study to Evaluate the Pharmacokinetics, 
Safety and Tolerability of TAK-123 after Intravenous Infusion in Japanese Healthy 
Adult Male Subjects 
NCT Number: NCT04155567 
Statistical analysis plan Approve Date: 12-DEC-2019 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-123-1001 
A Single Center, Open-Label, Phase 1 Study to Evaluate the Pharmacokinetics, Safety 
andTolerability of TAK-123 after Intravenous Infusion in Japanese Healthy Adult Male 
Subjects 
 
Version: 1st 
Date: 20 December 2019 
 
 
 
 
Prepared by: 
 
 
 
Based on: 
Protocol Version: Amendment 1 Version 
Protocol Date: 10 October 2019 
 
 
PPD
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1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 
 
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2.0 
TABLE OF CONTENTS 
 
1.1 
Approval Signatures........................................................................................... 2 
2.0 
TABLE OF CONTENTS ......................................................................................... 3 
List of In-Text Tables .................................................................................................... 4 
3.0 
LIST OF ABBREVIATIONS .................................................................................. 5 
4.0 
OBJECTIVES .......................................................................................................... 6 
4.1 
Primary Objectives ............................................................................................. 6 
4.2 
Secondary Objectives ......................................................................................... 6 
4.3 
Study Design ...................................................................................................... 6 
5.0 
ANALYSIS ENDPOINTS....................................................................................... 7 
5.1.1 
Primary Endpoint ......................................................................................... 7 
5.1.2 
Secondary Endpoints ................................................................................... 7 
5.1.3 
Safety Endpoints .......................................................................................... 7 
5.1.4 
Exploratory Endpoints ................................................................................. 7 
6.0 
DETERMINATION OF SAMPLE SIZE ................................................................ 8 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ........................................... 9 
7.1 
General Principles .............................................................................................. 9 
7.1.1 
Study Definitions ......................................................................................... 9 
7.2 
Analysis Sets ...................................................................................................... 9 
7.3 
Disposition of Subjects .................................................................................... 10 
7.3.1 
Study Information ...................................................................................... 10 
7.3.2 
Screen Failures ........................................................................................... 10 
7.3.3 
Subject Eligibility ...................................................................................... 10 
7.3.4 
Disposition of Subjects .............................................................................. 11 
7.3.5 
Protocol Deviations and Analysis Sets ...................................................... 11 
7.4 
Demographic and Other Baseline Characteristics ........................................... 13 
7.5 
Study Drug Exposure and Compliance ............................................................ 14 
7.6 
Efficacy Analysis ............................................................................................. 14 
7.6.1 
Primary Efficacy Endpoint(s) .................................................................... 14 
7.6.2 
Secondary Efficacy Endpoint(s) ................................................................ 14 
7.6.3 
Additional Efficacy Endpoint(s) ................................................................ 14 
7.6.4 
Statistical/Analytical Issues ....................................................................... 14 
7.7 
Pharmacokinetic/Pharmacodynamic Analysis ................................................. 15 
7.7.1 
Pharmacokinetic Analysis .......................................................................... 15 
7.7.2 
Pharmacodynamic Analysis ....................................................................... 16 
7.8 
Safety Analysis ................................................................................................ 17 
7.8.1 
Adverse Events .......................................................................................... 17 
7.8.2 
Clinical Laboratory Evaluations ................................................................ 20 
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7.8.3 
Vital Signs and Weight .............................................................................. 22 
7.8.4 
12-Lead ECGs ............................................................................................ 23 
7.8.5 
Other Observations Related to Safety ........................................................ 24 
7.9 
Interim Analysis ............................................................................................... 24 
7.10 
Changes in the Statistical Analysis Plan .......................................................... 24 
8.0 
REFERENCES ...................................................................................................... 25 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
Dosage of TAK-123 ..................................................................................... 6 
Table 4.b 
Dosage of ondansetron ................................................................................. 6 
 
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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
Ae 
amount of drug excreted in urine 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
aPTT 
activated partial thromboplastin time 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
CL R 
renal clearance 
Cmax 
maximum observed concentration 
ECG 
electrocardiogram 
fe 
fraction of administered dose of drug excreted in urine 
GGT 
gamma glutamyl transferase 
Lambda z 
terminal elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
NaBZ 
sodium benzoate 
NaPA 
sodium phenylacetate 
PK 
pharmacokinetics 
PT 
prothrombin time 
QTc 
corrected QT 
RBC 
red blood cell 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
tmax 
time of first occurrence of Cmax 
t1/2z 
half-life period 
Vz 
volume of distribution during the terminal elimination phase 
WBC 
white blood cell 
WHO Drug 
World Health Organization Drug Dictionary 
 
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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
• The primary objective of the study is to evaluate the PK of phenylacetate and benzoate 
after intravenous infusion of TAK-123 in Japanese healthy adult male subjects. 
4.2 
Secondary Objectives 
• The secondary objective of the study is to evaluate the safety and tolerability of TAK-123 
after intravenous infusion of TAK-123 in Japanese healthy adult male subjects. 
4.3 
Study Design 
This study is a single-center, open-label, uncontrolled study. 
In this study, TAK-123 will be administered intravenously as a loading dose over 90 minutes 
at the dose level of 3.75 g/m2 of NaPA and 3.75 g/m2 of NaBZ under the breakfast fasting 
condition, followed by an equivalent maintenance dose over 24 hours to evaluate the PK, 
safety and tolerability of TAK-123 in Japanese healthy adult male subjects. 
A 4 mg of dose of ondansetron will be administered intravenously 30-40 minutes before the 
start of TAK-123 infusion. 
The dose of TAK-123 to be investigated is shown in Table 4.a. The dose of ondansetron to be 
administered before the administration of TAK-123 is shown in Table 4.b. 
Table 4.a 
Dosage of TAK-123 
Study drug 
Dose 
Mode of administration 
TAK-123 
3.75 g/m2 of NaPA and 
3.75 g/m2 of NaBZ 
1) Intravenous infusion (via a peripheral vein) over 90 minutes as a 
loading dose 
2) An equivalent intravenous infusion (via a peripheral vein) over 24 
hours as a maintenance dose after the completion of the above 1). 
 
Table 4.b 
Dosage of ondansetron 
Premedication 
Dose 
Mode of administration 
Ondansetron 
4 mg 
Slow intravenous infusion 
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5.0 
ANALYSIS ENDPOINTS 
5.1.1 Primary Endpoint 
• PK parameters (Cmax, AUClast, AUC∞) of phenylacetate, benzoate, and these metabolites 
(phenylacetylglutamine and hippurate). 
5.1.2 Secondary Endpoints 
 
Number of subjects with treatment-emergent adverse events (TEAEs) 
5.1.3 Safety Endpoints 
 
TEAEs, laboratory tests, vital signs, body weight, and 12-lead ECG 
5.1.4 Exploratory Endpoints 
• 
Plasma PK parameters (tmax, t1/2z, λz) of phenylacetate, benzoate, and these metabolites 
(phenylacetylglutamine and hippurate) 
• 
Urinary excretion amounts (Ae) and excretion ratios (fe) of phenylacetate, benzoate, and 
these metabolites (phenylacetylglutamine and hippurate) 
 
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6.0 
DETERMINATION OF SAMPLE SIZE 
The sample size was determined as 10 subjects that are considered to be sufficient to evaluate 
the PK and safety of TAK-123. 
The sample size is not based on considerations of statistical power. 
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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1 Study Definitions 
The following definitions and calculation formulas will be used. 
• 
Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs 
on or after the start of study drug (TAK-123) 
• 
Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to 
administration of study drug (TAK-123) 
• 
Descriptive statistics: Number of subjects, mean, standard deviation, maximum, 
minimum, and quartiles 
• 
Coefficient of variation (CV) (%): Standard deviation / mean * 100  
 
7.2 
Analysis Sets 
• 
Safety analysis set: All subjects who received at least one dose of TAK-123 
• 
Pharmacokinetic analysis set: All subjects who received at least one dose of TAK-123 
and provided sufficient PK measurements available to estimate PK parameters, at least 1 
estimable PK parameter. 
 
 
 
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7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Date First Subject Signed Informed Consent Form 
 
Date of Last Subject’s Last Visit/Contact 
 
MedDRA Version 
 
SAS Version Used for Creating the Datasets 
Analytical 
Method(s) : 
 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
 
7.3.2 Screen Failures 
Analysis Set: All Subjects Who Did Not Receive Study Drug (TAK-123) 
Analysis 
Variable(s) : 
 
Age (years)  
 
Analytical 
Method(s) : 
 
(1) Screen Failures 
Descriptive statistics will be provided. 
 
7.3.3 Subject Eligibility 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Study Drug (TAK-123) 
Administration Status 
 
[Treated, Not Treated] 
 
Primary Reason for Subject Not 
Being Treated 
[Adverse Event, Death, Lost to 
Follow-up, Protocol Deviation, 
Sample Size Sufficient, Screen 
Failure, Study Terminated by 
Sponsor, Withdrawal by Subject, 
Other] 
 
Analytical 
Method(s) : 
 
(1) Study Drug (TAK-123) Administration Status 
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Frequency distributions will be provided. When calculating percentages for 
the primary reasons for subject not being treated, the total number of not 
treated subjects will be used as the denominator. 
 
7.3.4 Disposition of Subjects 
Analysis Set: All Subjects Who Received Study Drug (TAK-123) 
Analysis 
Variable(s) : 
 
Study Completion Status 
 
[Completed All Planned Study 
Visits, Did Not Complete All 
Planned Study Visits] 
 
Reason for Discontinuation of 
Study Visits 
[Adverse Event, Death, Lost to 
Follow-up, Protocol Deviation, 
Sample Size Sufficient, Study 
Terminated by Sponsor, Withdrawal 
by Subject, Other] 
Analytical 
Method(s) : 
 
(1) Disposition of Subjects 
Frequency distributions will be provided. When calculating percentages for 
the reasons for discontinuation, the total number of subjects who did not 
complete all planned study visits will be used as the denominator. 
 
7.3.5 Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Analysis Set: All Subjects Who Received Study Drug (TAK-123) 
Analysis 
Variable(s) : 
 
Significant Protocol 
Deviation 
 
[Entry Criteria, Concomitant Medication, Procedure 
Not Performed Per Protocol, Study Medication, 
Withdrawal Criteria, Major GCP Violations] 
Analytical 
Method(s) : 
 
(1) Protocol Deviations 
Frequency distribution will be provided for each deviation category. A 
subject who has several deviations will be counted once in each appropriate 
category. A subject who has several deviations that can be classified into 
the same category will be counted only once. 
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7.3.5.2 Analysis Sets 
Analysis Set: All Subjects Who Received Study Drug (TAK-123) 
Analysis 
Variable(s) : 
 
Handling of Subjects 
 
[Categories are based on the 
specifications in Subject Evaluability 
List] 
 
Analysis Sets 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
 
[Included] 
[Included] 
Analytical 
Method(s) : 
 
(1) Subjects Excluded from Analysis Sets 
(2) Analysis Sets 
Frequency distributions will be provided. For (1), a subject who has several 
reasons for exclusion will be counted once in each appropriate category. A 
subject who has several reasons for exclusion that can be classified into the 
same category will be counted only once. 
 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
 
 
Height (cm) 
 
 
Weight (kg) 
 
 
BMI (kg/m2) 
 
 
Smoking Classification 
[Never, Current, Former] 
 
Alcohol Classification 
[Daily, A Few Times Per Week, A 
Few Times Per Month, No] 
 
Caffeine Classification 
[Yes, No] 
Analytical 
Method(s) : 
 
(1) Summary of Demographics and Baseline Characteristics 
Frequency distributions for categorical variables and descriptive statistics 
for continuous variables will be provided. 
 
 
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7.5 
Study Drug Exposure and Compliance 
Not applicable. 
7.6 
Efficacy Analysis 
Not applicable. 
7.6.1 Primary Efficacy Endpoint(s) 
Not applicable. 
7.6.2 Secondary Efficacy Endpoint(s) 
Not applicable. 
7.6.3 Additional Efficacy Endpoint(s) 
Not applicable. 
7.6.4 Statistical/Analytical Issues 
7.6.4.1 Adjustments for Covariates 
Not applicable. 
7.6.4.2 Handling of Dropouts or Missing Data 
For plasma concentrations and laboratory test results, values below the lower limit of 
quantification will be treated as zero. For laboratory test results, values above the upper limit 
of quantification will be treated as the upper limit value. 
7.6.4.3 Multicenter Studies 
Not applicable. 
7.6.4.4 Multiple Comparison/Multiplicity 
Not applicable. 
7.6.4.5 Use of an "Efficacy Subset" of Subjects 
Not applicable. 
7.6.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable. 
7.6.4.7 Examination of Subgroups 
Not applicable. 
 
 
 
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7.7 
Pharmacokinetic/Pharmacodynamic Analysis 
7.7.1 Pharmacokinetic Analysis 
7.7.1.1 Plasma Concentrations 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma Concentrations of Phenylacetate, Benzoate and These Metabolites 
(Phenylacetylglutamine and Hippurate) 
Visit: 
Predose; 0.25, 0.75, 1.5, 2.5, 4.5, 6.5, 8.5, 10.5, 12.5, 16.5, 25.5, 26, 26.5, 
27, 27.5, 28, 28.5, 29.5, 30.5, 32.5 and 48 Hours Postdose;  
Analytical 
Method(s) : 
 
The following summaries will be provided. 
 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics and CV will be provided by visit. 
 
(2) Case Plot of Plasma Concentrations 
Plots over time for each subject will be presented. The vertical axis will 
be a normal scale and a common logarithmic scale. 
 
(3) Mean and Standard Deviation Plot of Plasma Concentrations 
Mean and standard deviation will be plotted for each analysis variable. 
Visit will be plotted on the horizontal axis and each of the analysis 
variables will be plotted on the vertical axis. The vertical axis will be a 
normal scale. 
 
(4) Mean Plot of Plasma Concentrations 
Mean will be plotted for each analysis variable. Visit will be plotted on 
the horizontal axis and each of the analysis variables will be plotted on 
the vertical axis. The vertical axis will be a common logarithmic scale. 
 
 
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7.7.1.2 Pharmacokinetic Parameters 
Analysis Set: Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Pharmacokinetic Parameters of Phenylacetate, Benzoate and These 
Metabolites (Phenylacetylglutamine and Hippurate) 
 
AUClast 
AUCinf 
AUC48 
 
Cmax 
tmax 
t1/2z 
 
Lambda z 
 Vz (for Phenylacetate 
and Benzoate) 
 CL (for Phenylacetate 
and Benzoate) 
Analytical 
Method(s) : 
 
The following summary will be provided. 
 
(1) Summary of Pharmacokinetic Parameters 
For AUClast, AUCinf, AUC48 and Cmax, descriptive statistics, 
geometric mean, CV and geometric CV will be provided. For tmax, 
descriptive statistics will be provided. For all other variables, 
descriptive statistics and CV will be provided. 
 
7.7.1.3 Urine Pharmacokinetic Parameter 
Analysis Set: Pharmacokinetic Analysis Set 
 
 
 
 
Analysis 
Variable(s) : 
 
Urine Pharmacokinetic Parameters of Phenylacetate, Benzoate and These 
Metabolites (Phenylacetylglutamine and Hippurate) 
Urine Pharmacokinetic Parameters of Sum of Phenylacetate and 
Phenylacetylglutamine, and Sum of Benzoate and Hippurate for fe48 
 
Ae48 
 
fe48 
CLR 
Analytical 
Method(s) : 
 
The following summary will be provided. 
 
(1) Summary of Urine Pharmacokinetic Parameter 
Descriptive statistics and CV will be provided. 
 
7.7.2 Pharmacodynamic Analysis 
Not applicable. 
 
 
 
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7.8 
Safety Analysis 
In this study, safety will be evaluated as the primary endpoint. 
7.8.1 Adverse Events 
7.8.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Relationship to Study Drug (TAK-
123) 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s) : 
 
The following summaries will be provided. 
 
(1) Overview of Treatment-Emergent Adverse Events 
 
1) All Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
2) Relationship of Treatment-Emergent Adverse Events to study drug 
(TAK-123) (number of events, number and percentage of subjects)  
 
3) Intensity of Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects)  
 
4) Treatment-Emergent Adverse Events leading to study drug (TAK-
123) discontinuation (number of events, number and percentage of 
subjects)  
 
5) Serious Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
6) Relationship of serious Treatment-Emergent Adverse Events to 
study drug (TAK-123) (number of events, number and percentage 
of subjects)  
 
7) Serious Treatment-Emergent Adverse Events leading to study drug 
(TAK-123) discontinuation (number of events, number and 
percentage of subjects)  
 
8) Treatment-Emergent Adverse Events resulting in death (number of 
events, number and percentage of subjects)  
 
TEAEs will be counted according to the rules below. Percentages will be 
based on the number of subjects in the safety analysis set. 
Number of subjects 
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• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., Related and 
Not Related) will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once for 
the TEAE with the maximum intensity. 
• Summaries other than 2) , 3) , and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
 
7.8.1.2 Displays of Treatment-Emergent Adverse events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Period 
[Loading Period, Maintenance 
Period, After Infusion Period] 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution. 
TEAEs will be coded using the MedDRA and will be summarized using 
SOC and PT. 
SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency for tables provided by SOC and PT. SOC and PT will be sorted 
in decreasing frequency for tables provided by System Organ Class only or 
PT only. 
 
(1) Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
(2) Treatment-Emergent Adverse Events by System Organ Class 
 
(3) Treatment-Emergent Adverse Events by Preferred Term 
 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(5) Intensity of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
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(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class, and Preferred Term 
 
(7) Treatment-Emergent Adverse Events Leading to Study Drug (TAK-
123) Discontinuation by System Organ Class and Preferred Term 
 
(8) Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(9) Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term by Period 
 
The frequency distribution will be provided according to the rules below. 
Percentages will be based on the number of subjects who were treated in the 
safety analysis set. 
Number of subjects 
• Summary tables other than (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
TEAE within a PT will be counted only once in that PT. 
• Summary tables for (5) and (6)  
A subject with multiple occurrences of TEAE within a SOC or a PT will 
be counted only once for the TEAE with the maximum intensity. 
 
 
7.8.1.3 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
PTE 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency. 
 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events by System Organ Class and Preferred 
Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
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A subject with multiple occurrences of PTE within a SOC will be counted 
only once in that SOC. A subject with multiple occurrences of PTE within a 
PT will be counted only once in that PT. 
 
7.8.2 Clinical Laboratory Evaluations 
7.8.2.1 Hematology and Serum Chemistry 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Hematology 
 
Red Blood Cell (RBC) 
Hemoglobin 
Hematocrit 
 
Platelets 
White Blood Cell 
(WBC) 
 
 
WBC Differentials (Neutrophils, Eosinophils, Basophils, Lymphocytes, 
Monocytes)  
 
PT 
aPTT 
 
 
Serum Chemistry 
 
Total Protein 
Albumin 
Blood Urea Nitrogen 
 
Creatinine 
Total Bilirubin 
Direct Bilirubin 
 
Sodium 
Potassium 
Chloride 
 
Calcium 
ALP 
Creatine kinase 
 
 AST 
ALT 
GGT 
 
Glucose 
Glucose 
(Self-monitoring) 
 
Visit: 
Glucose (Self-monitoring): 
Predose; 1 and 1.5 Hours Postdose; 
Sodium, Potassium and Chloride: 
Predose; 1.5, 25.5, and 48 Hours Postdose; Day 8 
Variables other than Glucose (Self-monitoring), Sodium, Potassium and 
Chloride: 
Predose; 25.5, and 48 Hours Postdose; Day 8 
(Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
 
The following summaries will be provided. 
 
(1) Summary of Laboratory Test Results and Change from Baseline by 
Visit 
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Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Laboratory Test Results 
Plots over time for each subject will be presented. 
 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. 
For each laboratory test, the laboratory values will be classified as 
"Low", "Normal" or "High" relative to the normal reference range. The 
shift tables will be based on these classifications. 
 
7.8.2.2 Urinalysis 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Specific Gravity 
 
 
pH 
[Min<= - <=8.0, 8.0< - <=Max] 
 
Protein 
[-, +-, 1+, 2+, 3+, 4+] 
 
Glucose 
[-, +-, 1+, 2+, 3+, 4+] 
 
Occult blood 
[-, 1+, 2+, 3+] 
 
Nitrite 
[-, 1+, 2+] 
 
Urobilinogen 
[-, +-, 1+, 2+, 3+, 4+] 
Visit: 
Predose; 25.5, and 48 Hours Postdose; Day 8 
 (Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
For specific gravity, summaries (1), (2) and (4) will be provided. 
For each variable other than specific gravity, summaries (3) and (4) will be 
provided. 
 
(1) Summary of Urine Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Urine Laboratory Test Results 
Plots over time for each subject will be presented. 
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(3) Number of Subjects in Categories of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. 
 
(4) Summary of Shifts of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at Predose 
and each postdose visit will be provided. The laboratory value for 
specific gravity will be classified as "Low", "Normal" or "High" 
relative to the normal reference range. If applicable, the laboratory 
value for each urine laboratory test other than specific gravity will be 
classified as "Normal" or "Abnormal" relative to the normal reference 
range. The shift tables will be based on these classifications. 
 
7.8.2.3 Blood Gas Test 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s): 
 
pH 
 
HCO3-b 
 
 
Visit: 
Predose; 1.5 and 25.5 Hours Postdose; 
 (Data obtained at Day -1 will be used as the "Predose" visit) 
Analytical 
Method(s) : 
 
 
The following summaries will be provided. 
 
(1) Summary of Blood Gas Test Results and Change from Baseline by 
Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Laboratory Test Results 
Plots over time for each subject will be presented. 
 
7.8.3 Vital Signs and Weight 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Temperature 
 
 
Systolic Blood Pressure 
 
 
Diastolic Blood Pressure 
 
 
Respiration Rate 
 
 
Pulse Rate 
 
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Weight 
 
Visit: 
Temperature, Systolic Blood Pressure, Diastolic Blood Pressure, 
Respiration Rate, Pulse Rate: Predose, 1.5, 4, 25.5, and 48 Hours Postdose; 
Day 8 
Weight: Predose; 48 Hours Postdose; Day 8 
Analytical 
Method(s) : 
 
The following summaries will be provided. 
 
(1) Summary of Vital Signs Parameters and Weight and Change from 
Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
 
(2) Case Plots of Vital Signs Parameters and Weight 
Plots over time for each subject will be presented. 
 
7.8.4 12-Lead ECGs 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QRS Interval 
 
 
QT Interval 
 
 
QTcF Interval 
 
 
Interpretation 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Visit: 
Predose, 1.5 and 48 Hours Postdose; Day 8 
Analytical 
Method(s) : 
 
For each variable other than 12-lead ECG interpretations, summaries (1) 
and (2) will be provided. 
For 12-lead ECG interpretation, summary (3) will be provided. 
 
(1) Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
(each postdose visit - Predose) will be provided by visit. 
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(2) Case Plots of ECG Parameters 
Plots over time for each subject will be presented. 
 
(3) Summary of Shift of 12-lead ECG Interpretation 
Shift table showing the number of subjects in each category at 
"Predose" visit and each postdose visit will be provided. 
 
7.8.5 Other Observations Related to Safety 
Not applicable. 
7.9 
Interim Analysis 
Not applicable. 
7.10 
Changes in the Statistical Analysis Plan  
The analyses in the statistical analysis plan do not differ from the analyses specified in the 
protocol.  
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8.0 
REFERENCES 
No reference. 
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